Cyclin k degrader drug and antibody conjugate thereof

Abstract

A Cyclin K degrader drug and an antibody conjugate thereof, as well as preparation methods therefor and use thereof.

Description

Cyclin K degrader drugs and antibody conjugates thereof TECHNICAL FIELD

[0001] The present disclosure relates to Cyclin K degrader drugs and antibody conjugates thereof, the antibody drug conjugates comprising a Cyclin K degrader and an antibody or antigen-binding fragment thereof that binds an antigen target, such as an antigen expressed on a cancer cell. The present disclosure further relates to methods of making and uses of antibody drug conjugates comprising a Cyclin K degrader. BACKGROUND

[0002] Antibody drug conjugates (ADCs) have shown good therapeutic effects in clinic in recent years due to their unique structure and targeted delivery of killing properties. Currently, more than ten ADC drugs have been approved for marketing, covering a variety of types of cancer, and providing more treatment options for patients.

[0003] An ADC drug is composed of three parts: an antibody, a biologically active molecule (payload), and a linker. The antibody mainly plays a role in targeted delivery, and the biologically active molecule is covalently coupled to the antibody through the linker, and mainly exerts biological activity (pharmacodynamics) in target tissues or target cells. The payloads used in the currently marketed ADC drugs are mainly microtubule inhibitors and DNA-damaging drugs, etc. cytotoxic drugs. These payloads of ADCs inevitably have drug resistance or payload-related toxicity in clinical use. Therefore, it is necessary to continuously develop some innovative mechanism of action payloads of ADCs to solve some problems of existing ADC drugs.

[0004] Cyclin K is a cell cycle protein, which mainly functions to regulate the activity of CDK (cell cycle-dependent kinase) in the cell cycle. As a regulatory subunit of CDK12 and CDK13, Cyclin K controls various biological processes by regulating gene transcription, messenger RNA splicing, and key cell signaling pathways. Some studies have found that Cyclin K plays an important role in cell growth and proliferation, and its overexpression can promote cell proliferation and tumor growth, and thus may become a potential target for anticancer drugs. In addition, Cyclin K may be involved in the regulation of DNA damage repair and apoptosis.

[0005] It has been found in research that Cyclin K degraders have a broad-spectrum tumor cell killing effect, and are suitable for innovative ADC drug development as payloads. At the same time, the development of ADCs with new mechanisms of action payloads is expected to solve the problem of drug resistance or patient non-response of existing traditional cytotoxic payload ADC drugs. SUMMARY

[0006] The present application provides a novel antibody drug conjugate, which is characterized by the innovative application of Cyclin K degrader as a biologically active molecule (payload) of the antibody drug conjugate. The antibody drug conjugate of the present application has high anti-tumor activity, can effectively kill tumor cells, and has a bystander killing effect. The disclosures of PCT / CN2022 / 114693 and PCT / CN2023 / 138417 are incorporated by reference into the present application.

[0007] In one aspect, the present disclosure provides an antibody-Cyclin K degrader conjugate represented by Formula I, or a stereoisomer, a tautomer, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

[0008] wherein,

[0009] Ab is an antibody or an antigen binding fragment, or an antigen ligand;

[0010] q is the number of L-P conjugated on Ab, q can represent the number of L-P conjugated on one Ab, q can also represent the average number of L-P conjugated on Ab in a batch of drugs, q is selected from any value between 1.0-16.0;

[0011] L is a fragment covalently linking Ab and P, L is -L1-L2-L3-L4-L5-, wherein L1 is connected to Ab, L4 or L5 can be a direct bond, L4 or L5 is connected to P;

[0012] P is a Cyclin K protein degrader fragment.

[0013] In some embodiments, P is a structural unit represented by Formula II, P is connected to L5 or L4 through the oxygen atom, sulfur atom or nitrogen atom contained therein:

[0014] wherein,

[0015] R cy is selected from:

[0016] each independently represents a single bond or a double bond;

[0017] W 1 each independently represents CR, N or a bond;

[0018] W 2 each independently represents CR 0 , N, NR a , S or O;

[0019] W 3 each independently represents C or N, but at most 2 W 3 are simultaneously N;

[0020] W 4 each independently represents CR 1 , N, NR a , S or O;

[0021] W 5 each independently represents CR or N, but at most 2 W 5 are simultaneously N;

[0022] R 4 represents a phenyl ring or a 5-6 membered heteroaromatic ring, which phenyl ring or 5-6 membered heteroaromatic ring can each optionally be substituted with 0, 1 or 2 R;

[0023] R, R 0 and R 1 each independently represents hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , -C1-C6alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, which alkyl, alkenyl or alkynyl can each optionally be substituted with 0 to 3 groups selected from -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b, -P(O)R a R b ; wherein said -NR a C(O)R b ; wherein R b is optionally substituted with 0, 1 or 2 substituents selected from -(C0-C3alkylene)OR a , -(C0-C3alkylene)SR a , -(C0-C3alkylene)NR a R b ;

[0024] R L and R L’ each independently represent hydrogen, fluoro, C1-C6alkyl or C3-C6cycloalkyl, R L and R L’ may form, together with the carbon atom to which they are attached, a 3-6 membered ring;

[0025] R 2 represents halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , (C2-C6)alkenyl, (C2-C6)alkynyl;

[0026] R 3 represents C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -NR M R N , -NHR M , -OR M , -SR M ;

[0027] R 3 represents C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C3-C10 Cycloalkyl, 3-10 membered heterocycloalkyl, when optionally substituted, is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halo, cyano, -R a , -(Co-C6 alkylene)OR a , -(Co-C6 alkylene)SR a , -(Co-C6 alkylene)NR a R b , -(Co-C6 alkylene)NR a C(O)R b , -(Co-C6 alkylene)C(O)R a , -(Co-C6 alkylene)C(O)OR a , -(Co-C6 alkylene)C(O)NR a R b , -(Co-C6 alkylene)S(O)2R a , -(Co-C6 alkylene)S(O)R a , -(Co-C6 alkylene)S(O)2NR a R b , -(Co-C6 alkylene)P(O)R a R b ;

[0028] When R 3 represents C6-C 10 aryl or 5-10 membered heteroaryl, it is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of nitro, halo, cyano, -R a , -(Co-C6 alkylene)OR a , -(Co-C6 alkylene)SR a , -(Co-C6 alkylene)NR a R b , -(Co-C6 alkylene)NR a C(O)R b , -(Co-C6 alkylene)C(O)R a , -(Co-C6 alkylene)C(O)OR a , -(Co-C6 alkylene)C(O)NR a R b , -(Co-C6 alkylene)S(O)2R a , -(Co-C6 alkylene)S(O)R a , -(Co-C6 alkylene)S(O)2NR a R b , -(Co-C6 alkylene)P(O)R a R b ;

[0029] when R 3 represents -NR M R N , -NHR M , -OR M , -SR M , R M and R N each independently represents C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); R M and R N each is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR a C(O)R b , -(C0-C6alkylene)C(O)R a , -(C0-C6alkylene)C(O)OR a , -(C0-C6alkylene)C(O)NR a R b , -(C0-C6alkylene)S(O)2R a , -(C0-C6alkylene)S(O)R a , -(C0-C6alkylene)S(O)2NR a R b , -(C0-C6alkylene)P(O)R a R b ; wherein, when R M or R N represents -(C0-C6alkylene)(3-10 membered heterocycloalkyl) containing a N atom and the substituent is on the N atom, the C atom on the N atom vicinal to the N atom can be further substituted with oxo;

[0030] wherein, R a , R b each independently represents hydrogen, C1-C6alkyl or C3-C8cycloalkyl, which alkyl or cycloalkyl can each optionally be substituted with 0, 1, 2, 3 halogen atoms.

[0031] In some embodiments, P is a structural unit according to Formula III-a, III-b, III-c, III-d, P is attached to L5or L4via an oxygen atom, a sulfur atom or a nitrogen atom contained therein:

[0032] wherein R cy , R 2 and R 3 are as defined above for Formula II.

[0033] In some embodiments, P is a structural unit according to Formula IV, P is attached to L5or L4via an oxygen atom, a sulfur atom or a nitrogen atom contained therein:

[0034] wherein R cy and R 2 are as defined above for Formula II.

[0035] R 41 is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl groups being optionally substituted with 1, 2 or 3 H, CN, halogen, hydroxyl, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, -NR M R N , -NHR M , -OR M , -SR M wherein R M and R N are as defined above for Formula II.

[0036] In some embodiments, P is a structural unit according to Formula V, P is attached to L5or L4via an oxygen atom, a sulfur atom or a nitrogen atom contained therein:

[0037] wherein R cy and R 3 are as defined above for Formula II.

[0038] R 51 is selected from the group consisting of C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl.

[0039] In some embodiments, P is a structural unit according to Formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, P is attached to L5or L4via an oxygen atom, a sulfur atom or a nitrogen atom contained therein:

[0040] wherein R 61 each independently is selected from a 5-12 membered heteroaromatic ring or a 6-12 membered aromatic ring, which aromatic and heteroaromatic rings can optionally be substituted with 1, 2, or 3 H, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl;

[0041] R 62 each independently is selected from H or C1-C4alkyl;

[0042] R 63 each independently is selected from H, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C6cycloalkyl.

[0043] In some embodiments, P is a structural unit according to Formula II, P is connected to L5or L4via an oxygen atom, a sulfur atom, or a nitrogen atom contained therein:

[0044] wherein,

[0045] R cy is selected from:

[0046] each independently represents a single bond or a double bond;

[0047] W 1 each independently represents CR, N, or a bond;

[0048] W 2 each independently represents CR 0 , N, NR a , S, or O;

[0049] W 3 each independently represents C or N, with at most 2 W 3 being N at the same time;

[0050] W 4 each independently represents CR 1 , N, NR a , S, or O;

[0051] W 5 each independently represents CR or N, with at most 2 W 5 being N at the same time;

[0052] R 4 represents a phenyl ring or a 5-6 membered heteroaromatic ring, which phenyl ring or 5-6 membered heteroaromatic ring can each optionally be substituted with 0, 1, or 2 R;

[0053] R, R 0 and R 1 each independently represents hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , C1-C6 alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, which alkyl, alkenyl or alkynyl can be optionally substituted by 0 to 3 substituents selected from -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b ; wherein R a in said -NR b C(O)R b may optionally be substituted by 0, 1 or 2 substituents selected from -(C0-C3 alkylene)OR a , -(C0-C3 alkylene)SR a , -(C0-C3 alkylene)NR a R b ;

[0054] R L and R L’ each independently represents hydrogen, fluorine, C1-C6 alkyl or C3-C6 cycloalkyl, R L and R L’may form, together with the carbon atom to which they are attached, a 3-6 membered ring;

[0055] R 2 represents halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , (C2-C6)alkenyl, (C2-C6)alkynyl;

[0056] R 3 represents -NR M R N , -NHR M , -OR M , -SR M , R M and R N each independently represent C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); R M and R N each are optionally substituted with 0, 1, 2, 3 substituents selected from oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR a C(O)R b , -(C0-C6alkylene)C(O)R a , -(C0-C6alkylene)C(O)OR a , -(C0-C6alkylene)C(O)NR a Rb -(C0-C6 alkylene)S(O)2R a -(C0-C6 alkylene)S(O)R a -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)P(O)R a R b ; where, when R M Or R N When a -(C0-C6 alkylene) (3-10 membered heterocyclic alkyl) containing an N atom and a substituent is located on the N atom, the C atom located adjacent to the N atom on the substituent can be further substituted by oxo-substitution;

[0057] Among them, R a R b Each of these can independently represent hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, and each of these alkyl or cycloalkyl groups may optionally be substituted with 0, 1, 2, or 3 halogen atoms.

[0058] In some implementations, P is the structural unit shown in Formula II, and P is connected to L5 or L4 through the oxygen, sulfur or nitrogen atoms it contains;

[0059] in,

[0060] R cy Selected from:

[0061] Where X independently represents NR. a O or S; W 1 Each can be represented independently as CR or N; W 2 Each represents CR independently. 0 Or N; W 4 Each represents CR independently. 1 Or N; W 5 Each can independently represent CR or N, and there can be at most 2 Ws. 5 Both are N;

[0062] R, R 0 and R 1 Each can independently represent hydrogen, halogen, nitro, cyano, -R a -OR a -SR a -NR a R b -C(O)R a -C(O)OR a, -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , C1-C6alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, which alkyl, alkenyl or alkynyl is optionally substituted with from 0 to 3 substituents selected from the group consisting of -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , -P(O)R a C(O)R b , wherein R b is optionally substituted with 0, 1 or 2 substituents selected from the group consisting of -(C0-C3alkylene)OR a , -(C0-C3alkylene)SR a , -(C0-C3alkylene)NR a R b ;

[0063] R L and R L’ each independently represent hydrogen, fluorine, C1-C6alkyl or C3-C6cycloalkyl, R L and R L’ may form, together with the carbon atom to which they are attached, a 3-6 membered ring;

[0064] R 2 represents halogen, -R a , nitro, cyano, -S(O)2R a , (C2-C6)alkenyl, (C2-C6)alkynyl;

[0065] R 3 represents -NR M RN -NHR M -OR M -SR M R M and R N Each independently represents a C1-C6 alkyl group, -(C0-C6 alkylene group) (C3-C6 alkylene group). 10 Cycloalkyl), -(C0-C6 alkylene) (3-10 membered heterocycloalkyl), -(C0-C6 alkylene) (C6-C 10 aryl), -(C0-C6 alkylene)(5-10 heteroaryl); R M and R N Each can be optionally substituted by 0, 1, 2, or 3 substituents selected from the following: oxo, nitro, halogen, cyano, -R. a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -(C0-C6 alkylene)NR a C(O)R b -(C0-C6 alkylene)C(O)R a -(C0-C6 alkylene)C(O)OR a -(C0-C6 alkylene)C(O)NR a R b -(C0-C6 alkylene)S(O)2R a -(C0-C6 alkylene)S(O)R a -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)P(O)R a R b ; where, when R M Or R N When a -(C0-C6 alkylene) (3-10 membered heterocyclic alkyl) containing an N atom and a substituent is located on the N atom, the C atom located adjacent to the N atom on the substituent can be further substituted by oxo-substitution;

[0066] Among them, R a R b Each of these can independently represent hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, and each of these alkyl or cycloalkyl groups may optionally be substituted with 0, 1, 2, or 3 halogen atoms.

[0067] In some implementations, P is the structural unit shown in Formula II, and P is connected to L5 or L4 through the oxygen, sulfur or nitrogen atoms it contains;

[0068] wherein,

[0069] R cy is selected from:

[0070] R and R 1 each independently represent hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , C1-C6 alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, which alkyl, alkenyl or alkynyl can be optionally substituted by 0 to 3 substituents selected from -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , wherein R a in said -NR b C(O)R b may optionally be substituted by 0, 1 or 2 substituents selected from -(C0-C3 alkylene)OR a , -(C0-C3 alkylene)SR a , -(C0-C3 alkylene)NR a R b ;

[0071] R L and R L’ each independently represent hydrogen, fluorine, C1-C6alkyl or C3-C6cycloalkyl, R L and R L’ may form together with the carbon atom to which they are attached a 3-6 membered ring;

[0072] R 2 represents halogen, -R a , nitro, cyano, -S(O)2R a , (C2-C6)alkenyl, (C2-C6)alkynyl;

[0073] R 3 represents -NR M R N , -NHR M , -OR M , -SR M , R M and R N each independently represent C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); R M and R N each independently can be optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR a C(O)R b , -(C0-C6alkylene)C(O)R a , -(C0-C6alkylene)C(O)OR a , -(C0-C6alkylene)C(O)NR a R b , -(C0-C6alkylene)S(O)2R a , -(C0-C6alkylene)S(O)R a , -(C0-C6alkylene)S(O)2NR a R b , -(C0-C6alkylene)P(O)R a R b; where, when R M Or R N When a -(C0-C6 alkylene) (3-10 membered heterocyclic alkyl) containing an N atom and a substituent is located on the N atom, the C atom located adjacent to the N atom on the substituent can be further substituted by oxo-substitution;

[0074] Among them, R a R b Each of these can independently represent hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, and each of these alkyl or cycloalkyl groups may optionally be substituted with 0, 1, 2, or 3 halogen atoms.

[0075] In some implementations, P is a structural unit shown in Formula II-a, Formula II-b, Formula II-c, or Formula II-d, and P is connected to L5 or L4 through oxygen, sulfur, or nitrogen atoms contained therein.

[0076] in,

[0077] R and R 1 Each can independently represent hydrogen, halogen, nitro, cyano, -R a -OR a -SR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a -S(O)R a -S(O)2NR a R b -P(O)R a R b C1-C6 alkyl, (C2-C6) alkenyl, (C2-C6) ynyl, wherein the alkyl, alkenyl, or ynyl group may be optionally composed of 0 to 3 groups selected from -OR. a -SR a -NR a R b -NR a C(O)R b -C(O)R a -C(O)OR a -C(O)NR a R b -S(O)2R a -S(O)R a-S(O)2NR a R b -P(O)R a R b Substituents of; wherein, the -NR a C(O)R b R in b Optionally, it may be selected from 0, 1, or 2 of -(C0-C3 alkylene) OR a -(C0-C3 alkylene)SR a -(C0-C3 alkylene)NR a R b Substituents of the substituents;

[0078] R 2 Indicates halogen, -R a nitro, cyano, -S(O)2R a (C2-C6)alkenyl, (C2-C6)ynyl;

[0079] R 3 Indicates -NR M R N -NHR M -OR M -SR M R M and R N Each independently represents a C1-C6 alkyl group, -(C0-C6 alkylene group) (C3-C6 alkylene group). 10 Cycloalkyl), -(C0-C6 alkylene) (3-10 membered heterocycloalkyl), -(C0-C6 alkylene) (C6-C 10 aryl), -(C0-C6 alkylene)(5-10 heteroaryl); R M and R N Each can be optionally substituted by 0, 1, 2, or 3 substituents selected from the following: oxo, nitro, halogen, cyano, -R. a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -(C0-C6 alkylene)NR a C(O)R b -(C0-C6 alkylene)C(O)R a -(C0-C6 alkylene)C(O)OR a -(C0-C6 alkylene)C(O)NR a R b -(C0-C6 alkylene)S(O)2R a, -(C0-C6alkylene)S(O)R a , -(C0-C6alkylene)S(O)2NR a R b , -(C0-C6alkylene)P(O)R a R b ; wherein, when R M or R N represents -(C0-C6alkylene)(3-10 membered heterocycloalkyl) containing a N atom and the substituent is located on said N atom, the C atom located adjacent to said N atom on said substituent can be further substituted with oxo;

[0080] wherein, R a , R b each independently represents hydrogen, C1-C6alkyl or C3-C8cycloalkyl, which alkyl or cycloalkyl can each optionally be substituted with 0, 1, 2, 3 halogen atoms.

[0081] In some embodiments, P is a structural unit represented by Formula II-a, Formula II-b, Formula II-c, Formula II-d, P is linked to L5or L4through the oxygen atom, sulfur atom or nitrogen atom contained therein;

[0082] wherein,

[0083] R and R 1 each independently represents hydrogen, halogen, cyano, -R a , -(C0-C2alkylene)OH, -(C0-C2alkylene)NH2;

[0084] R 2 represents halogen, trifluoromethyl, cyano, vinyl, ethynyl;

[0085] R 3 represents -NR M R N , -NHR M , -OR M , -SR M , R M and R N each independently represents C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); R M and R N each optionally can be substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -Ra -(C0-C6alkylene)OR a -(C0-C6alkylene)SR a -(C0-C6alkylene)NR a R b -(C0-C6alkylene)NR a C(O)R b -(C0-C6alkylene)C(O)R a -(C0-C6alkylene)C(O)OR a -(C0-C6alkylene)C(O)NR a R b -(C0-C6alkylene)S(O)2R a -(C0-C6alkylene)S(O)R a -(C0-C6alkylene)S(O)2NR a R b -(C0-C6alkylene)P(O)R a R b ; wherein, when R M or R N represents -(C0-C6alkylene)(3-10 membered heterocycloalkyl) containing a N atom and the substituent is on the N atom, the C atom on the N atom vicinal position of the substituent can be further substituted with oxo;

[0086] wherein R a , R b each independently represents hydrogen, C1-C6alkyl or C3-C8cycloalkyl, which alkyl or cycloalkyl can each optionally be substituted with 0, 1, 2, 3 halogen atoms.

[0087] In some embodiments, P is selected from fragments of the following structures, P is attached to L5or L4through an oxygen or nitrogen atom contained therein:

[0088] In some embodiments, -P is selected from the following structures:

[0089] In some embodiments, P is selected from fragments of the following structures, P is attached to L5or L4through an oxygen or nitrogen atom contained therein:

[0090] In some embodiments, P is selected from the following structures:

[0091] In some embodiments, P is selected from the group consisting of fragments of the following structures, P is attached to L5or L4through an oxygen atom or a nitrogen atom contained therein:

[0092] In some embodiments, P is selected from the group consisting of fragments of the following structures:

[0093] In some embodiments, q is selected from any value between 0.1 and 16.0.

[0094] In some embodiments, q is selected from any value between 1.0 and 8.0.

[0095] In some embodiments, q is selected from 1, 2, 3, 4, 5, 6, 7, or 8.

[0096] In some embodiments, q is selected from 2, 4, 6, or 8.

[0097] In some embodiments, L1is selected from the group consisting of:

[0098] In some embodiments, L2is selected from the group consisting of:

[0099] wherein each E is independently selected from a direct bond, an alkyne bond, a phenyl group, a 5-6 membered heteroaryl group, an amide group, said phenyl and 5-6 membered heteroaryl groups being optionally substituted with 0, 1, or 2 of the following substituents: F, Cl, methyl, methoxy;

[0100] each a1is independently selected from 1, 2, 3, 4, 5, and 6;

[0101] each a2is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0102] each a3is independently selected from 1, 2, 3, 4, 5, and 6;

[0103] R x1 each independently selected from H, methyl, or -CH2CH2N(Me)2;

[0104] R x2 each independently selected from H or methyl;

[0105] R x3 each independently selected from -NH2, -OH, -OMe, -NHMe, -N(Me)2, or -NHCH2COOH.

[0106] In some embodiments, L3is absent or present, when absent, L3is a direct bond; when present, L3is selected from the group consisting of: -M-L 3a - or -L 3a -M-,

[0107] wherein,

[0108] each M is independently selected from the group consisting of a direct bond,

[0109] L 3a each is independently selected from the group consisting of a direct bond,

[0110] each b1 is independently selected from the group consisting of 1, 2, 3, 4, and 5;

[0111] each b2 is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5;

[0112] each b3 is independently selected from the group consisting of 1, 2, 3, 4, and 5;

[0113] each b4 is independently selected from the group consisting of 0, 1, 2, and 3;

[0114] R y1 each is independently selected from the group consisting of H, methyl, -CH2CH2N(Me)2, or HL;

[0115] R y2 each is independently selected from the group consisting of H, methyl, -CH2CH2N(Me)2, or HL;

[0116] R y3 each is independently selected from the group consisting of H, methyl, or -CH2CH2N(Me)2;

[0117] R y4 each is independently selected from the group consisting of H, methyl, or -CH2CH2N(Me)2;

[0118] R y5 each is independently selected from the group consisting of H, C1-C4 alkyl, or HL;

[0119] HL is selected from the group consisting of: wherein c1 is selected from 0, 1, or 2; c2 is selected from 2-20; c3 is selected from 1-20; R y6 is selected from H, methyl, or acetyl.

[0120] In some embodiments, L4 is selected from a direct bond, a short peptide consisting of 2-5 amino acid residues, or an amide consisting of an amino acid residue and a carboxylic acid / amine.

[0121] In some embodiments, L4 is selected from a direct bond.

[0122] In some embodiments, L4 is selected from an amide consisting of an amino acid residue and a carboxylic acid residue, or an amide consisting of an amino acid residue and an amine residue.

[0123] In some embodiments, L4 is wherein p is selected from 2, 3, 4, or 5; R p each is independently optionally selected from: H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)Me, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2) p1 N(R z )2, -(CH2)3NHCOMe, -(CH2)3NHCONH2, -(CH2)4NHCONH2, wherein p1 is selected from 1, 2, 3, 4; R z each is independently optionally selected from H, C1-C4 alkyl, or HL, HL being as defined above.

[0124] In some embodiments, L4is wherein r is selected from 1 or 2; R p as defined above.

[0125] In some embodiments, L4is selected from:

[0126] wherein R z each is independently selected from H, C1-C4 alkyl, or HL, HL being as defined above.

[0127] In some embodiments, L4is selected from:

[0128] In some embodiments, L4is selected from:

[0129] In some embodiments, L5is selected from: a direct bond,

[0130] wherein R w1 each is independently selected from: -CH2NH-HL, -CH2N(Me)-HL, -CH2CH2NH-HL, -CH2CH2N(Me)-HL, wherein d1 is selected from 0, 1, or 2, and d2 is selected from 1-20;

[0131] R w2 each is independently selected from: H, Me, -CH2CH2N(Me)2, or -CH2CH2SO2Me;

[0132] R w3each independently selected from H, Me, -CH2CH2N(Me)2, -CH2CH2SO2Me, or -CH2CH2OCH2CH2OH;

[0133] R w4 each independently selected from H, Me, -CH2CH2N(Me)2, -CH2CH2SO2Me, or -CH2CH2OCH2CH2OH;

[0134] R w5 each independently selected from H, Me, or -CH2CH2N(Me)2;

[0135] R w6 each independently selected from H, Me, or -CH2CH2N(Me)2;

[0136] W 1 each independently selected from

[0137] W 2 is -L w1 -L w2 or -L w3 -L w4 wherein L w1 is a short peptide consisting of 2-5 amino acid residues; L w2 is H, C1-C4 alkyl, (C1-C4 alkyl)-acyl, HL, HL being defined as above; L w3 is a carboxylic acid / amine and an amide consisting of 1-3 amino acid residues; L w4 is -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, wherein R e is H or C1-C4 alkyl, each of e1 or e3 is optionally an integer from 1 to 20;

[0138] each d is independently selected from 0, 1 or 2.

[0139] In some embodiments, L5 is selected from a direct bond.

[0140] In some embodiments, L5 is selected from

[0141] wherein R w6 each independently selected from H or methyl;

[0142] each d is independently selected from 1 or 2;

[0143] W 2 is -L w1 -L w2 or -L w3 -Lw4 ,

[0144] wherein L w1 is L w1 is attached to the N-terminus of L w2 , p is selected from 2, 3, 4, or 5; R p are each independently optionally selected from: H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)Me, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3N(Me)2, -(CH2)3NHCOMe, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)4N(Me)2, -(CH2)4N(Et)2, -(CH2)4N(nPr)2, -(CH2)4NHCONH2;

[0145] L w2 is H, methyl, acetyl, HL, HL being as defined above;

[0146] L w3 is L w3 is attached to the left side of L w4 , wherein r is selected from 1 or 2; R p are each independently optionally selected from: H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)Me, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3N(Me)2, -(CH2)3NHCOMe, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)4N(Me)2, -(CH2)4N(Et)2, -(CH2)4N(nPr)2, -(CH2)4NHCONH2;

[0147] L w4 is -NHMe, -N(Me)2, wherein each of e1, e2, or e3 is optionally selected from an integer from 1 to 20.

[0148] In some embodiments, L5 is selected from:

[0149] In some embodiments, L5is selected from:

[0150] In some embodiments, -L4-L5- is selected from:

[0151] In some embodiments, -L4-L5- is selected from:

[0152] In some embodiments, -L1-L2- is selected from:

[0153] In some embodiments, -L3- is selected from: a direct bond,

[0154] In some embodiments, -L- is selected from the following structures or the hydrolytic ring-opening structure of the succinimidyl of the following structures:

[0155] In some preferred embodiments, -L- is selected from the following structures or the hydrolytic ring-opening structure of the succinimidyl of the following structures:

[0156] In some embodiments, the antibody drug conjugate can be obtained from Ab and the following L-P through a conjugation reaction:

[0157] In some preferred embodiments, the antibody drug conjugate can be obtained from Ab and the following L-P through a conjugation reaction:

[0158] In some embodiments, the antibody drug conjugate can be obtained from Ab and the following L-P through a conjugation reaction:

[0159] In some embodiments, the antibody drug conjugate can be obtained by conjugation reaction of Ab and the following L-P:

[0160] In some embodiments, Ab is an antibody or an antigen ligand.

[0161] In some embodiments, Ab is a ligand that binds to a target antigen, which is a target that is highly expressed on tumor cells, but lowly expressed or not expressed on normal cells.

[0162] In some embodiments, Ab is an antibody or antigenic ligand, the target of which is, for example, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ANGPTL4, ASLG659, Axl, B7H3, B7H4, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCL5, CCR5, CCR7, CD123, CD138, CD142, CD147, CD166, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD46, CD47, CD49D (ITGA4), CD56, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH3, CDH6, CDH11, CD11b, CEA, CEACAM5, CEACAM6, CLDN18.2, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTGF, CTSD, CTSS, CXCL11, CXCL10, CXCR5, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRH1, FGF2, FGFR2, FGFR3, FLT3, FOLR-a, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSMA, PTK7, RNF43, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STC2, STEAP1, STEAP2, TCF4, TENB2, TGF, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, and the like.

[0163] In some embodiments, the Ab is an anti-antigen antibody, the antigen target being, for example, HER2, TROP2, EGFR, HER3, B7H3, FGFR2b, B7H4, Nectin4, FOLR1, CD30, CD79b, CD19, CD33, 5T4, CLDN18.2, and the like.

[0164] In some embodiments, Ab is an antibody, e.g., adalimumab, aducanumab, alemtuzumab, altumomab, amivantamab, atezolizumab, anetumab, avelumab, bapineuzumab, basiliximab, bectumomab, bermekimab, besilesomab, bevacizumab, bezlotoxumab, brentuximab, brodalumab, catumaxomab, cemiplimab, cetuximab, cinpanemab, clivatuzumab, crenezumab, daclizumab, daratumumab, denosumab, dinutuximab, dostarlimab, durvalumab, edrecolomab, elotuzumab, emapalumab, enfortumab, epcoritamab, epratuzumab, etaracizumab, gemtuzumab, glofitamab, girentuximab, gosuranemab, ibritumomab, inebilizumab, infliximab, inotuzumab, ipilimumab, isatuximab, ixekizumab, J591, labetuzumab, lecanemab, loncastuximab, mirzotamab, mogamulizumab, mosunetuzumab, necitumumab, nimotuzumab, natalizumab, naratuximab, naxitamab, nivolumab, ocrelizumab, ofatumumab, olaratumab, oregovomab, panitumumab, pembrolizumab, pertuzumab, polatuzumab, prasinezumab, racotumomab, ramucirumab, rituximab, sacituzumab, semorinemab, siltuximab, solanezumab, tacatuzumab, tafasitamab, teprotumumab, tilavonemab, tocilizumab, tositumomab, trastuzumab, ustekinumab, vedolizumab,Votumumab, Zagotenemab, Zanidatamab, Zalutumumab, Zanolimumab, or fragments or analogs thereof.

[0165] In some embodiments, the Ab is an anti-HER2 antibody, such as Trastuzumab, Pertuzumab, Zanidatamab, etc.

[0166] In some embodiments, the Ab is an anti-TROP2 antibody, such as Sacituzumab.

[0167] In some embodiments, the Ab is an anti-HER3 antibody, such as Patritumab.

[0168] In some embodiments, the Ab is an anti-Nectin4 antibody, such as Enfortumab.

[0169] In some embodiments, the Ab is an anti-B7H3 antibody, such as Mirzotamab.

[0170] In some embodiments, the Ab is an anti-EGFR antibody, such as Cetuximab.

[0171] In some embodiments, the Ab is a diabody, such as a diabody for any combination of the above antigen targets.

[0172] In some embodiments, the Ab is a diabody, such as an EGFR / c-Met diabody, an EGFR / HER3 diabody, a FOLR1 / TRPV6 diabody, a HER2 / TROP2 diabody, a HER2 / HER2 diabody, an EGFR / MUC1 diabody, a HER3 / TROP2 diabody, etc.

[0173] In some embodiments, the antibody drug conjugate structure is shown as formula I-1:

[0174] wherein Ab, L1, L2, L3, L4, L5, P, q are defined as above in formula I.

[0175] In some embodiments, the antibody drug conjugate structure is shown as formula I-2a or formula I-2b:

[0176] wherein each group is defined as above, L5may be attached from the substituent of R cy or R 3 .

[0177] In some embodiments, the antibody drug conjugate structure is represented by Formula I-3a, Formula I-3b, Formula I-3c, Formula I-3d, Formula I-3e, Formula I-3f, Formula I-3g, or Formula I-3h:

[0178] wherein each group is as defined above, L5may be attached from a substituent of R cy or R 3 .

[0179] In some embodiments, the antibody drug conjugate structure is represented by Formula I-4a or Formula I-4b:

[0180] wherein each group is as defined above, L5may be attached from a substituent of R cy or R 41 .

[0181] In some embodiments, the antibody drug conjugate structure is represented by Formula I-5a or Formula I-5b:

[0182] wherein each group is as defined above, L5may be attached from a substituent of R cy or R 3 .

[0183] In some embodiments, the antibody drug conjugate structure is represented by Formula I-6a, Formula I-6b, Formula I-6c, Formula I-6d, Formula I-6e, or Formula I-6f:

[0184] wherein each group is as defined above.

[0185] In some embodiments, the antibody drug conjugate structure is represented by Formula I-2a-1 or Formula I-2b-1:

[0186] wherein each group is as defined above, L5may be attached from a substituent of R cy or R 3 .

[0187] In some embodiments, the antibody drug conjugate structure is represented by Formula I-2a-2 or Formula I-2b-2:

[0188] wherein each group is as defined above, L5may be attached from a substituent of R cy or R 3 .

[0189] In some embodiments, the antibody drug conjugate is selected from the following structures or the succinimide hydrolytic ring opening structure of the following structures:

[0190] wherein,

[0191] Ab is an antibody, for example Ab is an anti-HER2 antibody, for example is Trastuzumab; for example Ab is an anti-TROP2 antibody, for example is Sacituzumab; for example Ab is an anti-HER3 antibody, for example is Patritumab; for example Ab is an anti-Nectin4 antibody, for example is Enfortumab;

[0192] q is any number from 2 to 16, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; q is preferably any number from 4 to 8, for example q is 4, 5, 6, 7, 8; q is more preferably 4, 6, 8.

[0193] In some embodiments, the antibody drug conjugate is selected from the following structures or the succinimide hydrolytic ring opening structure of the following structures:

[0194] wherein,

[0195] Ab is an antibody, for example Ab is an anti-HER2 antibody, for example is Trastuzumab; for example Ab is an anti-TROP2 antibody, for example is Sacituzumab; for example Ab is an anti-HER3 antibody, for example is Patritumab; for example Ab is an anti-Nectin4 antibody, for example is Enfortumab;

[0196] q is any number from 2 to 16, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; q is preferably any number from 4 to 8, for example q is 4, 5, 6, 7, 8; q is more preferably 4, 6, 8.

[0197] In some preferred embodiments, the antibody drug conjugate is selected from the following structures or the hydrolytic ring opening structures of the following structures:

[0198] wherein,

[0199] Ab is an antibody, for example Ab is an anti-HER2 antibody, for example is Trastuzumab; for example Ab is an anti-TROP2 antibody, for example is Sacituzumab; for example Ab is an anti-HER3 antibody, for example is Patritumab; for example Ab is an anti-Nectin4 antibody, for example is Enfortumab;

[0200] q is any number from 2 to 16, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; q is preferably any number from 4 to 8, for example q is 4, 5, 6, 7, 8; q is more preferably 4, 6, 8.

[0201] In some embodiments, the antibody drug conjugate is selected from the following structures:

[0202] wherein,

[0203] Ab is an antibody, for example Ab is an anti-HER2 antibody, for example is Trastuzumab; for example Ab is an anti-TROP2 antibody, for example is Sacituzumab; for example Ab is an anti-HER3 antibody, for example is Patritumab; for example Ab is an anti-Nectin4 antibody, for example is Enfortumab;

[0204] q is any number from 2 to 16, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; q is preferably any number from 4 to 8, for example q is 4, 5, 6, 7, 8; q is more preferably 4, 6, 8.

[0205] In some embodiments, the antibody drug conjugate is selected from the following structures:

[0206] wherein,

[0207] Ab is as defined above, for example, Ab is an antibody; for example, Ab is an anti-HER2 antibody, for example, Trastuzumab; for example, Ab is an anti-TROP2 antibody, for example, Sacituzumab; for example, Ab is an anti-HER3 antibody, for example, Patritumab; for example, Ab is an anti-Nectin4 antibody, for example, Enfortumab;

[0208] q is any number from 1 to 16, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; q is preferably any number from 1 to 8, for example, q is 1, 2, 3, 4, 5, 6, 7, 8; q is more preferably 4, 6, 8.

[0209] Another aspect of the present application relates to a pharmaceutical composition comprising a compound or an antibody drug conjugate (ADC) as described herein, or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, a metabolite, an isotopic derivative, an N-oxide, or a prodrug thereof, and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

[0210] Another aspect of the present application relates to a use of a compound or an antibody drug conjugate (ADC) as described herein, or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, a metabolite, an isotopic derivative, an N-oxide, or a prodrug thereof, or a pharmaceutical composition as described herein in the manufacture of a medicament for preventing or treating a cancer-related disease or disorder. The cancer is a solid tumor or a hematological tumor, in particular, can be selected from the group consisting of esophageal cancer, lung cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, ovarian cancer, uterine cancer, liver cancer, kidney cancer, head and neck cancer, brain tumor, urothelial cancer, skin cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, leukemia, lymphoma, and the like. BRIEF DESCRIPTION OF DRAWINGS

[0211] Figure 1, the compounds ADC1-80 of the present application have excellent bystander killing effect.

[0212] Figure 2, the compounds ADC1-72, ADC1-80, ADC1-94 of the present application have strong in vivo efficacy on NCI-N87 xenograft model, ADC1-72 and ADC1-80 can completely regress the tumor of mice at 10 mpk single dose, and the efficacy can last for 96 days without tumor recurrence.

[0213] Figure 3, the drug loads P-13 and P-23 used in the ADCs of the present application have strong degradation activity on Cyclin K protein.

[0214] Figure 4, the ADC1-1 compound of the application also has strong degradation activity on Cyclin K protein in tumor tissues of NCI-N87 tumor-bearing mice.

[0215] Figure 5, the anti-TROP2 ADC of the application has an antitumor effect on NCI-N87 mouse xenograft models.

[0216] Figure 6, the anti-TROP2 ADC of the application has an effect on the body weight of mice in NCI-N87 mouse xenograft models.

[0217] Figure 7, the ADC of the application has an antitumor effect on BT-474 mouse xenograft models.

[0218] Figure 8, the ADC of the application has an effect on the body weight of mice in BT-474 mouse xenograft models.

[0219] DETAILED DESCRIPTION

[0220] It is particularly noted that, in the present text, when referring to a "compound" or "antibody drug conjugate" having a specific structural formula, it is generally also encompassing its stereoisomers, diastereoisomers, enantiomers, racemic mixtures and isotopic derivatives.

[0221] It is well known to the person skilled in the art that a salt, solvate, hydrate of a compound or antibody drug conjugate is an alternative form of existence of the compound, which can be converted into the compound under certain conditions, and therefore, it is particularly noted that in the present text, when referring to a compound, it is generally also encompassing its pharmaceutically acceptable salts, and further encompassing its solvates and hydrates.

[0222] Similarly, in the present text, when referring to a compound or antibody drug conjugate, it is generally also encompassing its prodrugs, metabolites and nitroxides.

[0223] The "stereoisomers" of the compounds or antibody drug conjugates of the present application refer to enantiomers when the compound of formula (I) has asymmetric carbon atoms; to cis-trans isomers when the compound has carbon-carbon double bonds or cyclic structures; to tautomers when the compound has ketones or oximes, etc. All enantiomers, diastereoisomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, rotational isomers and mixtures thereof of the compounds of formula (I) are included in the scope of the present application.

[0224] The "pharmaceutically acceptable salts" described in this invention refer to pharmaceutically acceptable addition salts of acids and bases or their solvates. Such pharmaceutically acceptable salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and alkanes (such as acetic acid, HOOC-(CH2)n-COOH (where n is 0-4)). Salts of bases include: sodium salts, potassium salts, calcium salts, ammonium salts, etc. Many non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

[0225] The precursors or metabolites described in this invention can be any precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form a compound. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism.

[0226] definition

[0227] Unless otherwise specified, the terms used in this application (including the specification and claims) are defined as follows. It should be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0228] In the description and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof whether or not specifically referred to. All chiral (enantiomeric and diastereomeric) and racemic forms are intended, unless otherwise indicated. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such isomers are contemplated in the present application. The present application describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the application and they can be isolated as a mixture of isomers or as separate isomers. The compounds of the application can be isolated in optically active or racemic forms. All processes used to prepare the compounds of the application and intermediates used therein are considered to be part of the present application. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, e.g., by chromatography or fractional crystallization. Depending on the process conditions the end products of the application are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the application. If desired, one form of a compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the application can be separated into the individual isomers. The compounds of the application, free forms and salts, can exist in various tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged accordingly. It is understood that all tautomeric forms, which can exist, are included within the application.

[0229] In the present application, the term "ligand" generally refers to a macromolecular compound that can recognize and bind to a target cell-associated antigen or receptor, including but not limited to antibodies, polypeptides, fusion proteins, nanobodies, or other molecules that can bind to a cell, receptor, or antigen.

[0230] The term "antibody" generally refers to an immunoglobulin molecule consisting of two pairs of polypeptide chains (each pair having one light (LC) and one heavy (HC) chain). Antibody light chains can be classified as kappa (kappa) and lambda (lambda) light chains. Heavy chains can be classified as mu, delta, gamma, alpha, or epsilon, and define a different class of antibodies as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 3 or more amino acids. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region is comprised of one domain, CL. The constant domains are not involved directly in binding of an antibody to an antigen, but exhibit various effector functions, such as mediating the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy chain / light chain pair (VH and VL) form the antigen binding site. Assignment of amino acids to each region or domain can follow various numbering systems known in the art.

[0231] The term "complementarity determining region" or "CDR" refers to amino acid residues within the variable region of an antibody that are responsible for antigen binding. There are three CDRs in each of the variable regions of the heavy and light chains, designated CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, e.g., as defined by the Rabat numbering system (Rabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86:9268-9272). For a given antibody, one of skill in the art will readily be able to identify the CDRs defined by each numbering system. Moreover, the correspondence between different numbering systems is well known to those skilled in the art (e.g., see Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0232] In the present application, the CDRs contained by an antibody or antigen-binding fragment thereof can be determined according to various numbering systems known in the art, e.g., by the Rabat, Chothia, IMGT, or AbM numbering system. In certain embodiments, the CDRs contained by an antibody or antigen-binding fragment thereof are defined by the Chothia numbering system.

[0233] The term "framework region" or "FR" residues refer to those amino acid residues in the variable region of an antibody that are not CDR residues as defined above.

[0234] The term "antigen binding fragment" of an antibody refers to a polypeptide of a fragment of an antibody, e.g., a polypeptide of a fragment of a full-length antibody, that retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen, which is also referred to as an "antigen binding portion". See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nded. Raven Press, N.Y. (1989)), which is incorporated herein by reference in its entirety for all purposes. Antigen binding fragments of an antibody can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen binding fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fd, Fv, scFv, di-scFv, (scFv)2, disulfide stabilized Fv proteins ("dsFv"), single domain antibodies (sdAb, nanobodies), and polypeptides comprising at least a portion of an antibody that is sufficient to confer specific antigen binding ability to the polypeptide. Engineered antibody variants are reviewed in the literature (Holliger et al., 2005, Nat Biotechnol, 23: 1126-1136).

[0235] The term "Fd" means an antibody fragment consisting of a VH and CH1 domain; the term "dAb fragment" means an antibody fragment that consists of a VH domain (Ward et al., Nature 341 :544 546 (1989)); the term "Fab fragment" means an antibody fragment consisting of a VL, VH, CL and CH1 domain; the term "F(ab')2 fragment" means an antibody fragment that comprises two Fab fragments linked by disulfide bridges on the hinge region; the term "Fab' fragment" means the fragment obtained by reducing the disulfide bonds of a F(ab')2 fragment, consisting of an intact light chain and a Fd fragment of a heavy chain (consisting of a VH and CH1 domain).

[0236] The term "Fv" means an antibody fragment consisting of the VL and VH domains of a single arm of an antibody. The Fv fragment is commonly considered the smallest fragment of an antibody that is capable of forming a complete antigen binding site. It is generally considered that the six CDRs confer antigen binding specificity to an antibody. However, even a single variable region (e.g., a Fd fragment, which contains only three CDRs specific for an antigen) is capable of recognizing and binding antigen, although it may do so at a lower affinity than the entire binding site.

[0237] The term "Fc" means an antibody fragment formed by disulfide bonds between the second, third constant regions of the first heavy chain and the second, third constant regions of the second heavy chain of an antibody. The Fc fragment of an antibody has various diverse functions, but is not involved in antigen binding.

[0238] The term "scFv" refers to a single polypeptide chain comprising a VL and a VH domain, wherein the VL and VH are connected by a linker (see, e.g., Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113; Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994)). Such scFv molecules can have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeating GGGGS amino acid sequences or variants thereof. For example, a linker having the amino acid sequence (GGGGS)4 can be used, but variants thereof can also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448). Other linkers useful in the present application are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol. In some cases, a disulfide bond can also exist between the VH and VL of the scFv. In certain embodiments, the VH and VL domains can be positioned relative to each other in any suitable arrangement. For example, scFv comprising NH2-VH-VH-COOH, NH2-VL-VL-COOH.

[0239] The term "single-domain antibody (sdAb)" has the meaning generally understood by those skilled in the art and refers to an antibody fragment consisting of a single monomeric variable antibody domain, such as a single heavy chain variable region, that retains the ability to specifically bind the same antigen to which a full-length antibody binds (Holt, L. et al., Trends in Biotechnology, 21(11):484-490, 2003). Single-domain antibodies are also known as nanobodies.

[0240] Each of the above-described antibody fragments is capable of specifically binding to the same antigen bound by the full-length antibody from which the fragment was derived, and / or competes with the full-length antibody for specific binding to the antigen.

[0241] In the present context, the term "antibody" includes not only intact antibodies, but also antigen-binding fragments of antibodies, unless the context specifically indicates otherwise.

[0242] Antigen-binding fragments of antibodies (e.g., the above-described antibody fragments) can be obtained using conventional techniques known to those of skill in the art (e.g., recombinant DNA technology or enzymatic or chemical cleavage methods) from a given antibody (e.g., an antibody provided herein) and screened for specificity in the same manner as is used for the intact antibody.

[0243] The term "murine antibody" refers to an antibody obtained by fusing B cells of an immunized mouse with myeloma cells, screening for murine hybridoma cells that both proliferate indefinitely and secrete antibody, followed by screening, antibody production, and antibody purification, or refers to an antibody secreted by a plasma cell that developed from a B cell that proliferated in response to an antigen invading a mouse.

[0244] The term "humanized antibody" refers to a non-human antibody that has been genetically engineered to have an amino acid sequence that is modified to increase homology to the sequence of a human antibody. Typically, all or a portion of the CDR regions of a humanized antibody are derived from a non-human antibody (donor antibody), and all or a portion of the non-CDR regions (e.g., variable region FR and / or constant region) are derived from a human immunoglobulin (acceptor antibody). A humanized antibody typically retains the desired properties of the donor antibody, including but not limited to, antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance an immune response, and the like. The donor antibody can be a mouse, rat, rabbit, or non-human primate (e.g., cynomolgus monkey) antibody that has the desired properties (e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and / or ability to enhance an immune response).

[0245] The term "semi-humanized antibody" refers to an antibody in which one antibody chain comprises a murine variable region (as in a chimeric antibody) and the other antibody chain comprises a humanized variable region, relative to a humanized or fully humanized antibody.

[0246] The term "chimeric antibody" refers to an antibody in which the variable region sequence is from one species while the constant region sequence is from another species, such as an antibody in which the variable region sequence is from a mouse antibody while the constant region sequence is from a human antibody. Chimeric antibodies according to the application or fragments thereof can be prepared using genetic recombination techniques. For example, the chimeric antibody can be produced by cloning a recombinant DNA comprising a promoter and a sequence encoding the variable region of a non-human, in particular mouse, monoclonal antibody according to the application, and a sequence encoding the constant region of a human antibody. The chimeric antibody encoded by this recombinant gene will be, for example, a murine-human chimera, the specificity of which is determined by the variable region derived from the murine DNA, and the isotype of which is determined by the constant region derived from the human DNA.

[0247] The term "monoclonal antibody" or "monoclonal" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0248] The term "bispecific antibody" or "bi-specific" refers to an antibody that has the ability to bind to two antigenic epitopes simultaneously. The two antigenic epitopes can be on different antigens or on the same antigen. Bispecific antibodies can have a variety of structural configurations. For example, a bispecific antibody can be composed of two Fc fragments and two binding moieties fused to each, respectively (similar to a natural antibody, except that the two arms bind to different antigenic determinants or epitopes), the antigen binding moieties can be single chain antibodies (scFv) or Fab fragments.

[0249] In the present application, the term "antibody or antigen binding fragment" refers generally to immunological binding reagents extending to all antibodies from all species. Antibodies include monoclonal antibodies, polyclonal antibodies, dimers, multimers, pro-antibodies, chimeric antibodies fully human antibodies, humanized antibodies, recombinant antibodies and fragments thereof. Antigen binding fragments can refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.

[0250] In the present application, the term "antibody drug conjugate" or "ADC" refers to a substance obtained by linking a fragment of a biologically active compound (a drug molecule) to an antibody or antigen binding fragment. In some embodiments of the present application, the biologically active molecule is linked to the targeting moiety via a linker L. The linker can be cleavable in a particular environment (e.g. a hydrolytic enzyme in the tumor and / or a low pH environment) or by a particular action (e.g. the action of a lysosomal protease), thereby separating the biologically active molecule from the antibody or antigen binding fragment. In some embodiments of the present application, the biologically active molecule is linked directly to the antibody or antigen binding fragment via a covalent bond, which can be cleavable in a particular environment or by a particular action, thereby separating the biologically active molecule from the antibody or antigen binding fragment.

[0251] In the present application, the term "drug antibody ratio" or "DAR" refers to the ratio of drug to antibody in an antibody drug conjugate, for example can represent the number of drug molecules attached per antibody, or can represent the average number of drug molecules attached to a population of ADCs (i.e. the average or mean DAR). The DAR of an ADC can be any value in the range of 1 to 20. For example, the DAR can be 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 10.0, 12.0, 20.0.

[0252] In the present application, L1 is connected to Ab through S atom, and those skilled in the art can understand that the disulfide bond of Ab can be opened by reagents (such as reducing agent TCEP, etc.), and the obtained thiol group and linker drug conjugate (i.e. L-P) are reacted (such as substitution reaction or addition reaction, etc.) to obtain the antibody drug conjugate.

[0253] In the present application, the term "Cyclin K protein degrading agent" refers to a degrading agent that can induce ubiquitination and degradation of Cyclin K protein, which can not only degrade Cyclin K protein, but also can induce degradation of other proteins (such as CDK12) at the same time. The Cyclin K protein degrading agent of the present application is a molecular glue type degrading agent. The linker of the antibody drug conjugate of the present application can be broken under a specific environment (such as the action of a specific protease / hydrolase, a low pH environment), releasing the bioactive molecules of the Cyclin K protein degrading agent, thereby playing a role in degrading proteins / killing cells.

[0254] In the present application, when the listed linking groups do not indicate their connection direction, their connection direction is arbitrary, for example In the present application, when the listed linking groups do not indicate their connection direction, their connection direction is arbitrary, for example In the present application, when the listed linking groups do not indicate their connection direction, their connection direction is arbitrary, for example The combination of the linking group and the connected group is only allowed in the case of producing a stable compound.

[0255] Unless otherwise defined, the definition of the substituents of the present application is independent of each other, not mutually related, for example, for R a (or R b ) in the definition of the substituent, it is independent of each other in the definition of different substituents. Specifically, for R a (or R b ) to select one definition in one substituent, it does not mean that the R a (or R bThe same definition applies to all other substituents. More specifically, for example (a non-exhaustive list only) for NR... a R b In the middle, when R a (or R) b When the definition of ) is taken from hydrogen, it does not mean that in -C(O)-NR a R b In the middle, R a (or R) b It must be hydrogen. On the other hand, when a substituent contains more than one R... a (or R) b When these R a (or R) b They are also independent. For example, in the substituent -(CR) a R b ) m -O-(CR a R b ) n In the case where m+n is greater than or equal to 2, there are m+n R values. a (or R) b Each of these is independent; they can have the same or different meanings.

[0256] Unless otherwise defined, when a substituent is labeled “optionally substituted,” the substituent is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine group (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamide (e.g., -SO2NH2), substituted sulfonamide, nitro, cyano, carboxyl, carbamoyl (e.g., -CONH2), substituted carbamoyl (e.g., -CONHalkyl), -CONHaryl, -CONHarylalkyl, or having two substituents selected from alkyl, aryl, or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc., and substituted heterocyclic groups.

[0257] In the present invention, the term "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-C6alkyl" denotes an alkyl group having from one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, and the like. Preferred alkyl groups in the present invention include Ci-C6alkyl or Ci-C4alkyl. The alkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0258] In the present invention, the term "alkylene" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, which is a residue derived from removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, "C0-C6alkylene" denotes an alkylene group having from zero to six carbon atoms, and C0alkylene denotes the absence of an alkylene group (a bond). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylidene (-CH(CH3)-), 1,2-ethylidene (-CH2CH2-), 1,1-propylidene (-CH(CH2CH3)-), 1,2-propylidene (-CH2CH(CH3)-), 1,3-propylidene (-CH2CH2CH2-), 1,4-butylidene (-CH2CH2CH2CH2-), and the like. Preferred alkylene groups in the present invention include C0-C6alkylene.

[0259] In the present invention, the term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkenyl" contains from two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Preferred alkenyl groups in the present invention include C2-C6alkenyl.

[0260] In the present invention, the term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkynyl" contains from two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. Preferred alkynyl groups in the present invention include C2-C6alkynyl.

[0261] In the present invention, the term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), and t-butyloxy. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached through a sulfur bridge; for example, methyl-S- and ethyl-S-. Preferred alkoxy groups in the present invention include C1-C6 alkoxy or C1-C4 alkoxy.

[0262] In the present invention, the term "carbonyl" refers to an organic functional group (C=0) connected by a double bond between a carbon and an oxygen atom.

[0263] In the present invention, the term "aryl" alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on either the cycloalkyl ring or the aromatic ring. The dashed line drawn through the ring system indicates that the bond can be attached to any suitable ring atom. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0264] In the present invention, the term "halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptafluoropropyl. Examples of haloalkyl groups also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0265] In the present application, the term "haloalkoxy" or "haloalkyloxy" denotes an oxygen-bridged haloalkyl group as defined above having the indicated number of carbon atoms. For example, "Ci-C6haloalkoxy" is intended to include Ci, C2, C3, C4, C5, C6haloalkoxy. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a sulfur-bridged haloalkyl group as defined above having the indicated number of carbon atoms; for example trifluoromethyl-S- and pentafluoroethyl-S-.

[0266] In the present application, when referring to some substituent groups the expression C x1 -C x2 is used, which means that the number of carbon atoms in said substituent group can be from x1 0 to x2 For example, C 0- C8means that said group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, Ci-C8means that said group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8means that said group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8means that said group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8means that said group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6means that said group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, Ci-C6means that said group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6means that said group contains 2, 3, 4, 5 or 6 carbon atoms, C3-C6means that said group contains 3, 4, 5 or 6 carbon atoms.

[0267] In the present application, the expression "x1-x2-membered ring" is used when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl) and indicates that the number of ring atoms of the group can be from x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; 3-6 membered ring indicates that the cyclic group can be a 3-, 4-, 5-, or 6-membered ring, which can have from 3, 4, 5, or 6 ring atoms; 3-8 membered ring indicates that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which can have from 3, 4, 5, 6, 7, or 8 ring atoms; 3-9 membered ring indicates that the cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring, which can have from 3, 4, 5, 6, 7, 8, or 9 ring atoms; 4-7 membered ring indicates that the cyclic group can be a 4-, 5-, 6-, or 7-membered ring, which can have from 4, 5, 6, or 7 ring atoms; 5-8 membered ring indicates that the cyclic group can be a 5-, 6-, 7-, or 8-membered ring, which can have from 5, 6, 7, or 8 ring atoms; 5-12 membered ring indicates that the cyclic group can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; 6-12 membered ring indicates that the cyclic group can be a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which can have from 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms can be carbon atoms or heteroatoms, e.g., heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle can contain 1, 2, 3, or 4 ring heteroatoms, e.g., heteroatoms optionally selected from N, O, and S.

[0268] In the present application, one or more halogen can each independently be selected from fluorine, chlorine, bromine, and iodine.

[0269] In the present application, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryls and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which can have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, e.g., 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatoms can be oxygen, nitrogen, or sulfur. The carbon atoms and heteroatoms of the heteroaryl group are optionally substituted with an oxo group (e.g., forming C=O, S(=O), or S(=O)2). The heteroaryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0270] In the present invention, the term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocycloalkyl system consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from N, O and S, the remainder being carbon atoms, wherein the N atoms can optionally be quaternized, and the N and S atoms can optionally be oxidized (i.e., NO, SO and SO2). When the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spiro, fused and bridged ring systems. The heterocycloalkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0271] In the present invention, the term "3-10 membered heterocycloalkyl" or "3-10 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocycloalkyl system consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from N, O and S, the remainder being carbon atoms, wherein the N atoms can optionally be quaternized, and the N and S atoms can optionally be oxidized (i.e., NO, SO and SO2). When the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spiro, fused and bridged ring systems. The "3-10 membered heterocyclyl" can be 3, 4, 5, 6, 7, 8, 9 or 10 membered heterocyclyl. Specific examples of 3-10 membered heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl (including 2-pyrrolidinyl and 3-pyrrolidinyl), piperidinyl (including 2-piperidinyl, 3-piperidinyl and 4-piperidinyl, etc.), piperazinyl, hexahydropyridazinyl, morpholinyl, dioxanyl, hexahydropyridazinyl, azepane, 1,4-diazepane, cyclopentylpyrrolidinyl, pyrrolidinylpyrrolidinyl, cyclopropylspiperazinyl, cyclobutylspiperazinyl, azetidinylspiperazinyl, cyclobutylspiperidinyl, azetidinylspiperidinyl, cyclobutylspiperidinyl, azetidinylspiperidinyl, cyclobutylspiperidinyl, azetidinylspiperidinyl, cyclopentylspiperidinyl, azepanylspiperidinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl or 8-azabicyclo[3.2.1]octanyl, etc.

[0272] In the present application, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic alkyl system consisting of 3 to 10 ring atoms, all of which are carbon atoms. It includes monocycloalkyl, bicycloalkyl, spirocycloalkyl and bridged cycloalkyl groups. The "3-12 membered cycloalkyl" can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered cycloalkyl group. Specific examples of 3-12 membered heterocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl bicycloalkyl, cyclobutyl spirocyclobutyl or bicyclo[l. l. l]pentanyl groups, and the like.

[0273] In the present application, the term "C3-C 10 In the present application, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic alkyl system consisting of 3 to 10 ring atoms, all of which are carbon atoms. It includes monocycloalkyl, bicycloalkyl, spirocycloalkyl and bridged cycloalkyl groups. The "3-12 membered cycloalkyl" can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered cycloalkyl group. Specific examples of 3-12 membered heterocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl bicycloalkyl, cyclobutyl spirocyclobutyl or bicyclo[l. l. l]pentanyl groups, and the like.

[0274] In the present application, the term "fused ring" or "fused ring" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms with each other.

[0275] In the present application, the term "aromatic fused ring" refers to a fused ring having aromaticity, wherein the aromaticity of the fused ring can be judged according to the method commonly used in the art, for example, Huckel rule, when the number of conjugated π electrons of the fused ring is 4n+2, it is determined to have aromaticity.

[0276] In the present application, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0277] In the present application, the term "spiro ring" refers to a polycyclic group in which single rings share one carbon atom (called spiro atom) with each other.

[0278] In the present application, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The ring double bond used herein is a double bond formed between two adjacent ring atoms (e.g. C=C, C=N or N=N).

[0279] In the case where nitrogen atoms (e.g. amines) exist on the compounds of the present application, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g. mCPBA and / or hydrogen peroxide) to obtain other compounds of the present application. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide to obtain derivatives of the present application.

[0280] When any variable occurs more than one time in any constituent or formula, its definition in each occurrence is independent of its definition in every other case. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, said group can optionally be substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0281] In the present application, the term "patient" refers to an organism that is treated by the methods of the present application. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians / monkeys, equines, bovines, porcines, canines, felines, etc.) and most preferably refer to humans.

[0282] In the present application, the term "effective amount" means that amount of a drug or pharmaceutical agent (i.e., a compound of the present application), which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount which, compared to a corresponding subject who does not receive the above-mentioned amount, results in improved treatment, healing, prevention, or amelioration of a disease, condition, or side effects, or decrease in the rate of advancement of a disease or condition. The effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.

[0283] In the present application, the term "treatment" includes its broadest meaning and encompasses therapeutic and / or prophylactic treatment of a subject. In particular, the "treatment" includes any treatment that results in the palliation, inhibition, elimination, and amelioration and / or prevention of a condition, disease, disorder, etc., such as reducing, decreasing, modulating, ameliorating, eliminating, preventing, protecting against, or improving symptoms thereof. The therapeutic treatment includes palliating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of a complication; ameliorating an underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; lessening a disease or symptom; causing regression of a disease or symptom; lessening complications resulting from a disease or symptom, or treating an indication resulting from a disease or symptom. The prophylactic treatment includes prior treatment to prevent, block, or delay, slow, lessen, or reduce the occurrence or progression of a disease or condition or to lessen the severity of a disease or condition.

[0284] Likewise, a "therapeutic agent" also includes an agent or reagent that has therapeutic and / or prophylactic treatment of a subject.

[0285] In the present application, the term "pharmaceutical" or "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0286] In the present application, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0287] In the present application, the term "pharmaceutical composition" means a composition comprising a compound of the present application in combination with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of a biologically active agent to an animal, particularly a mammal, including, i.e., an adjuvant, excipient, or vehicle, such as a diluent, preservative, filler, flow regulator, disintegrating agent, wetting agent, emulsifying agent, suspending agent, sweetening agent, flavoring agent, perfuming agent, antibacterial agent, antifungal agent, lubricating agent, and dispersing agent, depending on the mode of administration and nature of the dosage form.

[0288] Specific Pharmaceutical and Medical Terms

[0289] In the present application, the term "acceptable", as used herein, means no unreasonably deleterious effect on the health of the subject of the general treatment goal.

[0290] In the present application, the term "cancer", as used herein, refers to an abnormal growth of cells that is uncontrolled and, under some conditions, is capable of metastasizing (spreading). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, bowel, brain, breast, uterine, cardiac, kidney, lung, lymphatic tissue (lymphoma), ovarian, pancreatic, or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or blood (e.g., non-leukemic leukemia).

[0291] In the present application, the term "co-administration" or its grammatical equivalents, as used herein, means the administration of two or more selected therapeutic agents to a single patient at the same time by the same or different routes of administration.

[0292] As used herein, the term "enhance" or "enhancing" means that the intended result can be increased or prolonged in either potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" means the ability of the drug to increase or prolong potency or duration in the system. As used herein, "enhancing value" means the ability to maximize the enhancement of another therapeutic drug in the desired system.

[0293] As used herein, the term "immune disorder" means a disease or condition resulting from an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually a dysfunction of cells, or destruction and dysfunction as a result, or destruction of organs or tissues that can result in the immune condition.

[0294] As used herein, the terms "kit" and "product package" are synonymous.

[0295] As used herein, the terms "subject," "recipient," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and house cats; laboratory animals such as rats, mice, and guinea pigs; and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the mammal is a human.

[0296] As used herein, a compound or pharmaceutical composition is "effective" to treat a disease, condition, or disorder if it has the ability to cause an improvement in the disease, condition, or disorder, especially an improvement in the severity thereof, delay onset of the disease, slow the progression of the disease, or decrease the duration of the disease, whether by administration in a fixed or timed dosage regimen, or by administration on an intermittent or episodic basis. A condition is "associated with" or "attributable to" administration of a compound if it is caused by the administration, or is likely the result of the administration. DETAILED DESCRIPTION

[0297] The present application is further illustrated by the following description of specific embodiments, but this description is not intended to limit the application in any way. Various modifications and variations can be made by those skilled in the art without departing from the spirit or scope of the application. In the present application, when a preparation route is not mentioned, the relevant starting materials and intermediates are purchased from commercial reagents (e.g., from Aldrich, Sigma, etc.).

[0298] The abbreviations used in the present application have the following meanings:

[0299] In the following examples, the reaction temperature is room temperature (10-30°C) unless otherwise specified.

[0300] The compounds of the present application are isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography. The structure of the compounds is confirmed by1 H NMR and / or MS to confirm. Reaction monitoring was performed using TLC or LC-MS.

[0301] 1 H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values are expressed in parts per million, i.e. delta values. The following abbreviations are used for multiplicity in NMR signals: s = singlet, br s = broad singlet, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz. LC-MS experimental conditions: Instrument: Thermo U3000, ALLtech ELSD, MSQ, UV detector combined with ELSD and MSD (flow ratio of 4: 1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6 x 50 mm; column temperature: 30 °C. Gradient [time (min) / solvent B in A (%)] : 0.00 / 5.0, 1.40 / 95, 2.80 / 95, 2.82 / 5, 3.00 / 5. (Solvent A = 0.01% trifluoroacetic acid in water; solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214 / 254 / 280 / 300 nm; DAD detection: 210-350 nm; flow rate: 2 mL / min; MS: ESI, 100-1500 m / z.

[0302] Preparative HPLC was generally performed using either a basic method or an acidic method (basic method mobile phase: acetonitrile / 0.05% aqueous ammonium bicarbonate, acidic method mobile phase: acetonitrile / 0.05% aqueous formic acid); instrument: Thermo U3000 AFC-3000; column: Globalsil C-18 12 nm, 250 x 20 mm, 10 μm, or equivalent; flow rate: 20 mL / min, gradient elution separation.

[0303] Example 1: Synthesis of a biologically active molecule (drug payload)

[0304] Example 1.1: Synthesis of compound P-1

[0305] Step one: Synthesis of compound P-1-a

[0306] To a solution of compound P-1-a (4.7 g, 13.1 mmol) and 1,2,2,3,4,4- hexamethylphosphor-1-oxide (684 mg, 3.9 mmol) in n-butyl acetate (50 mL) was added phenylsilane (4.25 g, 39.2 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound P-1-b (2.75 g, yield 64.2%). ESI-MS (m / z): 328.3 [M+H] + .

[0307] Step two: synthesis of compound P-1-b

[0308] To a solution of compound P-1-a (4.7 g, 13.1 mmol) and 1,2,2,3,4,4- hexamethylphosphor-1-oxide (684 mg, 3.9 mmol) in n-butyl acetate (50 mL) was added phenylsilane (4.25 g, 39.2 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound P-1-b (2.75 g, yield 64.2%). ESI-MS (m / z): 328.3 [M+H] + .

[0309] Step three: synthesis of compound P-1-c

[0310] To a solution of compound P-1-b (1.08 g, 3.29 mmol) in tetrahydrofuran (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (601 mg, 3.95 mmol) and diphenyl phosphor azide (1.09 g, 3.95 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was added to 50 mL of ethyl acetate and washed with water once, 5% dilute hydrochloric acid once, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound P-1-c (1.1 g, yield 94.9%). ESI-MS (m / z): 353.3 [M+H] + .

[0311] Step four: synthesis of compound P-1-d

[0312] Compound P-1-c (280 mg, 795 pmol) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 5 hours, concentrated to give compound P-1-d (229 mg, yield 99.9%). ESI-MS (m / z): 253.3 [M+H] + .

[0313] Step five: synthesis of compound P-1-e

[0314] Compound P-1-e (277 mg, 941 pmol) was dissolved in dichloromethane (10 mL), m-chloroperoxybenzoic acid (325 mg, 1.88 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was added with 30 mL dichloromethane, washed with saturated sodium bicarbonate twice, water twice, saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated. The residue was purified by column chromatography to give compound P-1-f (150 mg, yield 48.9%). ESI-MS (m / z): 327.3 [M+H] + .

[0315] Step six: synthesis of compound P-1-f

[0316] Compound P-1-e (277 mg, 941 pmol) was dissolved in dichloromethane (10 mL), m-chloroperoxybenzoic acid (325 mg, 1.88 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was added with 30 mL dichloromethane, washed with saturated sodium bicarbonate twice, water twice, saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated. The residue was purified by column chromatography to give compound P-1-f (150 mg, yield 48.9%). ESI-MS (m / z): 327.3 [M+H] + .

[0317] Step seven: synthesis of compound P-1-g

[0318] Compound P-1-d (92 mg, 366 µmol) and N,N-diisopropylethylamine (142 mg, 1.10 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound P-1-f (120 mg, 366 µmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 93 / 7) to give compound P-1-g (94 mg, yield 51.4%). ESI-MS (m / z): 499.4 [M+H] + .

[0319] Step eight: synthesis of compound P-1

[0320] Compound P-1-g (94 mg, 188 µmol) was dissolved in tetrahydrofuran (5 mL), and triphenylphosphine (148 mg, 565 µmol) and water (40 µL) were added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated, and the residue was purified by preparative liquid chromatography (basic method) to give compound P-1 (46 mg, yield 52.4%). ESI-MS (m / z): 473.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 4.8 Hz, 1H), 8.30 (s, 1H), 8.18 – 8.11 (m, 1H), 8.11 – 8.06 (m, 1H), 7.68 – 7.62 (m, 2H), 7.52 – 7.43 (m, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.36 – 7.28 (m, 1H), 7.26 – 7.15 (m, 1H), 6.26 (d, J = 6.9 Hz, 1H), 4.78 – 4.55 (m, 3H), 4.16 (s, 2H), 2.06 – 1.61 (m, 2H), 0.84 – 0.62 (m, 3H).

[0321] Example 1.2: synthesis of compound P-2

[0322] Step one: synthesis of compound P-2-a

[0323] (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (200 mg, 929 pmol), N,N- diisopropylethylamine (480 mg, 3.72 mmol) and ammonium chloride (149 mg, 2.79 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (530 mg, 1.39 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and extraction was performed three times with ethyl acetate (20 mL), and the organic phase was combined and washed once with water and once with saturated brine, dried, and concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 98 / 2) to obtain compound P-2-a (160 mg, yield 80.4%).

[0324] Step two: synthesis of compound P-2-b

[0325] Compound P-2-a (160 mg, 746 pmol) was dissolved in dichloromethane (2 mL), and 4N hydrochloric acid dioxane solution (1 mL) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound P-2-b (112 mg, yield 99.6%).

[0326] Step three: synthesis of compound P-2-c

[0327] Compound P-2-b (100 mg, 664 pmol) and 4-chloro-2-(methylthio)-5- (trifluoromethyl)pyrimidine (152 mg, 664 pmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (257 mg, 1.99 mmol) was added. The mixture was stirred at 70°C for 2 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was performed three times with ethyl acetate (20 mL), and the organic phase was combined and washed once with water and once with saturated brine, dried, and concentrated. The residue was purified by flash column chromatography (PE / EA = 70 / 30) to obtain compound P-2-c (154 mg, yield 75.7%). ESI-MS (m / z): 307.3 [M+H] + .

[0328] Step four: synthesis of compound P-2-d

[0329] Compound P-2-c (154 mg, 503 pmol) was dissolved in dichloromethane (3 mL), and m-chloroperoxybenzoic acid (174 mg, 1.01 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was diluted with 20 mL of dichloromethane, washed twice with saturated sodium bicarbonate, twice with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product of compound P-2-d (140 mg). ESI-MS (m / z): 339.3 [M+H] + .

[0330] Step five: synthesis of compound P-2-e

[0331] Compound P-2-d (96 mg, 284 pmol) and compound P-l-d (72 mg, 284 pmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (110 mg, 852 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL) three times, the organic phase was combined, washed once with water, once with saturated brine, dried, and concentrated. The residue was purified by flash column chromatography (PE / EA = 50 / 50) to give compound P-2-e (45 mg, yield 31.0%). ESI-MS (m / z): 511.5 [M+H] + .\

[0332] Step six: synthesis of compound P-2

[0333] Compound P-2-e (45 mg, 88 pmol) was dissolved in tetrahydrofuran (3 mL), and triphenylphosphine (69.4 mg, 264 pmol) and water (0.1 mL) were added. The mixture was stirred at room temperature for 16 h. The reaction was concentrated, and the residue was purified by preparative liquid chromatography (basic method) to give compound P-2 (15 mg, yield 35.1%). ESI-MS (m / z): 485.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 8.39 (d, J = 4.7 Hz, 1H), 8.16 - 7.81 (m, 3H), 7.63 - 7.42 (m, 2H), 7.40 (d, J = 4.8 Hz, 1H), 7.33 - 7.13 (m, 2H), 6.27 - 6.13 (m, 1H), 4.82 - 4.51 (m, 2H), 4.32 - 4.10 (m, 3H), 1.31 - 0.91 (m, 1H), 0.64 - 0.09 (m, 4H).

[0334] Examples 1.3-1.9:

[0335] Using the same method and reaction conditions of Example 1.2, the target products in the following table were obtained respectively by using (tert-butoxycarbonyl)-D-valine, (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid, (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid, (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid, (R)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid, (R)-2-((tert-butoxycarbonyl)amino)-2-cyclobutylacetic acid, N-(tert-butoxycarbonyl)-O-methyl-D-threonine instead of (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid as the starting material.

[0336] Example 1.10: Synthesis of compound P-10

[0337] Step one: Synthesis of compound P-10-a

[0338] Dissolve 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (1 g, 4.37 mmol) and (2R, 3R)-3-aminobutan-2-ol hydrochloride (549 mg, 4.37 mmol) in N,N-dimethylformamide (10 mL), and add N,N-diisopropylethylamine (1.70 g, 13.1 mmol). Stir the mixture at 60 °C for 16 hours. Cool the reaction to room temperature, add 50 mL of ethyl acetate, wash with water three times, saturated brine once, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography (PE / EA = 80 / 20) to obtain compound P-10-a (700 mg, yield 56.9%). ESI-MS (m / z): 282.5 [M+H] + .

[0339] Step two: Synthesis of compound P-10-b

[0340] Dissolve compound P-10-a (630 mg, 2.24 mmol) in dichloromethane (10 mL), and add meta-chloroperoxybenzoic acid (773 mg, 4.48 mmol). Stir the mixture at room temperature for 2 hours. Add dichloromethane (20 mL) to the reaction, wash with saturated sodium bicarbonate solution once, water once, dry, and concentrate to obtain the crude product compound P-10-b (701 mg, yield 99.9%). ESI-MS (m / z): 314.3 [M+H] + .

[0341] Step three: Synthesis of compound P-10-c

[0342] Compound P-1-d (200 mg, 792 pmol) and N,N-diisopropyl ethylamine (307 mg, 2.38 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound P-10-b (248 mg, 793 pmol) was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound P-10-c (280 mg, yield 72.8%). ESI-MS (m / z): 486.6 [M+H] + .

[0343] Step four: synthesis of compound P-10

[0344] Compound P-10-c (39 mg, 80 pmol) was dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (63 mg, 241 pmol) and water (40 pL) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkali method) to obtain compound P-10 (32 mg, yield 87%). ESI-MS (m / z): 460.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d 8.36 (d, J = 4.7 Hz, 1H), 8.10 (br. s, 1H), 8.08 - 8.02 (m, 2H), 7.45 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.23 - 7.11 (m, 1H), 5.75 - 5.65 (m, 1H), 5.04 (br. s, 1H), 4.73 - 4.52 (m, 2H), 4.15 - 3.96 (m, 3H), 3.78 - 3.57 (m, 1H), 1.48 - 0.78 (m, 6H).

[0345] Example 1.11: synthesis of compound P-11

[0346] Step one: synthesis of compound P-11-a

[0347] Dissolve 6-bromo-lH-indazol-3-amine (2 g, 9.43 mmol) and 4-((tert-butyldimethylsilyloxy)but-2-ynal (6.2 g, 31.3 mmol) in acetonitrile (60 mL), add glacial acetic acid (566 mg, 9.43 mmol) and silver trifluoroacetate (625 mg, 2.83 mmol). Stir the mixture at room temperature for 16 hours. Add 80 mL of ethyl acetate and 50 mL of water, filter through celite, separate the organic phase, wash the organic phase with water once, saturated brine once, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography (PE / EA = 50 / 50) to obtain compound P-l l-a (700 mg, yield 18.9%). ESI-MS (m / z): 392.4 [M+H] + .

[0348] Step two: synthesis of compound P-l l-b

[0349] Dissolve compound P-l l-a (700 mg, 1.78 mmol) and ((tert-butoxycarbonylamino)methyl)potassium trifluoroborate (383 mg, 1.62 mmol) in a mixture of 1,4-dioxane (6 mL) and water (1 mL), add dicyclohexyl(2',6'-dimethoxy-(l,l'-biphenyl)-2-yl)phosphine (73 mg, 178 μmol), potassium carbonate (740 mg, 5.35 mmol), and palladium acetate (40 mg, 178 μmol). Stir the mixture at 90 °C under nitrogen protection for 16 hours. Cool the reaction to room temperature, add 50 mL of ethyl acetate and 30 mL of water, filter through celite, separate the organic phase, wash the organic phase with water once, saturated brine once, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography (PE / EA = 50 / 50) to obtain compound P-l l-b (400 mg, yield 18.9%). ESI-MS (m / z): 443.4 [M+H] + .

[0350] Step three: synthesis of compound P-l l-c

[0351] Dissolve compound P-l l-b (90 mg, 203 μmol) in a mixture of methanol (1 mL) and dichloromethane (5 mL), add 4N hydrochloric acid dioxane solution (1 mL). Stir the mixture at room temperature for 2 hours. Concentrate the reaction to obtain compound P-l l-c (53 mg, yield 98.5%). ESI-MS (m / z): 229.4 [M+H] + .

[0352] Step four: synthesis of compound P-l l

[0353] Compound P-11-c (10 mg, 38 µmol) and compound P-1-f (12 mg, 38 µmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (24.4 mg, 189 µmol) was added. The mixture was stirred at 80 °C for 6 hours. After the reaction solution was cooled to room temperature, compound P-11 (3 mg, yield 16.7%) was obtained by purification through preparative liquid chromatography (alkali method). ESI-MS (m / z): 475.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.82-8.52 (m, 1H), 8.26-7.88 (m, 3H), 7.77-7.52 (m, 3H), 7.40-7.23 (m, 2H), 6.33-6.20 (m, 1H), 5.17-5.07 (m, 2H), 4.81-4.53 (m, 3H), 1.79-1.63 (m, 2H), 0.79-0.64 (m, 3H).

[0354] Example 1.12: Synthesis of compound P-12

[0355] Step one: Synthesis of compound P-12-a

[0356] Compound P-1-b (1.1 g, 3.36 mmol) was dissolved in a mixture of methanol (3 mL) and dichloromethane (15 mL), and 4N hydrochloric acid dioxane solution (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound P-12-a (884 mg, yield 100%). ESI-MS (m / z): 228.4 [M+H] + .

[0357] Step two: Synthesis of compound P-12

[0358] Compound P-12-a (200 mg, 758 µmol) and compound P-1-f (247 mg, 758 µmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (294 mg, 2.28 mmol) was added. The mixture was stirred at 80 °C for 6 hours. After the reaction solution was cooled to room temperature, compound P-12 (152 mg, yield 42.3%) was obtained by purification of the reaction solution through preparative liquid chromatography (alkali method). ESI-MS (m / z): 474.4 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 11.33 (s, 1H), 8.52 - 8.41 (m, 1H), 8.31 - 8.12 (m, 3H), 7.75 - 7.24 (m, 5H), 6.44 - 6.27 (m, 1H), 5.73 - 5.53 (m, 1H), 5.01 - 4.92 (m, 2H), 4.84 - 4.63 (m, 3H), 2.01 - 1.67 (m, 2H), 0.91 - 0.71 (m, 3H).

[0359] Example 1.13: Synthesis of compound P-13

[0360] Step one: Synthesis of compound P-13

[0361] Compound P-12-a (150 mg, 568 pmol) and N,N-diisopropyl ethylamine (220 mg, 1.71 mmol) were dissolved in N,N-dimethylformamide (5 mL), and compound P-10-b (169 mg, 568 pmol) was added. The mixture was stirred at 50 °C for 6 hours. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound P-13 (102 mg, yield 39%). ESI-MS (m / z): 461.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-de) d 11.25 (s, 1H), 8.39 (d, J = 4.7 Hz, 1H), 8.17 - 7.89 (m, 3H), 7.51 - 7.44 (m, 1H), 7.40 - 7.32 (m, 1H), 7.24 - 7.13 (m, 1H), 5.80 - 5.63 (m, 1H), 5.62 - 5.46 (m, 1H), 5.11 - 4.94 (m, 1H), 4.94 - 4.84 (m, 2H), 4.74 - 4.55 (m, 2H), 4.17 - 3.99 (m, 1H), 3.83 - 3.57 (m, 1H), 1.21 - 0.86 (m, 6H).

[0362] Example 1.14: Synthesis of compound P-14

[0363] Step one: Synthesis of compound P-14

[0364] Compound P-11-c (73 mg, 242 μmol) and N,N-diisopropylethylamine (94 mg, 726 μmol) were dissolved in N,N-dimethylformamide (5 mL), and compound P-10-b (80 mg, 242 μmol) was added. The mixture was stirred at 50 °C for 6 hours. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound P-14 (40 mg, yield 36%). ESI-MS (m / z): 462.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.79-8.75 (m, 1H), 8.22-8.18 (m, 1H), 8.16-7.93 (m, 2H), 7.71-7.62 (m, 1H), 7.56-7.53 (m, 1H), 7.33-7.25 (m, 1H), 6.14-6.05 (m, 1H), 5.78-5.65 (m, 1H), 5.16-5.10 (m, 2H), 5.07-4.94 (m, 1H), 4.73-4.57 (m, 2H), 4.16-3.99 (m, 1H), 3.77-3.60 (m, 1H), 1.08-0.88 (m, 6H).

[0365] Example 1.15: Synthesis of compound P-15

[0366] Step one: Synthesis of compound P-15-a

[0367] N-(tert-butoxycarbonyl)-O-methyl-D-threonine (620 mg, 2.66 mmol), ammonium chloride (284 mg, 5.32 mmol) and N,N-diisopropylethylamine (1.37 g, 10.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.52 g, 3.99 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 30 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 10 / 90) to obtain compound P-15-a (600 mg, yield 97%).

[0368] Step two: Synthesis of compound P-15-b

[0369] Compound P-15-a (600 mg, 2.58 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound P-15-b (630 mg, yield 99%).

[0370] Step three: synthesis of compound P-15-c

[0371] Compound P-15-b (630 mg, 2.57 mmol) and 4-chloro-2-(methylthio)-5- (trifluoromethyl)pyrimidine (470 mg, 2.06 mmol) were dissolved in N,N- dimethylformamide (10 mL), and N,N-diisopropylethylamine (1.33 g, 10.3 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 60 / 40) to obtain compound P-15-c (414 mg, yield 50%). ESI-MS (m / z): 325.5 [M+H] + .

[0372] Step four: synthesis of compound P-15-d

[0373] Compound P-15-c (320 mg, 986 μmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (340 mg, 1.97 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 30 mL of dichloromethane, washed with saturated sodium bicarbonate twice, water twice, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound P-15-d (340 mg). ESI-MS (m / z): 357.3 [M+H] + .

[0374] Step five: synthesis of compound P-15

[0375] Compound P-11-c (50 mg, 219 μmol) and N,N-diisopropylethylamine (142 mg, 1.10 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound P-15-d (82 mg, 230 μmol) was added. The mixture was stirred at 80 °C for 6 hours. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound P-15 (84 mg, yield 76%). ESI-MS (m / z): 505.4 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.81 - 8.75 (m, 1H), 8.25 - 7.96 (m, 3H), 7.75 - 7.62 (m, 1H), 7.58 - 7.53 (m, 1H), 7.45 - 7.26 (m, 3H), 6.19 - 5.91 (m, 2H), 5.19 - 5.07 (m, 2H), 4.82 - 4.60 (m, 3H), 3.96 - 3.75 (m, 1H), 3.20 - 3.10 (m, 3H), 1.11 - 0.91 (m, 3H).

[0376] Example 1.16: Synthesis of compound P-16

[0377] Step one: Synthesis of compound P-16

[0378] Compound P-12-a (30 mg, 100 μmol) and N,N-diisopropyl ethylamine (65 mg, 500 μmol) were dissolved in N,N-dimethylformamide (2 mL), and compound P-15-d (34 mg, 100 μmol) was added. The mixture was stirred at 80 °C for 6 hours. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound P-16 (15 mg, yield 30%). ESI-MS (m / z): 504.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.25 - 7.89 (m, 3H), 7.51 - 7.30 (m, 4H), 7.25 - 7.12 (m, 1H), 6.05 - 5.88 (m, 1H), 5.54 (t, J = 5.5 Hz, 1H), 4.88 (d, J = 5.4 Hz, 2H), 4.76 - 4.48 (m, 3H), 3.95 - 3.66 (m, 1H), 3.33 - 3.14 (m, 3H), 1.10 - 0.84 (m, 3H).

[0379] Example 1.17: Synthesis of compound P-17

[0380] Step one: Synthesis of compound P-17-a

[0381] Dissolve (6-bromopyridin-2-yl)methanol (200 mg, 1.06 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (425 mg, 1.28 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), add 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (78 mg, 106 µmol) and potassium carbonate (367 mg, 2.66 mmol). Stir the mixture at 100 °C for 16 hours. Cool the reaction to room temperature, add 30 mL of ethyl acetate, filter through celite, wash the filtrate with water three times, saturated brine once, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (PE / EA = 25 / 75) to give compound P-17-a (300 mg, yield 89.7%). ESI-MS (m / z): 315.5 [M+H] + .

[0382] Step two: synthesis of compound P-17-b

[0383] Dissolve compound P-17-a (300 mg, 954 µmol) in dichloromethane (5 mL), add 4N hydrochloric acid dioxane solution (2 mL). Stir the mixture at room temperature for 3 hours, concentrate to give compound P-17-b (200 mg, yield 97.8%). ESI-MS (m / z): 215.3 [M+H] + .

[0384] Step three: synthesis of compound P-17

[0385] Dissolve compound P-17-b (30 mg, 119 µmol) and N,N-diisopropylethylamine (75 mg, 598 µmol) in N,N-dimethylformamide (2 mL), add compound P-15-d (41 mg, 119 µmol). Stir the mixture at 80 °C for 6 hours. Cool the reaction to room temperature, add 20 mL of ethyl acetate, wash with water three times, saturated brine once, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography (DCM / MeOH = 95 / 5) to give compound P-17 (18 mg, yield 31%). ESI-MS (m / z): 491.4 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.18 - 7.97 (m, 4H), 7.86 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.46 - 7.33 (m, 5H), 6.00 - 5.90 (m, 1H), 5.49 - 5.42 (m, 1H), 4.68 - 4.46 (m, 5H), 3.94 - 3.79 (m, 1H), 3.33 - 3.20 (m, 3H), 1.10 - 0.96 (m, 3H).

[0386] Example 1.18: Synthesis of compound P-18

[0387] Step one: Synthesis of compound P-18-a

[0388] (2-Bromopyridin-4-yl)methanol (1 g, 5.32 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.13 g, 6.38 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (1 mL), 1,1 '-bis(diphenylphosphino) ferrocene palladium(II) dichloride (389 mg, 532 μmol) and potassium carbonate (1.84 g, 13.3 mmol) were added. The mixture was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, 30 mL of ethyl acetate was added, filtered through celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 25 / 75) to give compound P-18-a (1.5 g, yield 90%). ESI-MS (m / z): 315.5 [M+H] + .

[0389] Step two: Synthesis of compound P-18-b

[0390] Compound P-18-a (300 mg, 954 μmol) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 5 hours, concentrated to give compound P-18-b (200 mg, yield 97.8%). ESI-MS (m / z): 215.3 [M+H] + .

[0391] Step three: Synthesis of compound P-18

[0392] Compound P-18-b (175 mg, 490 μmol) and N,N-diisopropylethylamine (181 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound P-15-d (100 mg, 466 μmol) was added. The mixture was stirred at 50 °C for 6 h. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound P-18 (206 mg, yield 90%). ESI-MS (m / z): 491.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 5.0 Hz, 1H), 8.19 - 7.96 (m, 4H), 7.84 (s, 1H), 7.48 - 7.32 (m, 4H), 7.28 (d, J = 5.0 Hz, 1H), 5.96 (d, J = 7.9 Hz, 1H), 5.50 (s, 1H), 4.72 - 4.43 (m, 5H), 3.93 - 3.72 (m, 1H), 3.33 - 3.18 (m, 3H), 1.10 - 0.91 (m, 3H).

[0393] Example 1.19: Synthesis of compound P-19

[0394] Step one: Synthesis of compound P-19-a

[0395] Compound 2-chloro-6-(hydroxymethyl)pyridine-4-carbonitrile (182 mg, 1.08 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)carbamate (432 mg, 1.30 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), and 1,1'-bis (di-tert-butylphosphino) ferrocene palladium (II) dichloride (78 mg, 106 μmol) and cesium carbonate (1.06 g, 3.24 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction was cooled to room temperature, 30 mL of ethyl acetate was added, filtered through celite, the filtrate was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 60 / 40) to give compound P-19-a (238 mg, yield 65%). ESI-MS (m / z): 340.5 [M+H] + .

[0396] Step two: Synthesis of compound P-19-b

[0397] Compound P-19-a (30 mg, 88 µmol) was dissolved in dichloromethane (2 mL), 4N hydrochloric acid dioxane solution (1 mL) was added. The mixture was stirred at room temperature for 5 hours, concentrated to give compound P-19-b (25 mg, yield 100%). ESI-MS (m / z): 240.3 [M+H] + .

[0398] Step three: synthesis of compound P-19

[0399] Compound P-19-b (25 mg, 104 µmol) and N,N-diisopropylethylamine (32 mg, 250 µmol) were dissolved in N,N-dimethylformamide (2 mL), compound P-15-d (43 mg, 125 µmol) was added. The mixture was stirred at 80 °C for 6 hours. The reaction was cooled to room temperature, 20 mL ethyl acetate was added, washed with water for three times, saturated brine for one time, dried over anhydrous sodium sulfate, filtered, concentrated. The residue was purified by preparative liquid chromatography (alkali method) to give compound P-19 (12 mg, yield 19%). ESI-MS (m / z): 516.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.19-7.83 (m, 4H), 7.72 (s, 1H), 7.49-7.28 (m, 4H), 5.96 (d, J = 7.2 Hz, 1H), 5.69 (t, J = 5.8 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 4.67-4.46 (m, 3H), 3.94-3.75 (m, 1H), 3.27 (s, 3H), 1.08-0.94 (m, 3H).

[0400] Example 1.20: synthesis of compound P-20

[0401] Step one: synthesis of compound P-20-a

[0402] Dissolve compound P-20-a (154 mg, 503 μmol) in dichloromethane (5 mL), add m-chloroperoxybenzoic acid (152 mg, 881 μmol). Stir the mixture at room temperature for 2 hours. Add saturated sodium bicarbonate (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate to get the crude product compound P-20-b (190 mg). ESI-MS (m / z): 441.5 [M+H] + .

[0403] Step two: synthesis of compound P-20-b

[0404] Dissolve compound P-20-a (154 mg, 503 μmol) in dichloromethane (5 mL), add m-chloroperoxybenzoic acid (152 mg, 881 μmol). Stir the mixture at room temperature for 2 hours. Add saturated sodium bicarbonate (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate to get the crude product compound P-20-b (190 mg). ESI-MS (m / z): 441.5 [M+H] + .

[0405] Step three: synthesis of compound P-20-c

[0406] Dissolve compound P-12-a (50 mg, 220 μmol) and crude product compound P-20-b (97 mg) in N,N-dimethylformamide (3 mL), add N,N-diisopropyl ethylamine (85.3 mg, 660 μmol). Stir the mixture at room temperature overnight. Purify the reaction mixture by column chromatography (DCM / MeOH = 98 / 2) to get compound P-20-c (95 mg, yield 73.5%). ESI-MS (m / z): 588.4 [M+H] + .

[0407] Step four: synthesis of compound P-20

[0408] Compound P-20-c (95 mg, 161 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography (basic method) to give compound P-20 (35 mg, yield 44.4%). ESI-MS (m / z): 488.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.42 - 8.35 (m, 1H), 8.19 - 7.95 (m, 3H), 7.53 - 7.42 (m, 1H), 7.39 - 7.32 (m, 1H), 7.25 - 7.15 (m, 1H), 5.81 - 5.67 (m, 1H), 5.59 - 5.48 (m, 1H), 5.13 - 4.81 (m, 3H), 4.71 - 4.56 (m, 2H), 4.19 - 4.00 (m, 1H), 3.89 - 3.73 (m, 1H), 2.86 - 2.66 (m, 2H), 2.58 - 2.51 (m, 2H), 1.64 - 1.51 (m, 2H).

[0409] Example 1.21: Synthesis of compound P-21

[0410] Step one: Synthesis of compound P-21-a

[0411] Compound P-18-b (47 mg, 219 μmol) and compound P-20-b (97 mg, 219 μmol) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (85 mg, 658 μmol) was added. The mixture was stirred at room temperature overnight. The reaction was purified by column chromatography (DCM / MeOH = 98 / 2) to give compound P-21-a (118 mg, yield 93.6%). ESI-MS (m / z): 575.8 [M+H] + .

[0412] Step two: Synthesis of compound P-21

[0413] Compound P-21-a (118 mg, 205 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, the residue was purified by preparative liquid chromatography (basic method) to give compound P-21 (40 mg, yield 41.0%). ESI-MS (m / z): 475.7 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 8.59 - 8.53 (m, 1H), 8.15 - 8.06 (m, 1H), 8.05 - 7.88 (m, 3H), 7.86 - 7.81 (m, 1H), 7.48 - 7.36 (m, 2H), 7.29 - 7.25 (m, 1H), 5.79 - 5.64 (m, 1H), 5.54 - 5.44 (m, 1H), 5.17 - 4.98 (m, 1H), 4.62 - 4.58 (m, 2H), 4.57 - 4.40 (m, 2H), 4.16 - 4.02 (m, 1H), 3.87 - 3.76 (m, 1H), 2.83 - 2.67 (m, 2H), 2.58 - 2.51 (m, 2H), 1.67 - 1.53 (m, 2H).

[0414] Example 1.22: Synthesis of compound P-22

[0415] Step one: Synthesis of compound P-22-a

[0416] Compound P-l-b (1 g, 3.05 mmol) was dissolved in dichloromethane (30 mL), and Dess-Martin reagent (1.43 g, 3.36 mmol) was added under ice bath. The mixture was slowly warmed to room temperature and stirred at room temperature overnight. Saturated sodium bicarbonate (20 mL) was added to the reaction mixture, and dichloromethane was removed under reduced pressure. The residue was extracted with ethyl acetate (30 mL) for three times. The organic phase was combined, washed with water once, saturated brine once, dried, and concentrated to give the crude product compound P-22-a (1 g). ESI-MS (m / z): 326.8 [M+H] + .

[0417] Step two: Synthesis of compound P-22-b

[0418] The crude product compound P-22-a (1 g) was dissolved in 95% ethanol (20 mL), and sodium acetate (756 mg, 9.22 mmol) and hydroxylamine hydrochloride (320 mg, 4.61 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the residue was added to water (30 mL) and extracted with ethyl acetate (30 mL) for three times. The organic phase was combined, washed with water once, saturated brine once, dried, and concentrated to give the crude product compound P-22-b (1.05 g). ESI-MS (m / z): 341.7 [M+H] + .

[0419] Step three: Synthesis of compound P-22-c

[0420] The crude product compound P-22-b (1.05 g) was dissolved in pyridine (10 mL), trifluoroacetic anhydride (2.57 g, 12.2 mmol) was added slowly under ice bath. The mixture was slowly warmed to room temperature and stirred at room temperature for 4 hours. Methanol (5 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was added to water (30 mL) and extracted with ethyl acetate (30 mL) for three times. The organic phase was combined, washed with saturated citric acid solution once, saturated brine once, dried and concentrated. The residue was purified by flash column chromatography (PE / EA = 50 / 50) to give compound P-22-c (400 mg, yield 40.6%). ESI-MS (m / z): 323.7 [M+H] + .

[0421] Step four: synthesis of compound P-22-d

[0422] The crude product compound P-22-c (250 mg, 775 μmol) was dissolved in dichloromethane (5 mL), 4 M hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give compound P-22-d (229 mg, yield 100%). ESI-MS (m / z): 223.5 [M+H] + .

[0423] Step five: synthesis of compound P-22

[0424] Compound P-22-d (17 mg, 67 μmol) and N,N-diisopropylethylamine (43 mg, 336 mmol) were dissolved in N,N-dimethylformamide (2 mL), compound P-10-b (20 mg, 67 μmol) was added. The mixture was stirred at 50 °C for 6 hours. The reaction mixture was cooled to room temperature, 20 mL ethyl acetate was added, washed with water for three times, saturated brine once, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography (basic method) to give compound P-22 (10 mg, yield 33%). ESI-MS (m / z): 456.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.62 - 12.17 (m, 1H), 8.60 - 8.53 (m, 1H), 8.20 - 7.95 (m, 3H), 7.82 - 7.47 (m, 2H), 7.35 - 7.27 (m, 1H), 5.79 - 5.65 (m, 1H), 5.12 - 4.93 (m, 1H), 4.80 - 4.55 (m, 2H), 4.19 - 3.92 (m, 1H), 3.83 - 3.57 (m, 1H), 1.16 - 0.85 (m, 6H).

[0425] Example 1.23: Synthesis of compound P-23

[0426] Step one: Synthesis of compound P-23-a

[0427] Compound P-22-d (28 mg, 112 μmol) and compound P-20-b (50 mg, 112 μmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (44 mg, 337 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was purified by column chromatography (PE / EA = 30 / 70) to give compound P-23-a (42 mg, yield 64%). ESI-MS (m / z): 583.4 [M+H] + .

[0428] Step two: Synthesis of compound P-23

[0429] Compound P-23-a (42 mg, 72 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkali method) to give compound P-23 (11 mg, yield 32%). ESI-MS (m / z): 483.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.25 - 7.95 (m, 3H), 7.79 (d, J = 5.0 Hz, 1H), 7.63 - 7.46 (m, 1H), 7.40 - 7.26 (m, 1H), 5.82 - 5.68 (m, 1H), 5.15 - 4.90 (m, 1H), 4.75 - 4.56 (m, 2H), 4.23 - 3.93 (m, 1H), 3.86 - 3.72 (m, 1H), 2.88 - 2.52 (m, 4H), 1.65 - 1.49 (m, 2H).

[0430] Example 1.24: Synthesis of compound P-24

[0431] Step one: Synthesis of compound P-24-a

[0432] 4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (1 g, 4.37 mmol) and (2R,3R)-2,3-butanediol (473 mg, 5.25 mmol) were dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (589 mg, 5.25 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added, and the mixture was washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 90 / 10) to give compound P-24-a (400 mg, yield 32.4%). ESI-MS (m / z): 283.1 [M+H] + .

[0433] Step 2: Synthesis of compound P-24-b

[0434] Compound P-24-a (400 mg, 1.42 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (318 mg, 1.84 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE / EA = 70 / 30) to give compound P-24-b (250 mg, yield 56.1%). ESI-MS (m / z): 315.3 [M+H] + .

[0435] Step 3: Synthesis of compound P-24-c

[0436] Compound P-1-d (115 mg, 455 μmol) and N,N-diisopropylethylamine (177 mg, 1.37 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound P-24-b (136 mg, 455 μmol) was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate was added, and the mixture was washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound P-24-c (68 mg, yield 31%). ESI-MS (m / z): 487.5 [M+H] + .

[0437] Step 4: Synthesis of compound P-24

[0438] Compound P-24-c (68 mg, 139 μmol) was dissolved in tetrahydrofuran (5 mL), triphenylphosphine (110 mg, 419 μmol) and water (30 μL) were added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography (basic method) to give compound P-24 (20 mg, yield 31%). ESI-MS (m / z): 461.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.66 - 8.41 (m, 1H), 8.39 - 8.30 (m, 2H), 8.10 - 8.05 (m, 1H), 7.49 - 7.44 (m, 1H), 7.42 - 7.37 (m, 1H), 7.23 - 7.17 (m, 1H), 5.30 - 5.13 (m, 1H), 4.86 - 4.60 (m, 3H), 4.06 (s, 2H), 3.86 - 3.68 (m, 1H), 1.09 - 1.06 (m, 3H), 1.00 - 0.93 (m, 3H).

[0439] Example 1.25: Synthesis of compound P-25

[0440] Step one: Synthesis of compound P-25

[0441] N-(tert-butoxycarbonyl)glycine (3.6 mg, 21 μmol) and N-hydroxysuccinimide (2.9 mg, 25 μmol) were dissolved in dichloromethane (2 mL), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (6 mg, 31 μmol) was added. The mixture was stirred at room temperature for 0.5 hours, compound P-23 (10 mg, 21 μmol) and N,N- diisopropylethylamine (6 mg, 50 μmol) were added, the mixture was continued to stir at room temperature for 2 hours. Water (5 mL) was added to the reaction, dichloromethane (10 mL) was extracted three times, the organic phase was combined and concentrated. The residue was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, the mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography (basic method) to give compound P-25 (3 mg, yield 23%). ESI-MS (m / z): 540.4 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 8.53 - 8.45 (m, 1H), 8.25 - 7.98 (m, 3H), 7.75 - 7.68 (m, 1H), 7.53 - 7.43 (m, 1H), 7.29 - 7.20 (m, 1H), 5.72 - 5.57 (m, 1H), 5.45 - 5.27 (m, 1H), 4.82 - 4.04 (m, 3H), 3.96 - 3.37 (m, 5H), 3.12 - 2.69 (m, 2H), 1.63 - 1.44 (m, 2H).

[0442] Example 1.26: Synthesis of compound P-26

[0443] Step one: Synthesis of compound P-26

[0444] Compound P-23 (450 mg, 867 pmol) was dissolved in dichloromethane (10 mL) and methanol (3 mL), and aqueous formaldehyde (34% aqueous solution, 213 pL) and glacial acetic acid (52 mg, 867 pmol) were added. The mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (919 mg, 4.34 mmol) was added, after which it was stirred at room temperature overnight. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, which was extracted three times with ethyl acetate (30 mL), and the organic phases were combined and concentrated. The residue was purified by preparative liquid chromatography (basic method) to give compound P-26 (200 mg, yield 46.5%). ESI-MS (m / z): 497.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-de) d 12.40 (s, 1H), 8.63 - 8.54 (m, 1H), 8.27 - 8.07 (m, 3H), 7.85 - 7.77 (m, 1H), 7.55 (s, 1H), 7.39 - 7.27 (m, 1H), 5.81 - 5.67 (m, 1H), 5.16 - 4.55 (m, 3H), 4.32 - 4.07 (m, 1H), 3.84 - 3.63 (m, 1H), 3.29 - 3.18 (m, 2H), 2.36 - 1.87 (m, 5H), 1.74 - 1.41 (m, 2H).

[0445] Example 1.27: Synthesis of compound P-27

[0446] Step one: Synthesis of compound P-27

[0447] Compound P-20 (20 mg, 41 μmol) and 2-hydroxyacetic acid (3 mg, 41 μmol) were dissolved in N,N-dimethylformamide (2 mL), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (17 mg, 45 μmol) and triethylamine (8.4 mg, 82 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added with water (0.1 mL) and directly purified by preparative liquid chromatography to obtain compound P-27 (6.5 mg, yield 29%). ESI-MS (m / z): 546.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.26 - 11.16 (m, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.25 - 7.98 (m, 3H), 7.53 - 7.42 (m, 1H), 7.35 (d, J = 4.7 Hz, 1H), 7.23 - 7.14 (m, 1H), 5.76 - 5.64 (m, 1H), 5.59 - 5.41 (m, 2H), 4.88 (d, J = 5.4 Hz, 2H), 4.80 - 4.59 (m, 2H), 4.53 - 4.37 (m, 1H), 4.32 - 4.02 (m, 2H), 4.02 - 3.54 (m, 3H), 3.48 - 3.38 (m, 1H), 3.26 - 3.07 (m, 2H), 1.72 - 1.51 (m, 2H).

[0448] Example 1.28: Synthesis of compound P-28

[0449] Step one: Synthesis of compound P-28-a

[0450] Compound P-1-d (500 mg, 2.2 mmol) and crude product compound P-20-b (1 g) were dissolved in N,N-dimethylformamide (20 mL), N,N-diisopropylethylamine (850 mg, 6.6 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was purified by column chromatography (DCM / MeOH = 98 / 2) to obtain compound P-28-a (750 mg, yield 56%). ESI-MS (m / z): 613.6 [M+H] + .

[0451] Step two: Synthesis of compound P-28-b

[0452] Compound P-28-a (300 mg, 489 µmol) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 5 hours, concentrated to give compound P-29-a (280 mg, yield 100%). ESI-MS (m / z): 513.5 [M+H] + .

[0453] Step three: synthesis of compound P-28

[0454] Compound P-28-b (18 mg, 30 µmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography (alkali method) to give compound P-28 (10 mg, yield 67%). ESI-MS (m / z): 487.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.41-8.37 (m, 1H), 8.27-8.25 (m, 1H), 8.21-8.05 (m, 3H), 7.53-7.43 (m, 1H), 7.40-7.38 (m, 1H), 7.26-7.15 (m, 1H), 5.80-5.72 (m, 1H), 5.32-5.04 (m, 1H), 4.74-4.57 (m, 2H), 4.18-4.08 (m, 3H), 3.80-3.77 (m, 1H), 2.89-2.57 (m, 4H), 1.70-1.55 (m, 2H).

[0455] Example 1.29: synthesis of compound P-29

[0456] Step one: synthesis of compound P-29-a

[0457] Compound P-28-a (300 mg, 489 µmol) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 5 hours, concentrated to give compound P-29-a (280 mg, yield 100%). ESI-MS (m / z): 513.5 [M+H] + .

[0458] Step two: synthesis of compound P-29-b

[0459] Compound P-29-a (280 mg, 489 pmol) was dissolved in a mixture of dichloromethane (3 mL) and methanol (3 mL), 37% aqueous formaldehyde solution (0.5 mL) was added, sodium triacetoxyborohydride (208 mg, 979 pmol) was added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, and extraction was performed three times with ethyl acetate (10 mL). The organic phase was combined, washed once with water and once with saturated brine, dried, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 70 / 30) to obtain compound P-29-b (217 mg, yield 84%). ESI-MS (m / z): 527.4 [M+H] + .

[0460] Step three: synthesis of compound P-29

[0461] Compound P-29-b (100 mg, 163 pmol) was dissolved in tetrahydrofuran (5 mL), triphenylphosphine (90 mg, 326 pmol) and water (50 pL) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkaline method) to obtain compound P-29 (40 mg, yield 34%). ESI-MS (m / z): 501.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.41 (s, 1H), 8.40-8.33 (m, 1H), 8.22-8.00 (m, 3H), 7.50-7.42 (m, 1H), 7.42-7.34 (m, 1H), 7.22-7.15 (m, 1H), 5.75-5.68 (m, 1H), 5.21-5.02 (m, 1H), 4.79-4.63 (m, 2H), 4.58-4.48 (m, 1H), 4.09-4.03 (m, 2H), 3.70-3.67 (m, 1H), 2.66-2.56 (m, 2H), 2.39-1.88 (m, 7H), 1.72-1.53 (m, 2H).

[0462] Example 1.30: synthesis of compound P-30

[0463] Step one: synthesis of compound P-30-a

[0464] Compound P-23 (25 mg, 52 μmol) was dissolved in dichloroethane (3 mL), and 3-(tert-butyldimethylsilyloxy)propanal (10 mg, 52 μmol) was added. The mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (92 mg, 434 μmol) was added, followed by stirring at room temperature overnight. The reaction solution was added with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (30 mL) for three times. The organic phase was combined and concentrated. The residue was purified by column chromatography (DCM / MeOH = 98 / 2) to give compound P-30-a (30 mg, yield 95%). ESI-MS (m / z): 655.5 [M+H] + .

[0465] Step two: synthesis of compound P-30

[0466] Compound P-30-a (30 mg, 45 μmol) was dissolved in tetrahydrofuran (2 mL), and 1M tetrabutylammonium fluoride tetrahydrofuran solution (150 μL) was added. The mixture was stirred at room temperature for 30 min. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (base method) to give compound P-30 (15 mg, yield 60%). ESI-MS (m / z): 541.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.28 - 8.07 (m, 3H), 7.80 (d, J = 5.0 Hz, 1H), 7.59 - 7.48 (m, 1H), 7.36 - 7.26 (m, 1H), 5.81 - 5.70 (m, 1H), 5.22 - 4.96 (m, 1H), 4.80 - 4.52 (m, 2H), 4.51 - 4.05 (m, 2H), 3.84 - 3.65 (m, 1H), 3.24 - 3.12 (m, 2H), 2.42 - 1.95 (m, 5H), 1.75 - 1.51 (m, 3H), 1.37 - 1.26 (m, 2H).

[0467] Example 1.31: synthesis of compound P-31

[0468] Step one: synthesis of compound P-31-a

[0469] Compound P-11-c (25 mg, 109 μmol) and compound P-20-b (48 mg, 109 μmol) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (44 mg, 337 μmol) was added. The mixture was stirred at room temperature overnight. The reaction was purified by column chromatography (PE / EA = 30 / 70) to give compound P-31-a (55 mg, yield 85%). ESI-MS (m / z): 589.5 [M+H] + .

[0470] Step two: synthesis of compound P-31

[0471] Compound P-31-a (55 mg, 93 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography (base method) to give compound P-31 (22 mg, yield 48%). ESI-MS (m / z): 489.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.79-8.72 (m, 1H), 8.22-7.96 (m, 3H), 7.76-7.61 (m, 1H), 7.56-7.53 (m, 1H), 7.34-7.24 (m, 1H), 6.19-5.96 (m, 1H), 5.80-5.67 (m, 1H), 5.15-4.98 (m, 3H), 4.73-4.55 (m, 2H), 4.20-3.98 (m, 1H), 3.89-3.71 (m, 1H), 2.86-2.52 (m, 4H), 2.49-2.45 (m, 1H), 1.63-1.50 (m, 2H).

[0472] Example 1.32: synthesis of compound P-32

[0473] Step one: synthesis of compound P-32

[0474] Compound P-20 (15 mg, 31 μmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL), aqueous formaldehyde (34% aqueous solution, 50 μL) was added. The mixture was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (33 mg, 153 μmol) was added, then stirred at room temperature overnight. Saturated sodium bicarbonate (10 mL) was added to the reaction, extracted with ethyl acetate (30 mL) three times, the organic phase was combined and concentrated. The residue was purified by preparative liquid chromatography (base method) to give compound P-32 (9 mg, yield 58%). ESI-MS (m / z): 502.5 [M+H]+ ; 1 H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.43-8.35 (m, 1H), 8.28-8.01 (m, 3H), 7.49-7.41 (m, 1H), 7.40-7.33 (m, 1H), 7.23-7.12 (m, 1H), 5.75-5.68 (m, 1H), 5.61-5.53 (m, 1H), 5.31-4.99 (m, 2H), 4.94-4.84 (m, 2H), 4.78-4.64 (m, 1H), 4.32-4.10 (m, 1H), 3.84-3.66 (m, 1H), 2.49-1.78 (m, 7H), 1.75-1.50 (m, 2H).

[0475] Example 1.33: Synthesis of compound P-33

[0476] Step one: Synthesis of compound P-33-a

[0477] Dissolve 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 mg, 437 µmol) in N,N-dimethylformamide (3 mL), add ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester (95 mg, 437 µmol) and N,N-diisopropylethylamine (170 mg, 1.31 mmol). Stir the mixture at room temperature overnight. Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate. Purify the residue by column chromatography (PE / EA = 60 / 40) to give compound P-33-a (170 mg, yield 95%). ESI-MS (m / z): 409.4 [M+H] + .

[0478] Step two: Synthesis of compound P-33-b

[0479] Dissolve compound P-33-a (55 mg, 135 µmol) in dichloromethane (3 mL), add meta-chloroperoxybenzoic acid (46 mg, 269 µmol). Stir the mixture at room temperature for 2 hours. Add saturated sodium bicarbonate (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate to give the crude product compound P-33-b (58 mg). ESI-MS (m / z): 441.5 [M+H] + .

[0480] Step three: Synthesis of compound P-33-c

[0481] Compound P-12-a (30 mg, 132 µmol) and crude compound P-33-b (58 mg) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (51 mg, 396 µmol) was added. The mixture was stirred at room temperature overnight. The reaction was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound P-33-c (59 mg, yield 76%). ESI-MS (m / z): 588.4 [M+H] + .

[0482] Step four: synthesis of compound P-33

[0483] Compound P-33-c (59 mg, 100 µmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, and the residue was purified by preparative liquid chromatography (base method) to give compound P-33 (25 mg, yield 51%). ESI-MS (m / z): 488.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.29-11.20 (m, 1H), 8.41-8.35 (m, 1H), 8.22-7.93 (m, 3H), 7.47-7.40 (m, 1H), 7.38-7.31 (m, 1H), 7.20-7.14 (m, 1H), 6.42-6.25 (m, 1H), 5.60-5.49 (m, 1H), 4.91-4.81 (m, 2H), 4.71-4.51 (m, 2H), 4.22-3.89 (m, 1H), 3.86-3.62 (m, 1H), 3.58-3.48 (m, 1H), 3.48-3.42 (m, 1H), 3.21-3.14 (m, 1H), 2.65-2.57 (m, 1H), 2.18-1.99 (m, 1H), 1.88-1.55 (m, 1H), 1.37-0.94 (m, 2H).

[0484] Example 1.34: synthesis of compound P-34

[0485] Step one: synthesis of compound P-34-a

[0486] Dissolve 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (127 mg, 554 pmol) in N,N-dimethylformamide (3 mL), add (3S,4R)-tert-butyl 4-amino-3- hydroxypiperidine-1-carboxylate (100 mg, 462 pmol) and N,N-diisopropylethylamine (178 mg, 1.38 mmol). Stir the mixture at 50 °C overnight. Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate. Purify the residue by column chromatography (PE / EA = 70 / 30) to give compound P-34-a (180 mg, yield 95%). ESI-MS (m / z): 409.3 [M+H] + .

[0487] Step two: synthesis of compound P-34-b

[0488] Dissolve compound P-34-a (90 mg, 220 pmol) in dichloromethane (5 mL), add m-chloroperoxybenzoic acid (76 mg, 440 pmol). Stir the mixture at room temperature for 2 hours. Add saturated sodium bicarbonate (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate to give crude compound P-34-b (90 mg). ESI-MS (m / z): 441.5 [M+H] + .

[0489] Step three: synthesis of compound P-34-c

[0490] Dissolve compound P-22-d (36 mg, 110 pmol) and crude compound P-34-b (40 mg) in N,N-dimethylformamide (3 mL), add N,N-diisopropylethylamine (43 mg, 330 pmol). Stir the mixture at room temperature overnight. Purify the reaction mixture by column chromatography (DCM / MeOH = 96 / 4) to give compound P-34-c (59 mg, yield 92%). ESI-MS (m / z): 583.4 [M+H] + .

[0491] Step four: synthesis of compound P-34

[0492] Dissolve compound P-34-c (20 mg, 34 pmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL). Stir the mixture at room temperature for 2 hours. Concentrate the reaction mixture, purify the residue by preparative liquid chromatography (base method) to give compound P-34 (12 mg, yield 72%). ESI-MS (m / z): 483.5 [M+H]+ ; 1 H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.52-8.41 (m, 1H), 8.25-7.90 (m, 3H), 7.74-7.69 (m, 1H), 7.51-7.40 (m, 1H), 7.27-7.16 (m, 1H), 5.71-5.54 (m, 1H), 5.24-5.04 (m, 1H), 4.70-4.49 (m, 2H), 4.14-3.81 (m, 1H), 3.68-3.39 (m, 1H), 2.94-2.51 (m, 3H), 2.37-2.27 (m, 1H), 1.76-1.46 (m, 1H), 1.39-1.09 (m, 2H).

[0493] Example 1.35: Synthesis of compound P-35

[0494] Step one: Synthesis of compound P-35-a

[0495] To a mixture of 2-chloro-4-methyl-3-nitropyridine (1.92 g, 11.1 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)carbamate (4.08 g, 12.2 mmol) in 1,4-dioxane (30 mL) and water (5 mL) was added l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (39 mg, 61 μmol) and cesium carbonate (7.98 g, 24.5 mmol). The mixture was stirred at 100 °C for 16 h. The reaction was cooled to room temperature, ethyl acetate was added, filtered through celite, the filtrate was washed with water for three times, saturated brine for once, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 50 / 50) to give compound P-35-a (3.68 g, yield 88%). ESI-MS (m / z): 344.5 [M+H] + .

[0496] Step two: Synthesis of compound P-35-b

[0497] Compound P-35-a (1 g, 2.9 mmol) and 1,2,2,3,4,4-hexamethylphosphorane-1-oxide (174 mg, 1 mmol) were dissolved in n-butyl acetate (20 mL), and phenylsilane (940 mg, 8.7 mmol) was added. The mixture was reacted at 110 °C for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound P-35-b (453 mg, yield 50%). ESI-MS (m / z): 312.3 [M+H] + .

[0498] Step three: synthesis of compound P-35-c

[0499] Compound P-35-b (38 mg, 122 μmol) was dissolved in dichloromethane (2 mL), and 4N hydrochloric acid dioxane solution (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound P-35-c (25 mg, yield 99%). ESI-MS (m / z): 212.4 [M+H] + .

[0500] Step four: synthesis of compound P-35-d

[0501] Compound P-35-c (24 mg, 112 μmol) and compound P-20-b (50 mg, 112 μmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (44 mg, 337 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was purified by column chromatography (PE / EA = 20 / 80) to obtain compound P-35-d (50 mg, yield 78%). ESI-MS (m / z): 572.4 [M+H] + .

[0502] Step five: synthesis of compound P-35

[0503] Compound P-35-d (50 mg, 87 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkali method) to obtain compound P-35 (12 mg, yield 29%). ESI-MS (m / z): 472.7 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.48 - 11.28 (m, 1H), 8.35 - 8.26 (m, 1H), 8.25 - 7.92 (m, 3H), 7.53 - 7.42 (m, 1H), 7.28 - 7.15 (m, 2H), 5.86 - 5.75 (m, 1H), 5.32 - 5.14 (m, 1H), 4.75 - 4.60 (m, 2H), 4.24 - 4.15 (m, 1H), 3.91 - 3.80 (m, 1H), 2.93 - 2.66 (m, 4H), 2.57 (s, 3H), 2.54 - 2.53 (m, 1H), 1.75 - 1.58 (m, 2H).

[0504] Example 1.36: Synthesis of compound P-36

[0505] Step one: Synthesis of compound P-36-a

[0506] Dissolve 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (115 mg, 503 µmol) in N,N-dimethylformamide (3 mL), add (3R,4S)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (102 mg, 503 µmol) and N,N-diisopropylethylamine (195 mg, 1.51 mmol). Stir the mixture at 50 °C overnight. Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate. Purify the residue by column chromatography (PE / EA = 70 / 30) to give compound P-36-a (190 mg, yield 96%). ESI-MS (m / z): 394.3 [M+H] + .

[0507] Step two: Synthesis of compound P-36-b

[0508] Dissolve compound P-36-a (190 mg, 482 µmol) in dichloromethane (5 mL), add meta-chloroperoxybenzoic acid (166 mg, 963 µmol). Stir the mixture at room temperature for 2 hours. Add saturated sodium bicarbonate (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL) for three times. Combine the organic phase, wash with water once, saturated brine once, dry and concentrate to give the crude product compound P-36-b (205 mg). ESI-MS (m / z): 427.5 [M+H] + .

[0509] Step three: Synthesis of compound P-36-c

[0510] Compound P-22-d (13 mg, 58 μmol) and crude compound P-36-b (25 mg) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (23 mg, 157 μmol) was added. The mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate three times. The organic phase was combined, washed with water once, saturated brine once, dried, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 96 / 4) to give compound P-36-c (24 mg, yield 72%). ESI-MS (m / z): 569.4 [M+H] + .

[0511] Step four: synthesis of compound P-36

[0512] Compound P-36-c (24 mg, 42 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkaline method) to give compound P-36 (9 mg, yield 46%). ESI-MS (m / z): 469.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.61-8.53 (m, 1H), 8.23-7.97 (m, 3H), 7.83-7.76 (m, 1H), 7.59-7.52 (m, 1H), 7.36-7.28 (m, 1H), 7.26-7.20 (m, 1H), 6.22-5.96 (m, 1H), 5.79-5.43 (m, 1H), 4.76-4.64 (m, 2H), 4.47-4.00 (m, 2H), 3.11-3.00 (m, 2H), 2.70-2.57 (m, 1H), 2.42-2.27 (m, 1H).

[0513] Example 1.37: synthesis of compound P-37

[0514] Step one: synthesis of compound P-37-a

[0515] Compound P-23 (80 mg, 165 μmol) was dissolved in dichloroethane (3 mL), and tert-butyl methyl(2-oxoethyl)carbamate (29 mg, 165 μmol) was added. The mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (176 mg, 829 μmol) was added, followed by stirring at room temperature overnight. The reaction was added with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (30 mL) for three times. The organic phase was combined and concentrated. The residue was purified by column chromatography (DCM / MeOH = 90 / 10) to give compound P-37-a (100 mg, yield 94%). ESI-MS (m / z): 640.5 [M+H] + .

[0516] Step two: synthesis of compound P-37

[0517] Compound P-37-a (100 mg, 156 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was concentrated, and the residue was purified by preparative liquid chromatography (base method) to give compound P-37 (20 mg, yield 24%). ESI-MS (m / z): 540.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.59 - 8.50 (m, 1H), 8.36 - 8.01 (m, 3H), 7.81 - 7.74 (m, 1H), 7.67 - 7.51 (m, 1H), 7.41 - 7.26 (m, 1H), 5.80 - 5.71 (m, 1H), 5.28 - 5.03 (m, 1H), 4.84 - 4.42 (m, 2H), 4.33 - 4.11 (m, 1H), 3.78 - 3.68 (m, 1H), 2.78 - 2.53 (m, 4H), 2.47 - 2.05 (m, 8H), 1.72 - 1.56 (m, 2H).

[0518] Example 1.38: synthesis of compound P-38

[0519] Step one: synthesis of compound P-38-a

[0520] 4-Cyclopropyl-1H-pyrazole-5-amine (3.58 g, 29 mmol) was dissolved in dichloromethane (15 mL), and ethyl isothiocyanate (3.85 g, 29.4 mmol) was slowly added under ice bath conditions. The mixture was stirred at room temperature for 1 hour, and the reaction solution was filtered. The resulting solid was dissolved in acetonitrile (30 mL), and potassium carbonate (6.03 g, 43.6 mmol) was added. The mixture was stirred at 60 °C for 3 hours. The reaction solution was cooled to room temperature, water (60 mL) was added, the pH was adjusted to 5 with dilute hydrochloric acid, and the mixture was stirred for 15 minutes. The mixture was filtered, the solid was washed three times with water, and dried under vacuum to give compound P-38-a (2.4 g, 40% yield). ESI-MS (m / z): 209.3 [M+H] + .

[0521] Step 2: Synthesis of compound P-38-b

[0522] Compound P-38-a (2.4 g, 11.5 mmol) was dissolved in ethanol (25 mL), and 2M sodium hydroxide solution (11.5 mL) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 10 minutes, and iodomethane (1.72 g, 12.1 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated to remove ethanol, and the remaining solution was slowly added to a mixture of 2N dilute hydrochloric acid and crushed ice. The mixture was stirred for 10 minutes, filtered, and the solid was washed three times with water and dried under vacuum to give compound P-38-b (2.45 g, 96% yield). ESI-MS (m / z): 223.3 [M+H] + .

[0523] Step 3: Synthesis of compound P-38-c

[0524] Compound P-38-b (1.45 g, 6.52 mmol) was dissolved in phosphorus oxychloride (30 mL), and N,N-diisopropylethylamine (2.53 g, 19.5 mmol) was added. The mixture was stirred at 90 °C for 4 hours. The reaction solution was cooled to room temperature, concentrated to remove most of the phosphorus oxychloride, and the residue was slowly added to ice water. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed once with water and once with brine, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 85 / 15) to give compound P-38-c (1 g, 64% yield). ESI-MS (m / z): 241.5 [M+H] + .

[0525] Step 4: Synthesis of compound P-38-d

[0526] To a solution of compound P-38-d (3 g, 9.96 mmol) in glacial acetic acid (30 mL) was added 4 N hydrochloric acid in dioxane (5 mL). The mixture was stirred at 70 °C for 2 h. The reaction was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution once, water once, and brine once, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 35 / 65) to give compound P-38-e (2.2 g, 78% yield). ESI-MS (m / z): 284.5 [M+H] + .

[0527] Step five: synthesis of compound P-38-e

[0528] To a solution of compound P-38-d (3 g, 9.96 mmol) in glacial acetic acid (30 mL) was added 4 N hydrochloric acid in dioxane (5 mL). The mixture was stirred at 70 °C for 2 h. The reaction was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution once, water once, and brine once, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 35 / 65) to give compound P-38-e (2.2 g, 78% yield). ESI-MS (m / z): 284.5 [M+H] + .

[0529] Step six: synthesis of compound P-38-f

[0530] To a solution of compound P-38-e (2.2 g, 7.77 mmol) in dichloromethane (15 mL) was added 4 N hydrochloric acid in dioxane (5 mL). The mixture was stirred at room temperature for 2 h. The reaction was concentrated to give compound P-38-f (1.42 g, 100% yield). ESI-MS (m / z): 184.3 [M+H] + .

[0531] Step seven: synthesis of compound P-38-g

[0532] Compound P-38-f (213 mg, 830 μmol) and compound P-38-c (200 mg, 830 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl ethylamine (537 mg, 4.15 mmol) was added. The mixture was stirred at 70 °C for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, washed with water three times, washed with brine once, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 10 / 90) to obtain compound P-38-g (320 mg, yield 99%). ESI-MS (m / z): 388.5 [M+H] + .

[0533] Step eight: synthesis of compound P-38-h

[0534] Compound P-38-g (320 mg, 825 μmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (286 mg, 1.66 mmol) was added. The mixture was stirred at room temperature for 2 hours. 20 mL of dichloromethane was added to the reaction solution, washed with saturated sodium bicarbonate twice, washed with water twice, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound P-38-h (300 mg). ESI-MS (m / z): 420.5 [M+H] + .

[0535] Step nine: synthesis of compound P-38-i

[0536] Compound P-38-h (300 mg) and piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl ethylamine (537 mg, 4.15 mmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, washed with water three times, washed with brine once, dried, and concentrated to obtain the crude product compound P-38-i (375 mg). ESI-MS (m / z): 526.5 [M+H] + .

[0537] Step ten: synthesis of compound P-38

[0538] The crude product compound P-38-i (375 mg) was dissolved in dichloromethane (8 mL), and 4N hydrochloric acid dioxane solution (3 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkali method) to obtain compound P-38 (200 mg, yield 66%). ESI-MS (m / z): 426.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.48 - 8.08 (m, 1H), 7.68 (s, 1H), 7.26 - 7.20 (m, 1H), 7.20 - 7.13 (m, 1H), 4.82 (s, 2H), 3.62 - 3.46 (m, 4H), 3.25 - 3.21 (m, 1H), 2.59 - 2.51 (m, 4H), 1.80 - 1.69 (m, 1H), 0.83 - 0.67 (m, 4H).

[0539] Example 1.39: Synthesis of compound P-39

[0540] Step one: Synthesis of compound P-39-a

[0541] Compound P-39-a (2 g, 10.4 mmol) was dissolved in phosphorus oxychloride (20 mL). The mixture was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, most of the phosphorus oxychloride was removed by concentration, the residue was slowly added to ice water, extracted with ethyl acetate for three times, the organic phase was combined, washed with water once, brine once, dried, concentrated. The residue was purified by column chromatography (PE / EA = 85 / 15) to give compound P-39-b (674 mg, yield 28%). ESI-MS (m / z): 229.6 [M+H] + .

[0542] Step two: Synthesis of compound P-39-b

[0543] Compound P-39-a (2 g, 10.4 mmol) was dissolved in phosphorus oxychloride (20 mL). The mixture was stirred at 100 °C for 16 hours. The reaction was cooled to room temperature, most of the phosphorus oxychloride was removed by concentration, the residue was slowly added to ice water, extracted with ethyl acetate for three times, the organic phase was combined, washed with water once, brine once, dried, concentrated. The residue was purified by column chromatography (PE / EA = 85 / 15) to give compound P-39-b (674 mg, yield 28%). ESI-MS (m / z): 229.6 [M+H] + .

[0544] Step three: Synthesis of compound P-39-c

[0545] Compound P-39-b (150 mg, 658 pmol) and (4-(pyridin-2-yl)phenyl)methanamine (133 mg, 723 pmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl ethylamine (255 mg, 1.97 mmol) was added. The mixture was stirred at 90 °C for 2 hours. The reaction was cooled to room temperature, ethyl acetate was added, washed with water three times, washed with brine once, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 30 / 70) to give compound P-39-c (200 mg, yield 80%). ESI-MS (m / z): 376.5 [M+H] + .

[0546] Step four: synthesis of compound P-39-d

[0547] Compound P-39-c (347 mg, 923 pmol) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyl dicarbonate (202 mg, 923 mmol) and 4-dimethylaminopyridine (11.29 mg, 92 pmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction was added with ethyl acetate, washed with water three times, washed with brine once, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 50 / 50) to give compound P-39-d (191 mg, yield 43%). ESI-MS (m / z): 476.5 [M+H] + .

[0548] Step five: synthesis of compound P-39-e

[0549] Compound P-39-d (151 mg, 317 pmol) and (S)-1-tert-butoxycarbonyl-3- aminopyrrolidine (295 mg, 1.59 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl ethylamine (123 mg, 951 pmol) was added. The mixture was stirred at 120 °C for 4 hours. The reaction was cooled to room temperature, ethyl acetate was added, washed with water three times, washed with brine once, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 30 / 70) to give compound P-39-e (65 mg, yield 33%). ESI-MS (m / z): 626.5 [M+H] + .

[0550] Step six: synthesis of compound P-39

[0551] Compound P-39-e (60 mg, 95 m mol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by preparative liquid chromatography (basic method) to give compound P-39 (33 mg, yield 81%). ESI-MS (m / z): 526.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 8.65 (d, J = 4.7 Hz, 1H), 8.05 (d, J = 8.1 Hz, 2H), 8.00 - 7.91 (m, 2H), 7.90 - 7.84 (m, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.37 - 7.30 (m, 1H), 6.81 (d, J = 5.9 Hz, 1H), 5.08 (s, 1H), 4.51 (d, J = 6.4 Hz, 2H), 4.29 - 4.22 (m, 1H), 3.19 - 3.16 (m, 1H), 3.04 - 2.99 (m, 1H), 2.97 - 2.91 (m, 1H), 2.79 - 2.74 (m, 1H), 2.08 - 2.00 (m, 1H), 1.80 - 1.74 (m, 1H), 1.71 - 1.61 (m, 1H), 0.82 - 0.72 (m, 4H).

[0552] Example 1.40: Synthesis of compound P-40

[0553] Step one: Synthesis of compound P-40-a

[0554] Methylamine hydrochloride (154 mg, 2.28 mmol) was dissolved in N,N- dimethylformamide (3 mL), N,N-diisopropylethylamine (884 mg, 6.84 mmol), (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid (500 mg, 2.28 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.3 g, 3.42 mmol) were added. The mixture was stirred at room temperature for 3 hours. The reaction was added with ethyl acetate, washed with water for three times, with brine for one time, dried, concentrated to give the crude product compound LP-40-a (529 mg). ESI-MS (m / z): 233.3 [M+H] + .

[0555] Step two: Synthesis of compound P-40-b

[0556] Dissolve the crude product compound P-40-a (529 mg) in dichloromethane (5 mL), add 4N hydrochloric acid in dioxane (2 mL). Stir the mixture at room temperature for 2 hours. Concentrate the reaction mixture to give the crude product compound P-40-b (300 mg).

[0557] Step three: synthesis of compound P-40-c

[0558] Dissolve 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (470 mg, 2.06 mmol) in N,N-dimethylformamide (5 mL), add the crude product compound P-40-b (300 mg) and N,N-diisopropylethylamine (797 mg, 6.17 mmol). Stir the mixture at 50 °C overnight. Add water to the reaction mixture, extract with ethyl acetate three times. Combine the organic phases, wash with water once, saturated brine once, dry, and concentrate. Purify the residue by column chromatography (PE / EA = 70 / 30) to give compound P-40-c (510 mg, yield 76%). ESI-MS (m / z): 325.3 [M+H] + .

[0559] Step four: synthesis of compound P-40-d

[0560] Dissolve compound P-40-c (466 mg, 1.44 mmol) in 1M borane in tetrahydrofuran (15 mL), stir the mixture at room temperature for 16 hours. Quench the reaction mixture with methanol and dilute hydrochloric acid, concentrate to give the crude product compound P-40-d (457 mg). ESI-MS (m / z): 311.3 [M+H] + .

[0561] Step five: synthesis of compound P-40-e

[0562] Dissolve the crude product compound P-40-d (457 mg) in tetrahydrofuran (10 mL), add N,N-diisopropylethylamine (571 mg, 4.42 mmol) and di-tert-butyl dicarbonate (482 mg, 2.21 mmol). Stir the mixture at room temperature for 2 hours. Add water to the reaction mixture, extract with ethyl acetate three times. Combine the organic phases, wash with water once, saturated brine once, dry, and concentrate. Purify the residue by column chromatography (PE / EA = 80 / 20) to give compound P-40-e (341 mg, yield 56%). ESI-MS (m / z): 411.5 [M+H] + .

[0563] Step six: synthesis of compound P-40-f

[0564] Compound P-40-e (55 mg, 134 μmol) was dissolved in dichloromethane (3 mL), and m-chloroperoxybenzoic acid (46 mg, 268 μmol) was added. The mixture was stirred at room temperature for 2 h. To the reaction was added saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (10 mL) for three times. The organic phase was combined, washed with water once, saturated brine once, dried, and concentrated to give the crude product of compound P-40-f (59 mg). ESI-MS (m / z): 443.5 [M+H] + .

[0565] Step seven: synthesis of compound P-40-g

[0566] Compound P-22-d (30 mg, 135 μmol) and the crude product of compound P-40-f (59 mg) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (52 mg, 404 μmol) was added. The mixture was stirred at room temperature overnight. To the reaction was added water, and extracted with ethyl acetate for three times. The organic phase was combined, washed with water once, saturated brine once, dried, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 96 / 4) to give compound P-40-g (78 mg, yield 99%). ESI-MS (m / z): 585.4 [M+H] + .

[0567] Step eight: synthesis of compound P-40

[0568] Compound P-40-g (78 mg, 133 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was concentrated, and the residue was purified by preparative liquid chromatography (base method) to give compound P-40 (20 mg, yield 31%). ESI-MS (m / z): 485.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.58 - 8.53 (m, 1H), 8.28 - 8.05 (m, 3H), 7.82 - 7.77 (m, 1H), 7.56 - 7.49 (m, 1H), 7.35 - 7.29 (m, 1H), 5.87 - 5.77 (m, 2H), 4.79 - 4.52 (m, 2H), 4.29 - 4.17 (m, 1H), 4.03 - 3.78 (m, 1H), 2.94 - 2.82 (m, 1H), 2.76 - 2.64 (m, 1H), 2.47 - 2.07 (m, 3H), 1.08 - 0.74 (m, 3H).

[0569] Example 1.41:

[0570] Using the same method and reaction conditions as in Example 1.1, (3R,4S)-3- aminotetrahydro-2H-pyran-4-ol was used instead of (R)-2-aminobutyric acid amide hydrochloride as the starting material to give the target product in the following table.

[0571] Example 1.42: Synthesis of compound P-42

[0572] Step one: Synthesis of compound P-42

[0573] Compound P-20 (25 mg, 51 μmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL), and acetone (15 mg, 256 μmol) was added. The mixture was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (87 mg, 410 μmol) was added, after which it was stirred at room temperature overnight. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, which was extracted three times with ethyl acetate (30 mL), and the organic phases were combined and concentrated. The residue was purified by preparative liquid chromatography (basic method) to give compound P-42 (4 mg, yield 15%). ESI-MS (m / z): 530.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.25 - 11.21 (m, 1H), 8.40 - 8.37 (m, 1H), 8.14 - 8.05 (m, 3H), 7.45 (s, 1H), 7.37 - 7.34 (m, 1H), 7.22 - 7.16 (m, 1H), 5.85 - 5.78 (m, 1H), 5.56 - 5.51 (m, 1H), 5.05 - 4.92 (m, 1H), 4.90 - 4.85 (m, 2H), 4.80 - 4.53 (m, 1H), 4.13 - 4.04 (m, 1H), 3.80 - 3.65 (m, 1H), 2.61 - 2.58 (m, 1H), 2.44 - 2.39 (m, 2H), 2.33 - 2.10 (m, 2H), 2.05 - 1.93 (m, 1H), 1.67 - 1.53 (m, 2H), 1.00 - 0.67 (m, 6H).

[0574] Example 1.43: Synthesis of compound P-43

[0575] Step one: Synthesis of compound P-43-a

[0576] Compound P-11-b (500 mg, 1.13 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (2.3 mL) was added under ice bath. The mixture was stirred under ice bath for 10 minutes, the reaction was quenched by water, 20 mL ethyl acetate was added, washed by water for three times, saturated brine for once, dried by anhydrous sodium sulfate, filtered, concentrated. The residue was purified by column chromatography (PE / EA = 60 / 40) to give compound P-43-a (325 mg, yield 88%). ESI-MS (m / z): 329.5 [M+H] + .

[0577] Step two: synthesis of compound P-43-b

[0578] Compound P-43-a (100 mg, 304 μmol), phthalimide (49 mg, 335 μmol) and triphenylphosphine (160 mg, 609 μmol) were dissolved in tetrahydrofuran (5 mL), diisopropyl azodicarboxylate (123 mg, 609 μmol) was added. The mixture was stirred at 60 °C for 6 hours, the reaction was quenched by water, 20 mL ethyl acetate was added, washed by water for three times, saturated brine for once, dried by anhydrous sodium sulfate, filtered, concentrated. The residue was purified by column chromatography (PE / EA = 60 / 40) to give compound P-43-b (113 mg, yield 81%). ESI-MS (m / z): 458.5 [M+H] + .

[0579] Step three: synthesis of compound P-43-c

[0580] Compound P-43-b (50 mg, 109 μmol) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated to give compound P-43-c (39 mg, yield 100%). ESI-MS (m / z): 358.3 [M+H] + .

[0581] Step four: synthesis of compound P-43-d

[0582] Compound P-43-c (39 mg, 109 μmol) and compound P-20-b (48 mg, 109 μmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (44 mg, 337 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was quenched with water, 20 mL of ethyl acetate was added, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 60 / 40) to obtain compound P-43-d (60 mg, yield 77%). ESI-MS (m / z): 718.0 [M+H] + .

[0583] Step five: synthesis of compound P-43-e

[0584] Compound P-43-d (60 mg, 83.6 μmol) was dissolved in dichloromethane (5 mL), and 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and concentrated to obtain compound P-43-e (51 mg, yield 100%). ESI-MS (m / z): 618.1 [M+H] + .

[0585] Step six: synthesis of compound P-43-f

[0586] Compound P-43-e (50 mg, 81 μmol) was dissolved in a mixture of dichloromethane (3 mL) and methanol (3 mL), 37% aqueous formaldehyde solution (0.2 mL) was added, and sodium triacetoxyborohydride (172 mg, 809 μmol) was added. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (10 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL) three times. The combined organic phase was washed with water once, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 90 / 10) to obtain compound P-43-f (29 mg, yield 57%). ESI-MS (m / z): 632.0 [M+H] + .

[0587] Step seven: synthesis of compound P-43

[0588] Compound P-43-f (15 mg, 24 μmol) was dissolved in anhydrous ethanol (5 mL), and 80% hydrazine hydrate (1 mL) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (alkali method) to obtain compound P-43 (3 mg, yield 25%). ESI-MS (m / z): 501.6 [M+H] + .

[0589] Example 1.44: Synthesis of compound P-44

[0590] Step one: Synthesis of compound P-44

[0591] Compound P-20 (22 mg, 45 pmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL), 5 M acetaldehyde tetrahydrofuran solution (50 pL) was added. The mixture was stirred at room temperature for 10 min, sodium triacetoxyborohydride (76 mg, 361 pmol) was added, then stirred at room temperature overnight. The reaction was added with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL) for three times, the organic phase was combined and concentrated. The residue was purified by preparative liquid chromatography (base method) to give compound P-44 (8 mg, yield 34%). ESI-MS (m / z): 516.9 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.21 (s, 1H), 8.38 (d, J = 4.7 Hz, 1H), 8.18 - 8.00 (m, 3H), 7.46 (s, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.21 - 7.14 (m, 1H), 5.75 (d, J = 7.7 Hz, 1H), 5.52 (t, J = 5.6 Hz, 1H), 5.13 - 4.99 (m, 1H), 4.87 (d, J = 5.6 Hz, 2H), 4.79 - 4.53 (m, 2H), 4.33 - 4.06 (m, 1H), 3.83 - 3.67 (m, 1H), 2.46 - 2.39 (m, 2H), 2.34 - 2.20 (m, 2H), 2.13 - 1.94 (m, 2H), 1.70 - 1.52 (m, 2H), 1.02 - 0.69 (m, 3H).

[0592] Example 1.45: Synthesis of compound P-45

[0593] Step one: Synthesis of compound P-45

[0594] Compound P-31 (5 mg, 10 pmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL), and an aqueous formaldehyde solution (34% aqueous solution, 50 pL) was added. The mixture was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (22 mg, 102 pmol) was added, followed by stirring at room temperature overnight. The reaction solution was added with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (30 mL) three times, and the organic phases were combined and concentrated. The residue was purified by preparative liquid chromatography (alkaline method) to obtain compound P-45 (3 mg, yield 58%). ESI-MS (m / z): 502.9 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 8.77 (d, J = 4.4 Hz, 1H), 8.24 - 8.17 (m, 2H), 8.12 - 8.04 (m, 1H), 7.70 - 7.61 (m, 1H), 7.54 (d, J = 4.3 Hz, 1H), 7.33 - 7.25 (m, 1H), 6.09 (s, 1H), 5.78 - 5.64 (m, 1H), 5.20 - 5.01 (m, 3H), 4.80 - 4.50 (m, 2H), 4.33 - 4.11 (m, 1H), 3.87 - 3.61 (m, 1H), 2.34 - 2.21 (m, 2H), 2.19 - 1.96 (m, 4H), 1.75 - 1.53 (m, 2H), 1.49 - 1.26 (m, 1H).

[0595] Example 2: Synthesis of linker-drug conjugate LP

[0596] Example 2.1: Synthesis of compound LP-1

[0597] Step one: Synthesis of compound LP-1-a

[0598] Compound 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-((S)-1-((4- (hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1- oxobutan-2-yl)hexanamide (200 mg, 349 pmol) and N,N-diisopropylethylamine (90 mg, 698 pmol) were dissolved in N,N-dimethylformamide (5 mL), and bis(4- nitrophenyl) carbonate (212 mg, 698 pmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was slurried in ethyl acetate to obtain solid compound LP-1-a (220 mg, yield 85.4%).

[0599] Step two: Synthesis of compound LP-1

[0600] Compound LP-1-a (58 mg, 78 pmol) and compound P-1 (37 mg, 78 pmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (20 mg, 156 pmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-1 (10 mg, yield 11.9%). ESI-MS (m / z): 1071.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.38 (s, 1H), 10.01 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.18 - 8.12 (m, 1H), 8.13 - 8.06 (m, 3H), 8.00 - 7.92 (m, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.67 - 7.56 (m, 3H), 7.51 - 7.43 (m, 1H), 7.36 - 7.17 (m, 5H), 7.00 (s, 2H), 6.30 - 6.24 (m, 1H), 6.03 - 5.96 (m, 1H), 5.42 (s, 2H), 5.00 (s, 2H), 4.77 - 4.54 (m, 5H), 4.43 - 4.35 (m, 1H), 4.23 - 4.16 (m, 1H), 3.39 - 3.35 (m, 2H), 3.04 - 3.00 (m, 1H), 2.96 - 2.92 (m, 1H), 2.22 - 2.08 (m, 2H), 2.04 - 1.90 (m, 2H), 1.87 - 1.76 (m, 1H), 1.75 - 1.56 (m, 3H), 1.53 - 1.42 (m, 5H), 1.40 - 1.33 (m, 1H), 1.21 - 1.14 (m, 2H), 0.87 - 0.81 (m, 6H), 0.71 - 0.64 (m, 2H).

[0601] Examples 2.2-2.8:

[0602] Using the same method and reaction conditions as in Example 2.1, compounds P-2 to P-8 were used as starting materials instead of P-1 to obtain the target products in the following table.

[0603] Example 2.9: Synthesis of compound LP-9

[0604] Step one: Synthesis of compound LP-9-a

[0605] Step one: synthesis of compound LP-9-a + .

[0606] Step two: synthesis of compound LP-9

[0607] Compound P-1 (10 mg, 21 μmol) and compound LP-9-a (14 mg, 21 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl ethylamine (8 mg, 61 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-9 (5 mg, yield 24%). ESI-MS (m / z): 985.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.46 - 11.34 (m, 1H), 9.96 (s, 1H), 8.36 (s, 1H), 8.21 - 8.06 (m, 4H), 8.00 - 7.88 (m, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.52 - 7.42 (m, 1H), 7.35 - 7.17 (m, 5H), 7.00 (s, 2H), 6.26 (d, J = 6.8 Hz, 1H), 5.00 (s, 2H), 4.76 - 4.55 (m, 5H), 4.43 - 4.35 (m, 1H), 4.21 - 4.13 (m, 1H), 3.36 (s, 2H), 2.20 - 2.08 (m, 2H), 2.00 - 1.92 (m, 1H), 1.87 - 1.76 (m, 1H), 1.72 - 1.61 (m, 1H), 1.52 - 1.42 (m, 4H), 1.33 - 1.28 (m, 3H), 1.26 - 1.11 (m, 2H), 0.90 - 0.77 (m, 7H), 0.69 - 0.64 (m, 2H).

[0608] Example 2.10: Synthesis of compound LP-10

[0609] Step one: Synthesis of compound LP-10

[0610] (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)glycylglycyl-L- phenylalanylglycine (13 mg, 25 μmol) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (2.9 mg, 25 μmol), 3-(3- dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (4.9 mg, 25 μmol) were added. The mixture was stirred at room temperature for 1 hour. To the reaction solution, compound P-1 (10 mg, 21 μmol) and N,N-diisopropylethylamine (2.6 mg, 25 μmol) were added, the mixture was continued to stir at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-10 (5 mg, yield 24%). ESI-MS (m / z): 984.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.46 - 8.39 (m, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.16 - 8.03 (m, 5H), 7.64 (s, 1H), 7.54 - 7.44 (m, 1H), 7.35 - 7.27 (m, 1H), 7.26 - 7.13 (m, 9H), 6.98 (s, 2H), 6.26 (d, J = 6.4 Hz, 1H), 4.73 - 4.68 (m, 1H), 4.65 - 4.57 (m, 4H), 4.53 - 4.47 (m, 1H), 3.82 - 3.63 (m, 8H), 3.38 - 3.31 (m, 2H), 3.09 - 3.05 (m, 1H), 2.86 - 2.80 (m, 1H), 2.12 - 2.07 (m, 2H), 1.50 - 1.42 (m, 4H), 1.22 - 1.11 (m, 2H), 0.83 - 0.77 (m, 1H), 0.69 - 0.64 (m, 2H).

[0611] Example 2.11: Synthesis of compound LP-11

[0612] Step one: Synthesis of compound LP-11-a

[0613] tert-Butyl 3-(2-aminoethoxy)propanoate (1 g, 5.28 mmol) and maleic anhydride (622 mg, 6.34 mmol) were dissolved in glacial acetic acid (20 mL). The mixture was stirred at 100 °C for 16 h. The reaction was cooled to room temperature and concentrated. The residue was purified by reverse phase column chromatography (water (0.05% formic acid) / acetonitrile = 90 / 10) to give compound LP-11-a (560 mg, yield 49.7%). ESI-MS (m / z): 236.3 [M+Na] + .

[0614] Step two: synthesis of compound LP-11-b

[0615] Compound LP-11-a (250 mg, 1.17 mmol) and N-hydroxysuccinimide (270 mg, 2.35 mmol) were dissolved in tetrahydrofuran (5 mL), and N,N'-dicyclohexylcarbodiimide (484 mg, 2.35 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was filtered, and the filter cake was washed with tetrahydrofuran twice. The filtrate was combined and concentrated. The residue was purified by reverse phase column chromatography (water / acetonitrile = 70 / 30) to give compound LP-11-b (560 mg, yield 49.7%). ESI-MS (m / z): 333.3 [M+Na] + .

[0616] Step three: synthesis of compound LP-11-c

[0617] (S)-2-((S)-2-amino-3-methylbutylamino)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (93 mg, 245 μmol) was dissolved in N,N-dimethylformamide (2 mL), and compound LP-11-b (127 mg, 409 μmol) was added. The mixture was stirred at room temperature for 4 h. Methyl tert-butyl ether was added to the reaction, which was filtered, and the filter cake was washed with methyl tert-butyl ether twice. The filter cake was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-11-c (36 mg, yield 15.3%). ESI-MS (m / z): 575.4 [M+H] + .

[0618] Step four: synthesis of compound LP-11-d

[0619] Compound LP-11-c (36 mg, 62 μmol) and N,N-diisopropylethylamine (8 mg, 62 μmol) were dissolved in N,N-dimethylformamide (5 mL), and bis(4-nitrophenyl) carbonate (22 mg, 73 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was slurried in ethyl acetate to obtain solid compound LP-11-d (40 mg, yield 88.8%). ESI-MS (m / z): 740.4 [M+H] + .

[0620] Step five: synthesis of compound LP-11

[0621] Compound LP-11-d (10 mg, 13 μmol) and compound P-1 (6.4 mg, 13 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (5.2 mg, 40 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-11 (5 mg, yield 34.5%). ESI-MS (m / z): 1073.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.00 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.18 - 8.07 (m, 4H), 7.96 - 7.82 (m, 2H), 7.66 - 7.43 (m, 5H), 7.36 - 7.27 (m, 3H), 7.25 - 7.18 (m, 3H), 7.01 (s, 2H), 6.32 - 6.22 (m, 1H), 5.99 (s, 1H), 5.41 (s, 2H), 5.01 (s, 2H), 4.76 - 4.53 (m, 5H), 4.44 - 4.35 (m, 2H), 4.25 - 4.19 (m, 1H), 3.56 - 3.49 (m, 4H), 3.06 - 2.92 (m, 3H), 2.45 - 2.30 (m, 3H), 2.01 - 1.91 (m, 2H), 0.88 - 0.64 (m, 11H).

[0622] Example 2.12: synthesis of compound LP-12

[0623] Step one: synthesis of compound LP-12

[0624] Compound LP-1-a (48 mg, 65 μmol) and compound P-10 (30 mg, 65 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl ethylamine (25 mg, 196 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-12 (10 mg, yield 14.5%). ESI-MS (m / z): 1058.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.02 (s, 1H), 8.36 (s, 1H), 8.16 - 8.01 (m, 4H), 7.98 - 7.90 (m, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.49 - 7.43 (m, 1H), 7.34 - 7.28 (m, 2H), 7.24 - 7.16 (m, 2H), 7.00 (s, 2H), 6.00 (t, J = 5.3 Hz, 1H), 5.75 - 5.65 (m, 1H), 5.42 (s, 2H), 5.08 - 4.92 (m, 3H), 4.73 - 4.64 (m, 1H), 4.64 - 4.49 (m, 3H), 4.45 - 4.34 (m, 1H), 4.22 - 4.15 (m, 1H), 4.15 - 3.99 (m, 1H), 3.76 - 3.63 (m, 1H), 3.39 - 3.35 (m, 2H), 3.09 - 2.91 (m, 3H), 2.22 - 2.08 (m, 2H), 2.01 - 1.93 (m, 1H), 1.74 - 1.65 (m, 1H), 1.65 - 1.56 (m, 1H), 1.51 - 1.44 (m, 4H), 1.38 - 1.32 (m, 1H), 1.22 - 1.18 (m, 1H), 1.07 - 0.81 (m, 13H).

[0625] Example 2.13: Synthesis of compound LP-13

[0626] Step one: Synthesis of compound LP-13-a

[0627] Methyl ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetate (109 mg, 295 μmol) was dissolved in dichloromethane (5 mL), and trimethylsilyl chloride (233 mg, 2.14 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound P-11 (70 mg, 147 μmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature, concentrated, and the residue was purified by preparative liquid chromatography (base method) to give compound LP-13-a (22 mg, 19% yield). ESI-MS (m / z): 783.5 [M+H] + .

[0628] Step two: synthesis of compound LP-13-b

[0629] Compound LP-13-a (29 mg, 37 μmol) was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (0.4 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-13-b (11 mg, 53% yield). ESI-MS (m / z): 561.4 [M+H] + .

[0630] Step three: synthesis of compound LP-13

[0631] Compound LP-13-b (2.4 mg, 4.2 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (2.4 mg, 5. μmol), and N,N- diisopropylethylamine (1.4 mg, 11 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (1.5 mg, 5 μmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction was quenched with acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-13 (1 mg, 24% yield). ESI-MS (m / z): 1015.6 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 8.87 - 8.79 (m, 1H), 8.75 (d, J = 4.5 Hz, 1H), 8.40 - 8.34 (m, 1H), 8.24 - 8.02 (m, 6H), 7.74 - 7.60 (m, 2H), 7.51 (d, J = 4.4 Hz, 1H), 7.35 - 7.19 (m, 6H), 7.17 (d, J = 6.5 Hz, 1H), 6.98 (s, 2H), 6.31 - 6.21 (m, 1H), 5.18 (s, 2H), 4.88 (d, J = 6.7 Hz, 2H), 4.80 - 4.56 (m, 2H), 4.51 - 4.46 (m, 1H), 3.79 - 3.60 (m, 6H), 3.37 - 3.34 (m, 2H), 3.08 - 3.00 (m, 1H), 2.84 - 2.75 (m, 1H), 2.12 - 2.05 (m, 2H), 1.84 - 1.62 (m, 2H), 1.51 - 1.41 (m, 4H), 1.20 - 1.15 (m, 2H), 0.83 - 0.76 (m, 2H), 0.70 - 0.63 (m, 2H).

[0632] Example 2.14: Synthesis of compound LP-14

[0633] Step one: Synthesis of compound LP-14-a

[0634] Methyl ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetate (39 mg, 105 pmol) was dissolved in dichloromethane (5 mL), and trimethylsilyl chloride (83 mg, 766 pmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound P-12 (25 mg, 53 pmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature, concentrated, and the residue was purified by preparative liquid chromatography (basic method) to give compound LP-14-a (10 mg, 24% yield). ESI-MS (m / z): 782.5 [M+H] + .

[0635] Step two: Synthesis of compound LP-14-b

[0636] Compound LP-14-a (8 mg, 10.2 pmol) was dissolved in N,N-dimethylformamide (1 mL), and diethylamine (0.1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was purified by preparative liquid chromatography (basic method) to give compound LP-14-b (3 mg, 52% yield). ESI-MS (m / z): 560.5 [M+H] + .

[0637] Step three: synthesis of compound LP-14

[0638] Compound LP-14-b (5 mg, 8.9 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (5.1 mg, 10.7 μmol) and N,N- diisopropylethylamine (2.9 mg, 22 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (3.2 mg, 11 μmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-14 (2 mg, 22% yield). ESI-MS (m / z): 1014.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.69 (s, 1H), 8.40 - 8.34 (m, 2H), 8.17 - 8.04 (m, 5H), 7.63 (s, 1H), 7.53 - 7.45 (m, 1H), 7.33 - 7.15 (m, 9H), 6.98 (s, 2H), 6.26 (d, J = 5.5 Hz, 1H), 4.83 (s, 2H), 4.76 - 4.43 (m, 6H), 3.83 - 3.57 (m, 7H), 3.09 - 3.05 (m, 2H), 2.87 - 2.77 (m, 2H), 1.49 - 1.40 (m, 5H), 1.21 - 1.13 (m, 3H), 0.83 - 0.76 (m, 1H), 0.70 - 0.64 (m, 3H).

[0639] Example 2.15: synthesis of compound LP-15

[0640] Step one: synthesis of compound LP-15-a

[0641] Compound P-12 (10 mg, 21 μmol) was dissolved in acetonitrile (2 mL), and N,N'- disuccinimidyl carbonate (6.5 mg, 25 μmol) and N,N-diisopropylethylamine (8.2 mg, 63 μmol) were added. The mixture was stirred at room temperature for 16 h. The reaction was diluted with 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product compound LP-15-a (10 mg). ESI-MS (m / z): 500.5 [M+H] + .

[0642] Step two: synthesis of compound LP-15-b

[0643] The crude product compound LP-15-a (10 mg) was dissolved in N,N- dimethylformamide (2 mL), N,N'-dimethyl-1,2-ethanediamine (8.8 mg, 100 μmol) and N,N-diisopropylethylamine (5.2 mg, 40 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-15-b (5 mg, yield 43%). ESI-MS (m / z): 588.5 [M+H] + .

[0644] Step three: synthesis of compound LP-15

[0645] The compound LP-1-a (6 mg, 8 μmol) and compound LP-15-b (5 mg, 8 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (3 mg, 25 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-15 (3 mg, yield 29.7%). ESI-MS (m / z): 1186.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.00 (s, 1H), 8.17 - 7.85 (m, 4H), 7.80 (d, J = 8.7 Hz, 1H), 7.67 - 7.44 (m, 4H), 7.35 - 7.16 (m, 5H), 6.99 (s, 2H), 6.26 (d, J = 6.4 Hz, 1H), 6.02 (s, 1H), 5.50 - 5.29 (m, 4H), 4.99 - 4.56 (m, 5H), 4.37 (d, J = 7.5 Hz, 1H), 4.18 (t, J = 7.6 Hz, 1H), 3.41 - 3.33 (m, 7H), 3.02 - 2.66 (m, 8H), 2.20 - 1.94 (m, 4H), 1.86 - 1.23 (m, 11H), 0.87 - 0.78 (m, 7H), 0.70 - 0.64 (m, 2H).

[0646] Example 2.16: synthesis of compound LP-16

[0647] Step one: synthesis of compound LP-16-a

[0648] Compound P-11 (30 mg, 63 μmol) was dissolved in acetonitrile (2 mL), bis(4-nitrophenyl) carbonate (29 mg, 94 μmol) and N,N-diisopropylethylamine (12 mg, 94 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product compound LP-16-a (41 mg). ESI-MS (m / z): 640.5 [M+H] + .

[0649] Step two: synthesis of compound LP-16-b

[0650] The crude product compound LP-16-a (15 mg) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (13 mg, 70 μmol) and N,N-diisopropylethylamine (3 mg, 23 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (basic method) to give compound LP-16-b (5 mg, yield 31%). ESI-MS (m / z): 689.5 [M+H] + .

[0651] Step three: synthesis of compound LP-16-c

[0652] Compound LP-16-b (4 mg, 5 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound LP-16-c (3 mg, yield 87%). ESI-MS (m / z): 589.6 [M+H] + .

[0653] Step four: synthesis of compound LP-16

[0654] Compound LP-16-c (3 mg, 4.8 μmol) and compound LP-1-a (4 mg, 4.8 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (2 mg, 18 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acidic method) to give compound LP-16 (3 mg, yield 50.8%). ESI-MS (m / z): 1187.5 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 9.96 (s, 1H), 8.80 - 8.66 (m, 1H), 8.27 - 7.88 (m, 4H), 7.82 - 7.67 (m, 2H), 7.64 - 7.52 (m, 3H), 7.45 - 7.22 (m, 5H), 6.99 (s, 2H), 6.32 - 6.20 (m, 1H), 6.03 - 5.94 (m, 1H), 5.77 - 5.63 (m, 2H), 5.40 (s, 2H), 5.05 - 4.90 (m, 2H), 4.80 - 4.57 (m, 3H), 4.44 - 4.31 (m, 1H), 4.22 - 4.13 (m, 1H), 3.51 - 3.43 (m, 4H), 3.38 - 3.33 (m, 2H), 3.05 - 2.82 (m, 8H), 2.24 - 1.93 (m, 4H), 1.82 - 1.23 (m, 11H), 0.86 - 0.79 (m, 7H), 0.70 - 0.61 (m, 2H).

[0655] Example 2.17: Synthesis of compound LP-17

[0656] Step one: Synthesis of compound LP-17-a

[0657] Compound P-15 (10 mg, 20 μmol) was dissolved in acetonitrile (2 mL), bis(4- nitrophenyl) carbonate (6 mg, 20 μmol) and N,N-diisopropylethylamine (5 mg, 40 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound LP-17-a (13 mg). ESI-MS (m / z): 670.5 [M+H] + .

[0658] Step two: Synthesis of compound LP-17-b

[0659] The crude product compound LP-17-a (13 mg) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (3.6 mg, 20 μmol) and N,N- diisopropylethylamine (3.6 mg, 20 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (alkali method) to obtain compound LP-17-b (4 mg, yield 28.7%). ESI-MS (m / z): 719.5 [M+H] + .

[0660] Step three: Synthesis of compound LP-17-c

[0661] Compound LP-17-b (4 mg, 5 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give compound LP-17-c (3 mg). ESI-MS (m / z): 619.7 [M+H] + .

[0662] Step four: synthesis of compound LP-17

[0663] Compound LP-17-c (3 mg) and compound LP-1-a (4 mg, 4.8 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (2 mg, 18 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-17 (3 mg, yield 50%). ESI-MS (m / z): 1217.9 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.02 - 9.94 (m, 1H), 8.77 - 8.67 (m, 1H), 8.19 - 8.08 (m, 2H), 7.86 - 7.72 (m, 2H), 7.70 - 7.51 (m, 3H), 7.44 - 7.21 (m, 7H), 7.00 (s, 2H), 6.73 - 6.60 (m, 1H), 6.01 - 5.95 (m, 2H), 5.73 - 5.66 (m, 2H), 5.42 (s, 2H), 5.01 - 4.62 (m, 6H), 4.39 - 4.33 (m, 1H), 4.20 - 4.16 (m, 1H), 3.85 - 3.73 (m, 1H), 3.59 - 3.40 (m, 6H), 3.39 - 3.37 (m, 2H), 3.05 - 2.82 (m, 10H), 2.23 - 2.07 (m, 3H), 2.03 - 1.91 (m, 4H), 1.10 - 1.06 (m, 1H), 0.96 - 0.79 (m, 11H).

[0664] Example 2.18: synthesis of compound LP-18

[0665] Step one: synthesis of compound LP-18-a

[0666] Compound P-17 (10 mg, 20 μmol) was dissolved in acetonitrile (2 mL), bis(4-nitrophenyl) carbonate (6 mg, 20 μmol) and N,N-diisopropylethylamine (5 mg, 40 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound LP-18-a (13 mg). ESI-MS (m / z): 656.5 [M+H] + .

[0667] Step two: synthesis of compound LP-18-b

[0668] The crude product compound LP-18-a (13 mg) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (3.6 mg, 20 μmol) and N,N-diisopropylethylamine (3.6 mg, 20 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound LP-18-b (13 mg). ESI-MS (m / z): 705.5 [M+H] + .

[0669] Step three: synthesis of compound LP-18-c

[0670] The crude product compound LP-18-b (13 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (basic method) to obtain compound LP-18-c (5 mg, yield 45%). ESI-MS (m / z): 605.7 [M+H] + .

[0671] Step four: synthesis of compound LP-18

[0672] Compound LP-18-c (5 mg, 8.2 μmol) and compound LP-1-a (4 mg, 4.8 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (6 mg, 53 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acidic method) to obtain compound LP-18 (4.5 mg, yield 45.2%). ESI-MS (m / z): 1203.9 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 9.93 (s, 1H), 8.09 - 8.02 (m, 3H), 7.97 - 7.93 (m, 2H), 7.88 (s, 1H), 7.84 - 7.72 (m, 4H), 7.54 - 7.31 (m, 6H), 7.29 - 7.14 (m, 5H), 6.93 (s, 2H), 5.95 - 5.88 (m, 2H), 5.36 (s, 2H), 5.14 - 4.83 (m, 5H), 4.61 - 4.27 (m, 5H), 4.16 - 3.70 (m, 3H), 3.30 - 3.28 (m, 5H), 3.14 (s, 3H), 2.96 - 2.92 (m, 1H), 2.90 - 2.85 (m, 2H), 2.81 - 2.71 (m, 6H), 2.15 - 1.98 (m, 2H), 1.98 - 1.85 (m, 2H), 1.13 - 1.09 (m, 2H), 0.93 - 0.88 (m, 3H), 0.79 - 0.76 (m, 3H), 0.76 - 0.73 (m, 3H).

[0673] Example 2.19: Synthesis of compound LP-19

[0674] Step one: Synthesis of compound LP-19-a

[0675] Compound P-14 (20 mg, 43 pmol) was dissolved in acetonitrile (2 mL), bis(4- nitrophenyl) carbonate (16 mg, 52 pmol) and N,N-diisopropylethylamine (11 mg, 87 pmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound LP-19-a (27 mg). ESI-MS (m / z): 627.5 [M+H] + .

[0676] Step two: Synthesis of compound LP-19-b

[0677] The crude product compound LP-19-a (20 mg) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (12 mg, 63 pmol) and N,N- diisopropylethylamine (12 mg, 94 pmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (alkali method) to obtain compound LP-19-b (10 mg, yield 46%). ESI-MS (m / z): 676.6 [M+H] + .

[0678] Step three: synthesis of compound LP-19-c

[0679] Compound LP-19-b (13 mg, 18 µmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give compound LP-19-c (10 mg, yield 100%). ESI-MS (m / z): 576.6 [M+H] + .

[0680] Step four: synthesis of compound LP-19

[0681] Compound LP-19-c (10 mg, 17 µmol) and compound LP-1-a (13 mg, 17 µmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (4.5 mg, 34 µmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-19 (11 mg, yield 53.2%). ESI-MS (m / z): 1174.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.02 – 9.93 (m, 1H), 8.78 – 8.66 (m, 1H), 8.24 – 7.93 (m, 4H), 7.81 (d, J = 8.6 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.61 – 7.51 (m, 2H), 7.44 – 7.20 (m, 4H), 7.00 (s, 2H), 5.99 (t, J = 5.3 Hz, 1H), 5.75 – 5.64 (m, 3H), 5.42 (s, 2H), 5.02 – 4.59 (m, 5H), 4.43 – 4.30 (m, 1H), 4.20 – 4.00 (m, 2H), 3.72 – 3.36 (m, 8H), 3.02 – 2.81 (m, 7H), 2.20 – 2.07 (m, 2H), 2.04 – 1.90 (m, 1H), 1.73 – 1.53 (m, 2H), 1.51 – 1.39 (m, 5H), 1.22 – 1.14 (m, 3H), 1.08 – 0.78 (m, 12H).

[0682] Example 2.20: synthesis of compound LP-20

[0683] Step one: synthesis of compound LP-20-a

[0684] Compound P-13 (14 mg, 31 μmol) was dissolved in acetonitrile (2 mL), N,N'- disuccinimidyl carbonate (16 mg, 64 μmol) and N,N-diisopropylethylamine (12 mg, 91 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was added to 20 mL ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product compound LP-20-a (13 mg). ESI-MS (m / z): 487.5 [M+H] + .

[0685] Step two: synthesis of compound LP-20-b

[0686] The crude product compound LP-20-a (13 mg) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (10 mg, 53 μmol) and N,N- diisopropylethylamine (7 mg, 53 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (basic method) to give compound LP-20-b (5 mg, yield 28%). ESI-MS (m / z): 675.6 [M+H] + .

[0687] Step three: synthesis of compound LP-20-c

[0688] Compound LP-20-b (5 mg, 7.4 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give compound LP-20-c (5 mg, yield 100%). ESI-MS (m / z): 575.6 [M+H] + .

[0689] Step four: synthesis of compound LP-20

[0690] Compound LP-20-c (4 mg, 7 μmol) and compound LP-1-a (5 mg, 7 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (2 mg, 16 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acidic method) to give compound LP-20 (3 mg, yield 37%). ESI-MS (m / z): 1173.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.52 - 11.44 (m, 1H), 9.99 (s, 1H), 8.44 - 8.34 (m, 1H), 8.14 - 7.89 (m, 4H), 7.80 (d, J = 8.6 Hz, 1H), 7.60 - 7.44 (m, 3H), 7.32 - 7.16 (m, 4H), 7.00 (s, 2H), 6.04 - 5.94 (m, 1H), 5.77 - 5.66 (m, 1H), 5.46 - 5.34 (m, 4H), 5.09 - 4.55 (m, 5H), 4.44 - 4.32 (m, 1H), 4.22 - 4.00 (m, 2H), 3.79 - 3.59 (m, 1H), 3.39 - 3.34 (m, 5H), 3.05 - 2.69 (m, 9H), 2.22 - 2.07 (m, 2H), 1.99 - 1.91 (m, 1H), 1.72 - 1.63 (m, 1H), 1.63 - 1.54 (m, 1H), 1.52 - 1.42 (m, 5H), 1.22 - 1.14 (m, 3H), 1.08 - 0.79 (m, 12H).

[0691] Example 2.21: Synthesis of compound LP-21

[0692] Step one: Synthesis of compound LP-21-a

[0693] Compound P-18 (20 mg, 41 μmol) was dissolved in acetonitrile (2 mL), bis(4- nitrophenyl) carbonate (24 mg, 82 μmol) and N,N-diisopropylethylamine (10 mg, 80 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product compound LP-21-a (26 mg). ESI-MS (m / z): 656.5 [M+H] + .

[0694] Step two: Synthesis of compound LP-21-b

[0695] The crude product compound LP-21-a (26 mg) was dissolved in N,N- dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (7.5 mg, 40 μmol) and N,N-diisopropylethylamine (10 mg, 80 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography (basic method) to give compound LP-21-b (20 mg, yield 72%). ESI-MS (m / z): 705.5 [M+H] + .

[0696] Step three: synthesis of compound LP-21-c

[0697] Compound LP-21-b (20 mg, 28 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give compound LP-21-c (17 mg, yield 99%). ESI-MS (m / z): 605.7 [M+H] + .

[0698] Step four: synthesis of compound LP-21

[0699] Compound LP-21-c (17 mg, 28 μmol) and compound LP-1-a (21 mg, 28 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (6 mg, 53 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acidic method) to give compound LP-21 (13 mg, yield 38%). ESI-MS (m / z): 1203.6 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 10.02 (s, 1H), 8.64 - 8.58 (m, 1H), 8.18 - 8.08 (m, 3H), 8.04 - 7.99 (m, 2H), 7.87 - 7.82 (m, 2H), 7.60 - 7.21 (m, 10H), 7.00 (s, 2H), 6.04 - 5.94 (m, 2H), 5.44 (s, 2H), 5.17 - 5.06 (m, 2H), 4.95 - 4.88 (m, 2H), 4.68 - 4.61 (m, 1H), 4.58 - 4.46 (m, 2H), 4.39 - 4.35 (m, 1H), 4.20 - 4.16 (m, 1H), 3.85 - 3.77 (m, 1H), 3.39 - 3.31 (m, 5H), 3.20 (s, 3H), 3.03 - 2.99 (m, 1H), 2.97 - 2.91 (m, 2H), 2.87 - 2.84 (m, 2H), 2.83 - 2.78 (m, 3H), 2.20 - 2.08 (m, 2H), 1.98 - 1.93 (m, 1H), 1.70 - 1.56 (m, 2H), 1.52 - 1.33 (m, 6H), 1.21 - 1.14 (m, 2H), 1.09 - 0.77 (m, 9H).

[0700] Example 2.22: Synthesis of compound LP-22

[0701] Step one: Synthesis of compound LP-22-a

[0702] Compound P-10-a (130 mg, 462 pmol) was dissolved in dichloromethane (5 mL), bis(4-nitrophenyl) carbonate (211 mg, 693 pmol) and N,N-diisopropylethylamine (60 mg, 470 pmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound LP-22-a (206 mg). ESI-MS (m / z): 447.5 [M+H] + .

[0703] Step two: Synthesis of compound LP-22-b

[0704] The crude product compound LP-22-a (206 mg) was dissolved in N,N- dimethylformamide (2 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (260 mg, 1.38 pmol) and N,N-diisopropylethylamine (119 mg, 922 pmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 85 / 15) to obtain compound LP-22-b (220 mg, yield 96%). ESI-MS (m / z): 496.5 [M+H] + .

[0705] Step three: synthesis of compound LP-22-c

[0706] The compound LP-22-b (40 mg, 80 pmol) was dissolved in dichloromethane (3 mL), and meta-chloroperoxybenzoic acid (21 mg, 121 pmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 10 mL of dichloromethane, washed with saturated sodium bicarbonate twice, water twice, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 50 / 50) to obtain compound LP-22-c (10 mg, yield 24%). ESI-MS (m / z): 528.6 [M+H] + .

[0707] Step four: synthesis of compound LP-22-d

[0708] The compound P-12-a (4.4 mg, 19 pmol) and N,N-diisopropylethylamine (5 mg, 39 pmol) were dissolved in N,N-dimethylformamide (2 mL), and compound LP-22-c (10 mg, 19 pmol) was added. The mixture was stirred at 50°C for 6 hours. The reaction solution was cooled to room temperature, added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound LP-22-d (8 mg, yield 61%). ESI-MS (m / z): 675.6 [M+H] + .

[0709] Step five: synthesis of compound LP-22-e

[0710] Compound LP-22-d (8 mg, 12 µmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give compound LP-22-e (6 mg). ESI-MS (m / z): 575.6 [M+H] + .

[0711] Step six: synthesis of compound LP-22

[0712] Compound LP-22-e (6 mg, 10 µmol) and compound LP-1-a (8 mg, 10 µmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (2.7 mg, 21 µmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-22 (5 mg, yield 41%). ESI-MS (m / z): 1173.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.01 (s, 1H), 8.38 (d, J = 4.7 Hz, 1H), 8.17 – 8.00 (m, 4H), 7.82 (d, J = 8.6 Hz, 1H), 7.61 – 7.54 (m, 2H), 7.49 – 7.45 (m, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.29 – 7.14 (m, 3H), 7.00 (s, 2H), 6.05 – 5.82 (m, 2H), 5.43 (s, 2H), 4.97 – 4.35 (m, 10H), 4.25 – 4.16 (m, 1H), 3.40 – 3.27 (m, 5H), 3.10 – 2.61 (m, 10H), 2.23 – 2.07 (m, 2H), 2.00 – 1.90 (m, 1H), 1.70 – 1.36 (m, 8H), 1.20 – 1.14 (m, 4H), 1.04 – 1.00 (m, 3H), 0.87 – 0.79 (m, 6H).

[0713] Example 2.23: synthesis of compound LP-23

[0714] Step one: synthesis of compound LP-23-a

[0715] Compound LP-16-a (15 mg, 23 pmol) was dissolved in N,N-dimethylformamide (2 mL), (S)-2-((methylamino)methyl)pyrrolidine-1 -carboxylate benzyl ester (17 mg, 70 pmol) and N,N-diisopropylethylamine (15 mg, 115 pmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-23-a (12 mg, yield 68%). ESI-MS (m / z): 749.5 [M+H] + .

[0716] Step two: synthesis of compound LP-23-b

[0717] Compound LP-23-a (8 mg, 10 pmol) was dissolved in concentrated hydrochloric acid (3 mL). The mixture was stirred at 100 °C for 2 hours. The reaction was concentrated to give crude compound LP-23-b (6 mg). ESI-MS (m / z): 615.6 [M+H] + .

[0718] Step three: synthesis of compound LP-23

[0719] Crude compound LP-23-b (6 mg) and compound LP-1-a (7 mg, 10 pmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (2.5 mg, 20 pmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-23 (2 mg, yield 17%). ESI-MS (m / z): 1213.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 10.12 (s, 1H), 8.78 - 8.68 (m, 1H), 8.23 - 8.18 (m, 1H), 8.08 - 7.79 (m, 3H), 7.72 - 7.15 (m, 8H), 6.99 (s, 2H), 6.92 - 6.65 (m, 1H), 6.33 - 6.00 (m, 1H), 5.80 - 5.63 (m, 2H), 5.52 - 5.39 (m, 2H), 5.09 - 4.57 (m, 5H), 4.42 - 4.00 (m, 5H), 3.26 - 2.74 (m, 11H), 2.18 - 2.06 (m, 3H), 2.00 - 1.94 (m, 1H), 1.88 - 1.57 (m, 10H), 1.19 - 1.11 (m, 3H), 0.88 - 0.57 (m, 11H).

[0720] Example 2.24: synthesis of compound LP-24

[0721] Step one: synthesis of compound LP-24-a

[0722] Compound LP-16-a (15 mg, 23 μmol) was dissolved in N,N-dimethylformamide (2 mL), (S)-methyl(pyrrolidin-2-ylmethyl)carbamic acid tert-butyl ester (17 mg, 70 μmol) and N,N-diisopropylethylamine (15 mg, 115 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-24-a (10 mg, yield 60%). ESI-MS (m / z): 715.5 [M+H] + .

[0723] Step two: synthesis of compound LP-24-b

[0724] Compound LP-24-a (10 mg, 14 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give crude compound LP-24-b (8 mg). ESI-MS (m / z): 615.6 [M+H] + .

[0725] Step three: synthesis of compound LP-24

[0726] Crude compound LP-24-b (8 mg) and compound LP-1-a (9.6 mg, 13 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (3 mg, 24 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-24 (7 mg, yield 44%). ESI-MS (m / z): 1213.5 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 10.00 (s, 1H), 8.79 - 8.69 (m, 1H), 8.25 - 8.07 (m, 4H), 7.83 (d, J = 8.7 Hz, 1H), 7.78 - 7.64 (m, 2H), 7.61 - 7.54 (m, 2H), 7.50 - 7.23 (m, 5H), 7.00 (s, 2H), 6.33 - 6.22 (m, 1H), 6.03 - 5.98 (m, 1H), 5.78 - 5.59 (m, 2H), 5.44 (s, 2H), 5.04 - 4.90 (m, 2H), 4.80 - 4.56 (m, 3H), 4.41 - 4.32 (m, 1H), 4.29 - 4.04 (m, 2H), 3.41 - 3.27 (m, 5H), 3.04 - 2.81 (m, 5H), 2.22 - 2.07 (m, 2H), 2.01 - 1.73 (m, 6H), 1.72 - 1.64 (m, 2H), 1.61 - 1.54 (m, 1H), 1.52 - 1.34 (m, 6H), 1.22 - 1.14 (m, 2H), 0.87 - 0.77 (m, 8H), 0.69 - 0.62 (m, 2H).

[0727] Example 2.25: Synthesis of compound LP-25

[0728] Step one: Synthesis of compound LP-25-a

[0729] N-(2-chloroethyl)-N-methylcarbamic acid tert-butyl ester (800 mg, 4.13 mmol) was dissolved in acetonitrile (20 mL), and N,N-dimethylethylenediamine (5.46 g, 62 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-25-a (600 mg, yield 59%). ESI-MS (m / z): 246.3 [M+H] + .

[0730] Step two: Synthesis of compound LP-25-b

[0731] Compound LP-16-a (15 mg, 23 pmol) was dissolved in N,N-dimethylformamide (2 mL), and compound LP-25-a (5.7 mg, 23 pmol) and N,N-diisopropylethylamine (15 mg, 115 pmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-25-b (10 mg, yield 57%). ESI-MS (m / z): 746.5 [M+H] +.

[0732] Step three: synthesis of compound LP-25-c

[0733] Compound LP-25-b (10 mg, 14 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give the crude product compound LP-25-c (8 mg). ESI-MS (m / z): 646.6 [M+H] + .

[0734] Step four: synthesis of compound LP-25

[0735] The crude product compound LP-25-c (8 mg) and compound LP-1-a (9.2 mg, 12 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (3 mg, 24 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-25 (5 mg, yield 32%). ESI-MS (m / z): 1244.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.81 - 8.65 (m, 1H), 8.26 - 8.18 (m, 2H), 8.13 - 8.07 (m, 2H), 7.97 - 7.73 (m, 2H), 7.69 - 7.22 (m, 9H), 7.00 (s, 2H), 6.33 - 6.22 (m, 1H), 6.02 - 5.95 (m, 1H), 5.73 - 5.63 (m, 2H), 5.42 (s, 2H), 5.04 - 4.51 (m, 6H), 4.43 - 4.29 (m, 1H), 4.18 (t, J = 7.7 Hz, 1H), 3.53 - 3.45 (m, 4H), 3.37 (s, 2H), 3.27 (s, 2H), 3.03 - 2.80 (m, 5H), 2.37 - 2.27 (m, 2H), 2.17 - 2.05 (m, 7H), 1.99 - 1.91 (m, 1H), 1.83 - 1.74 (m, 1H), 1.70 - 1.33 (m, 10H), 0.86 - 0.80 (m, 6H), 0.79 - 0.63 (m, 3H).

[0736] Example 2.26: synthesis of compound LP-26

[0737] Step one: synthesis of compound LP-26-a

[0738] N-(2-bromoethyl)-carbamic acid tert-butyl ester (2.5 g, 11.2 mmol) was dissolved in acetonitrile (25 mL), and N,N-dimethylethylenediamine (11.8 g, 134 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-26-a (1.8 g, yield 70%). ESI-MS (m / z): 232.3 [M+H] + .

[0739] Step two: synthesis of compound LP-26-b

[0740] Compound LP-16-a (15 mg, 23 μmol) was dissolved in N,N-dimethylformamide (2 mL), and compound LP-26-a (5.4 mg, 23 μmol) and N,N-diisopropylethylamine (15 mg, 115 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-26-b (8 mg, yield 47%). ESI-MS (m / z): 732.5 [M+H] + .

[0741] Step three: synthesis of compound LP-26-c

[0742] Compound LP-26-b (8 mg, 11 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give crude compound LP-26-c (6 mg). ESI-MS (m / z): 646.6 [M+H] + .

[0743] Step four: synthesis of compound LP-26

[0744] Crude compound LP-26-c (6 mg) and compound LP-1-a (7 mg, 9.5 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (3 mg, 24 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-26 (5 mg, yield 43%). ESI-MS (m / z): 1230.5 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 10.00 (s, 1H), 8.80 - 8.70 (m, 1H), 8.21 - 8.17 (m, 1H), 8.15 - 8.07 (m, 2H), 7.85 - 7.79 (m, 1H), 7.78 - 7.44 (m, 7H), 7.36 - 7.22 (m, 5H), 7.00 (s, 2H), 6.31 - 6.22 (m, 1H), 6.02 - 5.94 (m, 1H), 5.70 (s, 2H), 5.42 (s, 2H), 5.01 - 4.57 (m, 6H), 4.40 - 4.34 (m, 1H), 4.22 - 4.15 (m, 1H), 3.51 - 3.42 (m, 2H), 3.38 - 3.33 (m, 2H), 3.31 - 3.25 (m, 3H), 3.21 - 3.14 (m, 1H), 3.04 - 2.98 (m, 1H), 2.96 - 2.89 (m, 1H), 2.43 - 2.39 (m, 2H), 2.20 - 2.08 (m, 9H), 2.00 - 1.93 (m, 1H), 1.82 - 1.74 (m, 1H), 1.73 - 1.63 (m, 2H), 1.61 - 1.53 (m, 1H), 1.50 - 1.45 (m, 3H), 1.21 - 1.14 (m, 2H), 0.87 - 0.79 (m, 6H), 0.68 - 0.62 (m, 3H).

[0745] Example 2.27: Synthesis of compound LP-27

[0746] Step one: Synthesis of compound LP-27-a

[0747] Compound LP-16-a (15 mg, 23 pmol) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl (2-((2-(2-hydroxyethoxy)ethyl)amino)ethyl)carbamate (6.2 mg, 23 pmol) and N,N-diisopropylethylamine (15 mg, 115 pmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (base method) to give compound LP-27-a (10 mg, yield 56%). ESI-MS (m / z): 763.5 [M+H] + .

[0748] Step two: Synthesis of compound LP-27-b

[0749] Compound LP-27-a (10 mg, 13 µmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give the crude product compound LP-27-b (8 mg). ESI-MS (m / z): 663.6 [M+H] + .

[0750] Step three: synthesis of compound LP-27

[0751] The crude product compound LP-27-b (8 mg) and compound LP-1-a (9 mg, 12 µmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (3 mg, 24 µmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-27 (6 mg, 39% yield). ESI-MS (m / z): 1261.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.80-8.64 (m, 1H), 8.26-8.07 (m, 4H), 7.98-7.50 (m, 6H), 7.49-7.19 (m, 5H), 7.00 (s, 2H), 6.36-6.17 (m, 1H), 5.99 (t, J = 6.0 Hz, 1H), 5.77-5.61 (m, 2H), 5.43 (s, 2H), 5.05-4.31 (m, 8H), 4.18 (t, J = 7.7 Hz, 1H), 3.65-3.41 (m, 10H), 3.37-3.33 (m, 2H), 3.05-2.91 (m, 2H), 2.89-2.78 (m, 3H), 2.22-2.07 (m, 2H), 2.00-1.91 (m, 1H), 1.83-1.53 (m, 4H), 1.52-1.36 (m, 6H), 1.21-1.13 (m, 2H), 0.87-0.79 (m, 6H), 0.78-0.62 (m, 3H).

[0752] Example 2.28: synthesis of compound LP-28

[0753] Step one: synthesis of compound LP-28-a

[0754] Compound LP-16-a (20 mg, 31 pmol) was dissolved in N,N-dimethylformamide (2 mL), tert-butyl (2-(methylamino)ethyl)carbamate (5.5 mg, 31 pmol) and N,N- diisopropylethylamine (8 mg, 62 pmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (basic method) to give compound LP-28-a (11 mg, 52% yield). ESI-MS (m / z): 675.5 [M+H] + .

[0755] Step two: synthesis of compound LP-28-b

[0756] Compound LP-28-a (11 mg, 16 pmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give crude compound LP-28-b (9 mg). ESI-MS (m / z): 575.6 [M+H] + .

[0757] Step three: synthesis of compound LP-28

[0758] Crude compound LP-28-b (9 mg) and compound LP-1-a (12 mg, 16 pmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (4 mg, 32 pmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was purified by preparative liquid chromatography (acidic method) to give compound LP-28 (10 mg, 54% yield). ESI-MS (m / z): 1174.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 10.06 - 9.97 (m, 1H), 8.79 - 8.69 (m, 1H), 8.26 - 8.07 (m, 4H), 7.98 - 7.46 (m, 7H), 7.41 - 7.20 (m, 5H), 7.01 (s, 2H), 6.32 - 6.23 (m, 1H), 6.04 - 5.97 (m, 1H), 5.77 - 5.67 (m, 2H), 5.44 (s, 2H), 4.97 - 4.88 (m, 2H), 4.82 - 4.65 (m, 2H), 4.62 - 4.57 (m, 1H), 4.39 - 4.34 (m, 1H), 4.21 - 4.16 (m, 1H), 3.38 - 3.34 (m, 2H), 3.29 - 3.16 (m, 2H), 3.09 - 2.99 (m, 3H), 2.98 - 2.88 (m, 3H), 2.20 - 2.08 (m, 2H), 2.03 - 1.91 (m, 2H), 1.84 - 1.63 (m, 3H), 1.54 - 1.39 (m, 6H), 1.21 - 1.15 (m, 2H), 0.88 - 0.63 (m, 9H).

[0759] Example 2.29: Synthesis of compound LP-29

[0760] Step one: Synthesis of compound LP-29-a

[0761] Compound P-1-b (500 mg, 1.53 mmol) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (394 mg, 3.05 mmol) and acetic anhydride (234 mg, 2.29 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated, the residue was purified by column chromatography (PE / EA = 70 / 30) to give compound LP-29-a (434 mg, yield 77%). ESI-MS (m / z): 370.5 [M+H] + .

[0762] Step two: Synthesis of compound LP-29-b

[0763] Compound LP-29-a (275 mg, 1.02 mmol) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 5 hours, concentrated to give compound LP-29-b (230 mg, yield 99%). ESI-MS (m / z): 270.3 [M+H] + .

[0764] Step three: Synthesis of compound LP-29-c

[0765] Compound LP-29-b (230 mg, 1.02 mmol) and N,N-diisopropylethylamine (396 mg, 3.07 mmol) were dissolved in N,N-dimethylformamide (5 mL), and compound P-10-b (304 mg, 1.02 pmol) was added. The mixture was stirred at 50 °C for 6 h. The reaction was cooled to room temperature, diluted with 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-29-c (389 mg, 77% yield). ESI-MS (m / z): 503.4 [M+H] + .

[0766] Step four: synthesis of compound LP-29-d

[0767] Methyl ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetate (997 mg, 2.71 mmol) was dissolved in dichloromethane (10 mL), and trimethylsilyl chloride (1.71 g, 15.8 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was concentrated, and the residue was dissolved in dichloromethane (10 mL), and compound LP-29-c (340 mg, 676 pmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature and concentrated to give crude compound LP-29-d (800 mg). ESI-MS (m / z): 811.5 [M+H] + .

[0768] Step five: synthesis of compound LP-29-e

[0769] The crude compound LP-29-d (800 mg) was dissolved in N,N-dimethylformamide (5 mL), and diethylamine (0.5 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was purified by preparative liquid chromatography (basic method) to give compound LP-29-e (135 mg, 34% yield). ESI-MS (m / z): 589.5 [M+H] + .

[0770] Step six: synthesis of compound LP-29-f

[0771] Compound LP-29-e (135 mg, 222 μmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (1 mL), and 1 N lithium hydroxide (0.5 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was added with acetic acid to pH = 7, and concentrated. The residue was purified by preparative liquid chromatography (base method) to give compound LP-29-f (90 mg, yield 72%). ESI-MS (m / z): 547.4 [M+H] + .

[0772] Step seven: synthesis of compound LP-29

[0773] Compound LP-29-f (10 mg, 18 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (10 mg, 22 μmol), and N,N- diisopropylethylamine (8 mg, 60 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (6.6 mg, 22 μmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was quenched by adding acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-29 (2 mg, yield 22%). ESI-MS (m / z): 1001.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.33 - 11.23 (m, 1H), 8.56 - 8.47 (m, 1H), 8.40 - 8.37 (m, 1H), 8.17 - 7.96 (m, 7H), 7.47 (s, 1H), 7.36 - 7.34 (m, 1H), 7.26 - 7.15 (m, 7H), 6.99 (s, 2H), 5.65 - 5.43 (m, 2H), 4.91 - 4.86 (m, 2H), 4.71 - 4.46 (m, 6H), 4.31 - 4.18 (m, 1H), 3.73 - 3.63 (m, 7H), 3.09 - 3.04 (m, 1H), 2.84 - 2.77 (m, 1H), 2.13 - 2.08 (m, 2H), 1.51 - 1.43 (m, 4H), 1.21 - 1.15 (m, 2H), 1.12 - 0.90 (m, 6H).

[0774] Example 2.30: synthesis of compound LP-30

[0775] Step one: synthesis of compound LP-30-a

[0776] Compound P-10-a (200 mg, 710 μmol) was dissolved in dichloromethane (5 mL), pyridine (112 mg, 1.42 mmol) and acetic anhydride (145 mg, 1.42 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to 20 mL of ethyl acetate, washed once with aqueous citric acid solution, three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 70 / 30) to obtain compound LP-30-a (226 mg, yield 98%). ESI-MS (m / z): 324.5 [M+H] + .

[0777] Step two: synthesis of compound LP-30-b

[0778] Compound LP-30-a (116 mg, 358 μmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (93 mg, 537 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to saturated sodium bicarbonate (10 mL), extracted with dichloromethane (10 mL) three times. The combined organic phase was washed once with water, once with saturated brine, dried, and concentrated to obtain the crude product compound LP-30-b (121 mg). ESI-MS (m / z): 340.5 [M+H] + .

[0779] Step three: synthesis of compound LP-30-c

[0780] The crude product compound LP-30-b (121 mg) and N,N-diisopropylethylamine (137 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (5 mL), and compound P-12-a (81 mg, 356 μmol) was added. The mixture was stirred at 50°C for 6 hours. The reaction solution was cooled to room temperature, added to 20 mL of ethyl acetate, washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound LP-30-c (389 mg, yield 77%). ESI-MS (m / z): 503.4 [M+H] + .

[0781] Step four: synthesis of compound LP-30-d

[0782] Methyl ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetate (145 mg, 394 μmol) was dissolved in dichloromethane (10 mL), and trimethylsilyl chloride (171 mg, 1.58 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound LP-30-c (99 mg, 197 μmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature and concentrated to give crude compound LP-30-d (150 mg). ESI-MS (m / z): 811.5 [M+H] + .

[0783] Step five: synthesis of compound LP-30-e

[0784] The crude compound LP-30-d (150 mg) was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (basic method) to give compound LP-30-e (40 mg, 35% yield). ESI-MS (m / z): 589.5 [M+H] + .

[0785] Step six: synthesis of compound LP-30-f

[0786] The compound LP-30-e (40 mg, 67 μmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (1 mL), and 1 N lithium hydroxide (0.5 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction was added acetic acid to pH = 7 and concentrated. The residue was purified by preparative liquid chromatography (basic method) to give compound LP-30-f (20 mg, 54% yield). ESI-MS (m / z): 547.4 [M+H] + .

[0787] Step seven: synthesis of compound LP-30

[0788] Compound LP-30-f (10 mg, 18 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (9 mg, 20 μmol) and N,N- diisopropylethylamine (8 mg, 60 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (6.6 mg, 22 μmol) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-30 (5 mg, yield 27%). ESI-MS (m / z): 1001.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.76 - 8.68 (m, 1H), 8.44 - 8.41 (m, 2H), 8.41 - 8.36 (m, 2H), 8.21 - 8.16 (m, 1H), 8.13 - 8.03 (m, 5H), 7.51 - 7.45 (m, 1H), 7.33 - 7.30 (m, 1H), 7.27 - 7.15 (m, 7H), 6.99 (s, 2H), 5.74 - 5.66 (m, 1H), 5.12 - 4.86 (m, 1H), 4.85 - 4.81 (m, 2H), 4.76 - 4.49 (m, 5H), 3.83 - 3.56 (m, 7H), 3.09 - 3.05 (m, 1H), 2.84 - 2.78 (m, 2H), 2.12 - 2.08 (m, 2H), 1.52 - 1.41 (m, 5H), 1.07 - 0.88 (m, 6H).

[0789] Example 2.31: Synthesis of compound LP-31

[0790] Step one: Synthesis of compounds LP-31-a and LP-31-b

[0791] ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetic acid methyl ester (39 mg, 106 μmol) was dissolved in dichloromethane (10 mL), and trimethylsilyl chloride (43 mg, 394 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound P-14 (49 mg, 106 μmol) was added. The mixture was stirred at 60 °C overnight. The reaction solution was cooled to room temperature and concentrated. The residue was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (base method) to give compound LP-31-a (5 mg, yield 8%) and compound LP-31-b (5 mg, yield 8%).

[0792] Compound LP-31-a (2 mg, yield 4%). ESI-MS (m / z): 548.5 [M+H] + .

[0793] Compound LP-31-b (2 mg, yield 4%). ESI-MS (m / z): 548.4 [M+H] + .

[0794] Step two: synthesis of compound LP-31

[0795] Compound LP-31-a (2 mg, 3.7 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (2 mg, 4.4 μmol) and N,N- diisopropylethylamine (2 mg, 15 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (2.6 mg, 9 μmol) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-31 (1 mg, yield 27%). ESI-MS (m / z): 1002.6 [M+H] + .

[0796] Example 2.32: synthesis of compound LP-32

[0797] Step two: synthesis of compound LP-32

[0798] Compound LP-31-b (2 mg, 3.7 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (2 mg, 4.4 μmol) and N,N- diisopropylethylamine (2 mg, 15 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (2.6 mg, 9 μmol) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-32 (2 mg, yield 54%). ESI-MS (m / z): 1002.6 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 8.90 - 8.81 (m, 1H), 8.75 (d, J = 4.4 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.24 - 8.15 (m, 2H), 8.14 - 7.96 (m, 4H), 7.71 - 7.61 (m, 1H), 7.50 (d, J = 4.4 Hz, 1H), 7.39 - 7.12 (m, 8H), 6.99 (s, 2H), 5.78 - 5.66 (m, 1H), 5.22 - 5.13 (m, 2H), 4.92 - 4.81 (m, 2H), 4.75 - 4.45 (m, 3H), 4.16 - 3.96 (m, 2H), 3.74 - 3.61 (m, 7H), 3.07 - 3.03 (m, 1H), 2.84 - 2.77 (m, 1H), 2.15 - 2.05 (m, 2H), 1.50 - 1.40 (m, 5H), 1.10 - 0.89 (m, 7H).

[0799] Examples 2.33 - Example 2.36:

[0800] Using the same method and reaction conditions of Example 2.14, the target products in the following table were obtained by using compound P-15, P-17, P-18, P-19 as starting material instead of P-12, respectively.

[0801] Example 2.37: Synthesis of compound LP-37

[0802] Step one: Synthesis of compound LP-37

[0803] Compound P-10 (10 mg, 22 μmol) and compound LP-9-a (28 mg, 43 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (8 mg, 61 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-37 (6 mg, yield 28%). ESI-MS (m / z): 972.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.98 (s, 1H), 8.40 - 8.33 (m, 1H), 8.24 - 8.17 (m, 1H), 8.16 - 7.90 (m, 4H), 7.87 - 7.80 (m, 1H), 7.63 - 7.54 (m, 2H), 7.49 - 7.44 (m, 1H), 7.37 - 7.28 (m, 2H), 7.26 - 7.16 (m, 2H), 7.00 (s, 2H), 5.77 - 5.66 (m, 1H), 5.01 (s, 2H), 4.72 - 4.53 (m, 4H), 4.44 - 4.34 (m, 1H), 4.20 - 4.02 (m, 2H), 3.75 - 3.62 (m, 2H), 2.22 - 2.08 (m, 2H), 2.01 - 1.93 (m, 1H), 1.54 - 1.43 (m, 4H), 1.33 - 1.15 (m, 8H), 1.09 - 0.99 (m, 3H), 0.92 - 0.80 (m, 8H).

[0804] Example 2.38: Synthesis of compound LP-38

[0805] Step one: Synthesis of compound LP-38

[0806] (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)glycylglycyl-L-phenylalanyl glycine (11 mg, 22 μmol) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (5 mg, 44 μmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (8 mg, 44 μmol) were added. The mixture was stirred at room temperature for 1 hour. To the reaction solution, compound P-10 (10 mg, 22 μmol) and N,N-diisopropylethylamine (12 mg, 90 μmol) were added, the mixture was continued to stir at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-38 (7 mg, yield 33%). ESI-MS (m / z): 971.5 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 11.35 (s, 1H), 8.47 - 8.40 (m, 2H), 8.39 - 8.34 (m, 1H), 8.20 - 8.15 (m, 1H), 8.15 - 8.00 (m, 5H), 7.51 - 7.44 (m, 1H), 7.27 - 7.14 (m, 8H), 6.99 (s, 2H), 5.75 - 5.66 (m, 1H), 4.70 - 4.49 (m, 5H), 3.84 - 3.71 (m, 3H), 3.68 - 3.56 (m, 4H), 3.11 - 3.06 (m, 1H), 2.87 - 2.79 (m, 1H), 2.08 (t, J = 7.5 Hz, 2H), 2.04 - 1.95 (m, 1H), 1.49 - 1.41 (m, 5H), 1.18 - 1.12 (m, 3H), 1.05 - 0.82 (m, 6H).

[0807] Example 2.39: Synthesis of compound LP-39

[0808] Step one: Synthesis of compound LP-39-a

[0809] N-e-(tert-Butoxycarbonyl)-L-lysine (8 g, 32.5 mmol) was dissolved in dichloromethane (100 mL), N-benzyloxycarbonyl-L-valine succinimidyl ester (12.5 g, 35.7 mmol) and triethylamine (4.93 g, 48.7 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-39-a (6.5 g, yield 42%). ESI-MS (m / z): 480.6 [M+H] + .

[0810] Step two: Synthesis of compound LP-39-b

[0811] Compound LP-39-a (4 g, 8.4 mmol) was dissolved in ethanol (40 mL), 10% palladium carbon (0.5 g) was added. The mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction was filtered through celite, concentrated to give compound LP-39-b (2.5 g, yield 87%). ESI-MS (m / z): 346.3 [M+H] + .

[0812] Step three: Synthesis of compound LP-39-c

[0813] Compound LP-39-b (200 mg, 578 pmol) and 2,5-dioxopyrrolidin-l-yl l-(2,5-dihydro- 2,5-dihydro-lH-pyrrol-l-yl)-3-oxo-7,10,13,16-tetraoxo-4-azanonadecan-19-oate (594 mg, 1.16 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N-methylmorpholine (117 mg, 1.16 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated. The residue was purified by column chromatography (DCM / MeOH = 85 / 15) to give compound LP-39-c (230 mg, yield 53%). ESI-MS (m / z): 744.5 [M+H] + .

[0814] Step four: synthesis of compound LP-39-d

[0815] Compound LP-39-c (31 mg, 42 pmol) was dissolved in N,N-dimethylformamide (2 mL), and N-hydroxysuccinimide (10 mg, 84 pmol), 3-(3-dimethylaminopropyl)-l- ethylcarbodiimide hydrochloride (16 mg, 84 pmol) were added. The mixture was stirred at room temperature for 1 hour. To the reaction, compound P-l (20 mg, 42 pmol) and N,N- diisopropylethylamine (12 mg, 90 pmol) were added, and the mixture was stirred at room temperature for another 2 hours. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-39-d (10 mg, yield 20%). ESI-MS (m / z): 1198.5 [M+H] + .

[0816] Step five: synthesis of compound LP-39

[0817] Compound LP-39-d (10 mg, 8 pmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for another 0.5 hour. The reaction was concentrated, and the residue was lyophilized to give compound LP-39 (9 mg, yield 98%). ESI-MS (m / z): 1098.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.76 - 8.67 (m, 1H), 8.57 - 8.47 (m, 1H), 8.26 - 8.12 (m, 3H), 8.11 - 8.01 (m, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.71 - 7.50 (m, 5H), 7.45 - 7.29 (m, 3H), 7.00 (s, 2H), 6.57 - 6.27 (m, 1H), 4.81 - 4.65 (m, 4H), 4.58 - 4.52 (m, 1H), 4.33 - 4.28 (m, 1H), 4.19 - 4.16 (m, 1H), 3.60 - 3.54 (m, 7H), 3.47 - 3.45 (m, 5H), 3.37 - 3.34 (m, 2H), 3.16 - 3.13 (m, 2H), 2.78 - 2.75 (m, 2H), 2.38 - 2.30 (m, 4H), 2.03 - 1.93 (m, 2H), 1.80 - 1.71 (m, 2H), 1.68 - 1.60 (m, 2H), 1.56 - 1.51 (m, 2H), 1.39 - 1.29 (m, 3H), 0.87 - 0.63 (m, 11H).

[0818] Example 2.40: Synthesis of compound LP-40

[0819] Step one: Synthesis of compound LP-40-a

[0820] tert-Butyl ((S)-5-((S)-2-amino-3-methylbutanamido)-6-((4- (hydroxymethyl)phenyl)amino)-6-oxohexyl)carbamate (200 mg, 443 pmol) and 2,5-dioxopyrrolidin-1-yl 1-(2,5-dihydro-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16- tetraoxo-4-azanonadecanoate (251 mg, 488 pmol) were dissolved in N,N- dimethylformamide (5 mL), and N,N-diisopropylethylamine (172 mg, 1.33 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated. The residue was purified by reverse phase column chromatography (water / acetonitrile = 50 / 50) to give compound LP-40-a (100 mg, yield 26%). ESI-MS (m / z): 849.5 [M+H] + .

[0821] Step two: Synthesis of compound LP-40-b

[0822] Compound LP-40-a (45 mg, 53 μmol) was dissolved in N,N-dimethylformamide (5 mL), bis(4-nitrophenyl) carbonate (32 mg, 106 μmol) and N,N-diisopropylethylamine (16 mg, 122 μmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-40-b (32 mg, yield 60%). ESI-MS (m / z): 1014.5 [M+H] + .

[0823] Step three: synthesis of compound LP-40-c

[0824] Compound P-1 (5 mg, 10 μmol) and compound LP-40-b (10 mg, 10 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (8 mg, 61 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-40-c (8 mg, yield 60%). ESI-MS (m / z): 1347.5 [M+H] + .

[0825] Step four: synthesis of compound LP-40

[0826] Compound LP-40-c (8 mg, 6 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, the mixture was continued to stir at room temperature for 0.5 hours. The reaction solution was concentrated, the residue was obtained by lyophilization to obtain compound LP-40 (8 mg, yield 98%). ESI-MS (m / z): 1247.5 [M+H] + ; 1H NMR (500 MHz, DMSO-de) d 12.11 (s, 1H), 10.02 (s, 1H), 8.66-8.52 (m, 1H), 8.28-8.01 (m, 6H), 7.98-7.88 (m, 1H), 7.73-7.56 (m, 8H), 7.40-7.29 (m, 4H), 7.01 (s, 2H), 5.08-4.97 (m, 2H), 4.81-4.65 (m, 5H), 4.61-4.55 (m, 1H), 4.48-4.34 (m, 2H), 4.22-4.18 (m, 2H), 3.60-3.58 (m, 4H), 3.50-3.48 (m, 13H), 3.37-3.34 (m, 2H), 3.17-3.13 (m, 2H), 2.85-2.75 (m, 2H), 2.36-2.31 (m, 3H), 2.05-1.91 (m, 2H), 1.83-1.59 (m, 4H), 0.88-0.83 (m, 6H), 0.80-0.63 (m, 3H).

[0827] Example 2.41: Synthesis of compound LP-41

[0828] Step one: Synthesis of compound LP-41-a

[0829] Methyl ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetate (81 mg, 219 pmol) was dissolved in dichloromethane (5 mL), and trimethylsilyl chloride (428 mg, 3.94 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound P-22 (50 mg, 109 pmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature and concentrated to give the crude product compound LP-41-a (83 mg). ESI-MS (m / z): 764.5 [M+H] + .

[0830] Step two: Synthesis of compound LP-41-b

[0831] Compound LP-41-a (83 mg) was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (basic method) to give compound LP-14-b (26 mg, yield 44%). ESI-MS (m / z): 542.5 [M+H] + .

[0832] Step three: Synthesis of compound LP-41

[0833] Compound LP-41-b (20 mg, 36 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)glycylglycyl-L-phenylalanine (26 mg, 55 μmol) and N,N- diisopropylethylamine (29 mg, 222 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (17 mg, 55 μmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-41 (5 mg, yield 14%). ESI-MS (m / z): 996.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.57 - 12.32 (m, 1H), 8.60 - 8.50 (m, 2H), 8.39 - 8.31 (m, 1H), 8.22 - 7.98 (m, 6H), 7.78 (d, J = 4.9 Hz, 1H), 7.53 (s, 1H), 7.35 - 7.12 (m, 7H), 6.99 (s, 2H), 5.66 - 5.49 (m, 1H), 4.76 - 4.46 (m, 5H), 4.33 - 4.12 (m, 1H), 3.76 - 3.55 (m, 6H), 3.37 - 3.33 (m, 2H), 3.10 - 3.00 (m, 1H), 2.85 - 2.73 (m, 1H), 2.16 - 2.05 (m, 2H), 1.52 - 1.41 (m, 4H), 1.21 - 0.90 (m, 8H).

[0834] Example 2.42: Synthesis of compound LP-42

[0835] Step one: Synthesis of compound LP-42-a

[0836] Compound P-10 (10 mg, 22 μmol) and compound LP-40-b (22 mg, 22 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (8 mg, 61 μmol) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-42-a (8 mg, yield 28%). ESI-MS (m / z): 1334.6 [M+H] + .

[0837] Step two: Synthesis of compound LP-42

[0838] Compound LP-42-a (8 mg, 6 µmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, the mixture was continued to stir at room temperature for 0.5 hour. The reaction solution was concentrated, the residue was obtained by lyophilization to give compound LP-42 (8 mg, yield 99%). ESI-MS (m / z): 1234.7 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.02 (s, 1H), 8.65-8.47 (m, 2H), 8.29-8.24 (m, 1H), 8.16-8.08 (m, 2H), 8.06-8.01 (m, 1H), 7.95-7.89 (m, 1H), 7.71-7.51 (m, 7H), 7.38-7.31 (m, 2H), 7.01 (s, 2H), 6.30-5.79 (m, 1H), 5.02 (s, 2H), 4.77-4.65 (m, 4H), 4.38-4.30 (m, 2H), 4.21-4.16 (m, 2H), 3.60-3.58 (m, 2H), 3.51-3.45 (m, 13H), 3.37-3.34 (m, 2H), 3.16-3.13 (m, 2H), 2.96-2.89 (m, 2H), 2.80-2.75 (m, 2H), 2.38-2.35 (m, 1H), 2.35-2.31 (m, 2H), 2.05-1.90 (m, 2H), 1.76-1.50 (m, 5H), 1.17-1.13 (m, 3H), 1.01-0.89 (m, 4H), 0.89-0.82 (m, 7H).

[0839] Example 2.43: Synthesis of compound LP-43

[0840] Step one: Synthesis of compound LP-43-a

[0841] Compound LP-39-c (57 mg, 76 µmol) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (18 mg, 152 µmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (29 mg, 152 µmol) were added. The mixture was stirred at room temperature for 1 hour. To the reaction solution, compound P-10 (35 mg, 76 µmol) and N,N-diisopropylethylamine (30 mg, 228 µmol) were added, the mixture was continued to stir at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-43-a (38 mg, yield 42%). ESI-MS (m / z): 1185.5 [M+H] + .

[0842] Step two: synthesis of compound LP-43

[0843] Compound LP-43-a (38 mg, 32 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was continued to stir at room temperature for 0.5 hour. The reaction solution was concentrated, and the residue was obtained by lyophilization to give compound LP-43 (36 mg, yield 93%). ESI-MS (m / z): 1085.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.82-8.72 (m, 1H), 8.69-8.54 (m, 2H), 8.31-8.24 (m, 1H), 8.23-8.12 (m, 2H), 8.07-8.01 (m, 1H), 7.97-7.91 (m, 1H), 7.74-7.47 (m, 5H), 7.42-7.31 (m, 1H), 7.00 (s, 2H), 4.88-4.64 (m, 5H), 4.37-4.26 (m, 2H), 4.21-4.14 (m, 2H), 3.61-3.53 (m, 12H), 3.47-3.42 (m, 6H), 3.39-3.30 (m, 4H), 3.16-3.12 (m, 2H), 2.80-2.74 (m, 2H), 2.38-2.31 (m, 3H), 2.02-1.95 (m, 1H), 1.77-1.51 (m, 4H), 1.08-0.90 (m, 5H), 0.85-0.80 (m, 6H).

[0844] Example 2.44: synthesis of compound LP-44

[0845] Step one: synthesis of compound LP-44-a

[0846] 5-Bromo-2-methylthiopyrimidine (11 g, 54 mmol) and methyl 5-hexynate (8.1 g, 64 mmol) were dissolved in N,N-dimethylformamide (50 mL), and cuprous iodide (1.02 g, 5.36 mmol), bis(triphenylphosphine)palladium dichloride (1.88 g, 2.68 mmol), and triethylamine (21.7 g, 214 mmol) were added. The mixture was stirred at 95 °C for 6 hours. The reaction solution was cooled to room temperature, and 200 mL of ethyl acetate was added. The mixture was filtered through diatomaceous earth, washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 75 / 25) to give compound LP-44-a (12 g, 89% yield). ESI-MS (m / z): 251.2 [M+H] + .

[0847] Step 2: Synthesis of compound LP-44-b

[0848] Compound LP-44-a (12 g, 48 mmol) was dissolved in a mixture of tetrahydrofuran (100 mL) and water (100 mL), and lithium hydroxide monohydrate (6.03 g, 144 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 3 with dilute hydrochloric acid, and the tetrahydrofuran was removed by concentration. The residue was extracted with 200 mL of ethyl acetate, separated, and the organic phase was washed three times with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound LP-44-b (10.89 g, 96% yield). ESI-MS (m / z): 237.4 [M+H] + .

[0849] Step 3: Synthesis of compound LP-44-c

[0850] Compound LP-44-b (5.8 g, 24.5 mmol) was dissolved in dichloromethane (300 mL), and m-chloroperoxybenzoic acid (12.5 g, 61.4 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was purified by reversed-phase column chromatography (water (0.05% formic acid) / methanol = 50 / 50) to give compound LP-44-c (6 g, 91% yield). ESI-MS (m / z): 269.3 [M+H] + .

[0851] Step 4: Synthesis of compound LP-44-d

[0852] N-((9H-fluoren-9-yl)methoxy)carbonyl)-L-lysine tert-butyl ester hydrochloride (1.4 g, 3.04 mmol) was dissolved in dichloromethane (40 mL), N- benzyloxycarbonyl-L-valine succinimidyl ester (1.06 g, 3.04 mmol) and triethylamine (307 mg, 3.04 mmol) were added. The mixture was stirred at room temperature for 6 hours. The reaction solution was extracted with 100 mL dichloromethane, the organic phase was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 40 / 60) to give compound LP-44-d (1.43 g, yield 72%). ESI-MS (m / z): 658.6 [M+H] + .

[0853] Step five: synthesis of compound LP-44-e

[0854] Compound LP-44-d (1.4 g, 2.13 mmol) was dissolved in N,N-dimethylformamide (10 mL), diethylamine (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by reverse phase column chromatography (water / acetonitrile = 20 / 80) to give compound LP-44-e (510 mg, yield 55%). ESI-MS (m / z): 436.4 [M+H] + .

[0855] Step six: synthesis of compound LP-44-f

[0856] Compound LP-44-e (510 mg, 1.17 mmol) was dissolved in dichloromethane (20 mL), propanal (408 mg, 7.03 mmol) was added. The mixture was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (1.24 g, 5.85 mmol) was added, and stirring was continued for 6 hours. The reaction solution was quenched with 10 mL saturated ammonium chloride solution, extracted with 50 mL dichloromethane, the organic phase was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column chromatography (water / acetonitrile = 50 / 50) to give compound LP-44-f (310 mg, yield 51%). ESI-MS (m / z): 520.5 [M+H] + .

[0857] Step seven: synthesis of compound LP-44-g

[0858] Compound LP-44-f (310 mg, 596 μmol) was dissolved in ethyl acetate (10 mL), and 10% palladium on carbon (0.1 g) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and concentrated to give compound LP-44-g (200 mg, yield 87%). ESI-MS (m / z): 386.5 [M+H] + .

[0859] Step Eight: Synthesis of compound LP-44-h

[0860] Compound LP-44-g (770 mg, 2.00 mmol), compound LP-44-c (589 mg, 2.20 mmol) and N,N-diisopropylethylamine (516 mg, 3.99 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (987 mg, 2.60 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 30 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column chromatography (water / acetonitrile = 50 / 50) to give compound LP-44-h (1 g, yield 79%). ESI-MS (m / z): 636.5 [M+H] + .

[0861] Step Nine: Synthesis of compound LP-44-i

[0862] Compound LP-44-h (1 g, 1.57 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by reverse phase column chromatography (water / acetonitrile = 70 / 30) to give compound LP-44-i (870 mg, yield 95%). ESI-MS (m / z): 580.6 [M+H] + .

[0863] Step Ten: Synthesis of compound LP-44

[0864] Compound LP-44-i (37 mg, 63 pmol), compound P-1 (20 mg, 42 pmol) and N,N- diisopropylethylamine (29 mg, 222 pmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (19 mg, 63 pmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to obtain compound LP-44 (10 mg, yield 23%). ESI-MS (m / z): 1034.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 11.34 (s, 1H), 9.11 (s, 2H), 8.70-8.61 (m, 1H), 8.35-8.31 (m, 1H), 8.25-8.24 (m, 1H), 8.19-8.05 (m, 4H), 7.99-7.94 (m, 1H), 7.66-7.63 (m, 1H), 7.52-7.42 (m, 1H), 7.40-7.30 (m, 1H), 7.25-7.18 (m, 2H), 6.30-6.25 (m, 1H), 4.76-4.52 (m, 6H), 4.33-4.26 (m, 1H), 3.41 (s, 3H), 2.48-2.11 (m, 12H), 2.00-1.79 (m, 4H), 1.36-1.15 (m, 8H), 0.82-0.65 (m, 15H).

[0865] Example 2.45: Synthesis of compound LP-45

[0866] Step one: Synthesis of compound LP-45-a

[0867] ((((9H-fluoren-9-yl)methoxy)carbonyl)-L-alaninyl)carbamic acid (1.5 g, 4.07 mmol) and pyridine (386 mg, 4.89 mmol) were dissolved in a mixture of tetrahydrofuran (60 mL) and toluene (20 mL), and lead tetraacetate (2.17 g, 4.89 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled to room temperature, filtered through diatomite, concentrated, and the residue was purified by column chromatography (PE / EA = 40 / 60) to obtain compound LP-45-a (1.4 g, yield 90%). ESI-MS (m / z): 383.5 [M+H] + .

[0868] Step two: Synthesis of compound LP-45-b

[0869] Compound LP-45-a (121 mg, 317 μmol) was dissolved in dichloromethane (5 mL), and chlorotrimethylsilane (1.07 g, 9.85 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound P-12 (50 mg, 105 μmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature and concentrated to give crude compound LP-45-b (84 mg). ESI-MS (m / z): 796.5 [M+H] + .

[0870] Step Three: Synthesis of compound LP-45-c

[0871] The crude compound LP-45-b (84 mg) was dissolved in N,N-dimethylformamide (1 mL), and diethylamine (0.1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (base method) to give compound LP-45-c (20 mg, 33% yield). ESI-MS (m / z): 574.5 [M+H] + .

[0872] Step Four: Synthesis of compound LP-45

[0873] Compound LP-45-c (20 mg, 34 μmol), (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoyl)-L-valine (16 mg, 52 μmol), and N,N-diisopropylethylamine (9 mg, 69 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O- (N-succinimidyl)urea tetrafluoroborate (16 mg, 52 μmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction was quenched with acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-45 (10 mg, 33% yield). ESI-MS (m / z): 866.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.84-8.72 (m, 1H), 8.38-8.36 (m, 1H), 8.20-8.07 (m, 4H), 7.85-7.77 (m, 1H), 7.70-7.59 (m, 1H), 7.55-7.44 (m, 1H), 7.37-7.18 (m, 3H), 6.99 (s, 2H), 6.35-6.20 (m, 1H), 4.86-4.50 (m, 8H), 4.29-4.21 (m, 1H), 4.20-4.12 (m, 1H), 3.37-3.33 (m, 2H), 2.21-2.01 (m, 3H), 2.03-1.90 (m, 2H), 1.87-1.75 (m, 1H), 1.72-1.59 (m, 1H), 1.49-1.42 (m, 4H), 1.24-1.21 (m, 2H), 0.84-0.79 (m, 6H), 0.77-0.63 (m, 3H).

[0874] Example 2.46: Synthesis of compound LP-46

[0875] Step one: Synthesis of compound LP-46-a

[0876] (S)-3-((tert-butoxycarbonyl)amino)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoic acid (2.44 g, 8.58 mmol) and N-hydroxysuccinimide (1.09 g, 9.44 mmol) were dissolved in N,N-dimethylformamide (30 mL), and 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.81 g, 9.44 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was added to 100 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 30 / 70) to obtain compound LP-46-a (426 mg, yield 13%). ESI-MS (m / z): 382.5 [M+H] + .

[0877] Step two: Synthesis of compound LP-46-b

[0878] Compound LP-46-b (2.60 g, 5.36 mmol) was dissolved in a mixture of glacial acetic acid (2 mL) and methanol (20 mL), and zinc powder (3.50 g, 53.6 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was filtered through celite and concentrated. The residue was purified by column chromatography (PE / EA = 10 / 90) to give compound LP-46-c (1.67 g, yield 68%). ESI-MS (m / z): 456.5 [M+H] - .

[0879] Step three: synthesis of compound LP-46-c

[0880] Compound LP-46-b (2.60 g, 5.36 mmol) was dissolved in a mixture of glacial acetic acid (2 mL) and methanol (20 mL), and zinc powder (3.50 g, 53.6 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was filtered through celite and concentrated. The residue was purified by column chromatography (PE / EA = 10 / 90) to give compound LP-46-c (1.67 g, yield 68%). ESI-MS (m / z): 456.5 [M+H] + .

[0881] Step four: synthesis of compound LP-46-d

[0882] Compound LP-46-c (1.67 g, 3.67 mmol) and 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (1.71 g, 5.5 mmol) were dissolved in dichloromethane (20 mL), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.81 g, 7.33 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was concentrated, and the residue was purified by column chromatography (PE / EA = 50 / 50) to give compound LP-46-d (2.09 g, yield 76%). ESI-MS (m / z): 749.5 [M+H] + .

[0883] Step five: synthesis of compound LP-46-e

[0884] Compound LP-46-d (100 mg, 133 μmol) and N,N-diisopropylethylamine (52 mg, 400 μmol) were dissolved in dichloromethane (10 mL), and bis(4-nitrophenyl) carbonate (54 mg, 267 μmol) was added. The mixture was stirred at 40 °C overnight. The reaction solution was added to 20 mL of dichloromethane, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product compound LP-46-e (80 mg). ESI-MS (m / z): 914.5 [M+H] + .

[0885] Step six: synthesis of compound LP-46-f

[0886] The crude product compound LP-46-e (40 mg) and compound P-1 (20 mg, 42 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (22 mg, 168 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 90 / 10) to give compound LP-46-f (33 mg, yield 70%). ESI-MS (m / z): 1247.7 [M+H] + .

[0887] Step seven: synthesis of compound LP-46-g

[0888] Compound LP-46-f (33 mg, 26 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL), and 1 N aqueous lithium hydroxide solution (0.2 mL) was added. The mixture was stirred in an ice bath for 2 hours. The reaction solution was added to acetic acid to pH = 7, concentrated, and the residue was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (alkali method) to give compound LP-46-g (9 mg, yield 38%). ESI-MS (m / z): 885.5 [M+H] + .

[0889] Step eight: synthesis of compound LP-46

[0890] Compound LP-46-g (9 mg, 10 μmol) and compound LP-46-a (6 mg, 15 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropyl ethylamine (5.5 mg, 42 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was purified by preparative liquid chromatography (acid method) to obtain compound LP-46 (9 mg, yield 38%). ESI-MS (m / z): 1051.5 [M+H] +

[0891] Example 2.47: Synthesis of compound LP-47

[0892] Step one: Synthesis of compound LP-47-a

[0893] Compound LP-44-b (100 mg, 423 μmol) and N-hydroxysuccinimide (58 mg, 507 μmol) were dissolved in N,N-dimethylformamide (30 mL), N,N'-dicyclohexyl carbodiimide (105 mg, 507 μmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain compound LP-47-a (426 mg, yield 13%). ESI-MS (m / z): 334.5 [M+H] + .

[0894] Step two: Synthesis of compound LP-47-b

[0895] Compound LP-39-b (200 mg, 578 μmol) was dissolved in N,N-dimethylformamide (5 mL), compound LP-47-a (140 mg, 419 μmol) was added. The mixture was stirred at room temperature for 16 hours. 20 mL of water was added to the reaction solution, the pH was adjusted to 10 with saturated sodium bicarbonate solution, it was washed with ethyl acetate twice, the water phase was adjusted to pH 4-5 with citric acid solution, extracted with ethyl acetate three times. The organic phase was combined, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound LP-47-b (200 mg, yield 84%). ESI-MS (m / z): 564.5 [M+H] + .

[0896] Step three: Synthesis of compound LP-47-c

[0897] Compound LP-47-b (200 mg, 354 μmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL), and oxone (654 mg, 1.06 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was purified by reverse phase column chromatography (0.1% formic acid in water / acetonitrile = 50 / 50) to give compound LP-47-c (130 mg, 62% yield). ESI-MS (m / z): 596.6 [M+H] + .

[0898] Step four: synthesis of compound LP-47-d

[0899] Compound LP-47-c (15 mg, 25 μmol), compound P-l (10 mg, 21 μmol) and N,N- diisopropylethylamine (15 mg, 108 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (10 mg, 31 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by acetic acid, and purified by preparative liquid chromatography (acid method) to give compound LP-47-d (8 mg, 36% yield). ESI-MS (m / z): 1050.7 [M+H] + .

[0900] Step five: synthesis of compound LP-47

[0901] Compound LP-47-d (8 mg, 7.6 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction was concentrated, and the residue was lyophilized to give compound LP-47 (6 mg, 82% yield). ESI-MS (m / z): 950.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.11 (s, 2H), 8.74-8.65 (m, 1H), 8.48-8.38 (m, 1H), 8.26-8.11 (m, 4H), 8.00-7.92 (m, 1H), 7.72-7.59 (m, 4H), 7.55-7.47 (m, 1H), 7.37-7.23 (m, 3H), 6.41-6.28 (m, 1H), 4.79-4.56 (m, 5H), 4.34-4.27 (m, 1H), 4.21-4.15 (m, 1H), 3.41 (s, 3H), 2.80-2.72 (m, 2H), 2.43-2.29 (m, 3H), 2.03-1.96 (m, 3H), 1.83-1.71 (m, 4H), 1.65-1.51 (m, 4H), 0.86-0.81 (m, 6H), 0.80-0.63 (m, 3H).

[0902] Examples 2.48-2.50:

[0903] Using the same method and reaction conditions of Example 2.1, using compounds P-9, P-20 and P-21 as starting material instead of compound P-1, the target products in the following table were obtained.

[0904] Example 2.51: Synthesis of compound LP-51

[0905] Step one: Synthesis of compound LP-51-a

[0906] Dissolve 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (400 mg, 1.75 mmol) and (R)-methyl 2-aminobutanoate hydrochloride (275 mg, 1.75 mmol) in N,N-dimethylformamide (5 mL), add N,N-diisopropylethylamine (678 mg, 5.25 mmol). The mixture was stirred at 70 °C for 2 hours. The reaction was cooled to room temperature, added 50 mL ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated. The residue was purified by column chromatography (PE / EA = 80 / 20) to give compound LP-51-a (408 mg, yield 75%). ESI-MS (m / z): 310.8 [M+H] + .

[0907] Step two: Synthesis of compound LP-51-b

[0908] Compound LP-51-a (100 mg, 323 μmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (112 mg, 646 mmol) was added. The mixture was stirred at room temperature for 2 hours. 30 mL of dichloromethane was added to the reaction solution, and the mixture was washed twice with saturated sodium bicarbonate, twice with water, and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound LP-51-b (110 mg, 99% yield). ESI-MS (m / z): 342.3 [M+H] + .

[0909] Step 3: Synthesis of compound LP-51-c

[0910] Compound P-12-a (69 mg, 303 μmol) and N,N-diisopropylethylamine (118 mg, 910 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound LP-51-b (110 mg, 320 μmol) was added. The mixture was stirred overnight at room temperature. 20 mL of ethyl acetate was added to the reaction mixture, which was washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-51-c (87 mg, 59% yield). ESI-MS (m / z): 489.4 [M+H] + .

[0911] Step 4: Synthesis of compound LP-51-d

[0912] Compound LP-51-c (47 mg, 96 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL), and 0.2 mL of 1 N lithium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 3 hours. Acetic acid was added to the reaction solution to pH 7, and the solution was concentrated. The residue was purified by preparative liquid chromatography (alkaline method) to give compound LP-51-d (20 mg, yield 38%). ESI-MS (m / z): 475.5 [M+H] + .

[0913] Step 5: Synthesis of compound LP-51-e

[0914] Step five: synthesis of compound LP-51-e + .

[0915] Step six: synthesis of compound LP-51-f

[0916] Compound LP-51-e (50 mg, 85 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 0.5 h. The reaction was concentrated to give compound LP-51-f (41 mg, yield 99%). ESI-MS (m / z): 485.5 [M+H] + .

[0917] Step seven: synthesis of compound LP-51

[0918] Compound LP-51-f (15 mg, 31 μmol), compound LP-51-d (10 mg, 21 μmol) and N,N- diisopropylethylamine (8.17 mg, 63 μmol) were dissolved in N,N-dimethylformamide (2 mL), and O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (10 mg, 31 μmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was quenched by acetic acid, and purified by preparative liquid chromatography (acid method) to give compound LP-51 (3 mg, yield 15%). ESI-MS (m / z): 942.7 [M+H] + ; 1HNMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.89 (s, 1H), 8.68-8.59 (m, 1H), 8.45-8.35 (m, 4H), 8.19-8.13 (m, 2H), 8.12-8.04 (m, 2H), 7.85-7.81 (m, 1H), 7.56-7.48 (m, 3H), 7.36-7.34 (m, 1H), 7.22-7.16 (m, 2H), 7.13-7.11 (m, 1H), 7.00 (s, 2H), 4.86 (s, 2H), 4.72-4.58 (m, 3H), 4.38-4.35 (m, 1H), 4.28-4.24 (m, 1H), 4.18-4.15 (m, 1H), 4.11-4.06 (m, 1H), 2.22-2.06 (m, 5H), 2.03-1.92 (m, 4H), 1.83-1.75 (m, 2H), 1.72-1.62 (m, 2H), 0.87-0.83 (m, 5H), 0.83-0.79 (m, 4H), 0.68-0.64 (m, 2H).

[0919] Example 2.52: Synthesis of compound LP-52

[0920] Step one: Synthesis of compound LP-52-a

[0921] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5- oxopentanoic acid (5 g, 11.8 mmol) and (4-aminophenyl)methanol aniline (2.89 g, 23.5 mmol) were dissolved in dichloromethane (50 mL), and 2- ethoxy-1-ethyloxycarbonyl-1,2-dihydroquinoline (2.91 g, 11.8 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated, and the residue was slurried in methyl tert-butyl ether three times to give compound LP-52-a (4.6 g, yield 74%). ESI-MS (m / z): 531.4 [M+H] + .

[0922] Step two: Synthesis of compound LP-52-b

[0923] Compound LP-52-a (4.6 g, 8.67 mmol) was dissolved in N,N-dimethylformamide (20 mL), and diethylamine (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, and the residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-52-b (2.5 g, yield 94%). ESI-MS (m / z): 309.4 [M+H] + .

[0924] Step three: synthesis of compound LP-52-c

[0925] (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (2 g, 6.42 mmol), N,N- diisopropylethylamine (2.49 g, 19 mmol) and compound LP-52-b (2.97 g, 9.64 mmol) were dissolved in N,N-dimethylformamide (30 mL), and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.66 g, 9.64 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, which was extracted with ethyl acetate (100 mL) three times. The organic phases were combined and washed with water once and saturated brine once, dried, and concentrated. The residue was purified by flash column chromatography (PE / EA = 20 / 80) to obtain compound LP-52-c (2 g, yield 52%). ESI-MS (m / z): 602.5 [M+H] + .

[0926] Step four: synthesis of compound LP-52-d

[0927] Compound LP-52-c (2 g, 3.32 mmol) was dissolved in N,N-dimethylformamide (20 mL), and diethylamine (4 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound LP-52-d (600 mg, yield 48%). ESI-MS (m / z): 380.4 [M+H] + .

[0928] Step five: synthesis of compound LP-52-e

[0929] ((9H-fluoren-9-yl)methoxy)carbonyl)-D-leucine (605 mg, 1.71 mmol), N,N- diisopropylethylamine (511 mg, 3.95 mmol) and compound LP-52-d (500 mg, 1.32 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (752 mg, 1.98 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, which was extracted with ethyl acetate (30 mL) three times. The organic phases were combined and washed with water once and saturated brine once, dried, and concentrated. The residue was purified by flash column chromatography (PE / EA = 20 / 80) to obtain compound LP-52-e (900 mg, yield 96%). ESI-MS (m / z): 715.5 [M+H]+ .

[0930] Step six: synthesis of compound LP-52-f

[0931] Compound LP-52-e (900 mg, 1.26 mmol) was dissolved in N,N-dimethylformamide (20 mL), diethylamine (3 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated, the residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-52-f (450 mg, yield 72%). ESI-MS (m / z): 493.4 [M+H] + .

[0932] Step seven: synthesis of compound LP-52-g

[0933] Compound LP-52-f (380 mg, 771 μmol) was dissolved in N,N-dimethylformamide (5 mL), 3-maleimidopropionic acid N-hydroxysuccinimide ester (246 mg, 926 μmol) was added. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction, extracted with ethyl acetate (30 mL) three times, the organic phase was combined, washed with water once, saturated brine once, dried, concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-52-g (450 mg, yield 91%). ESI-MS (m / z): 644.5 [M+H] + .

[0934] Step eight: synthesis of compound LP-52-h

[0935] Compound LP-52-g (100 mg, 155 μmol) was dissolved in N,N-dimethylformamide (2 mL), bis(4-nitrophenyl) carbonate (94 mg, 310 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by column chromatography (EA = 100) to give compound LP-52-h (70 mg, yield 56%). ESI-MS (m / z): 809.5 [M+H] + .

[0936] Step nine: synthesis of compound LP-52-i

[0937] Compound P-1 (20 mg, 42 μmol) and N,N-diisopropylethylamine (11 mg, 85 mmol) were dissolved in N,N-dimethylformamide (2 mL), and compound LP-52-h (34 mg, 42 μmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-52-i (25 mg, yield 52%). ESI-MS (m / z): 1142.4 [M+H] + .

[0938] Step ten: synthesis of compound LP-52

[0939] Compound LP-52-i (25 mg, 22 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was continuously stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and the residue was obtained by lyophilization to obtain compound LP-52 (20 mg, yield 84%). ESI-MS (m / z): 1086.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.53 (s, 1H), 8.56-8.49 (m, 1H), 8.44-8.35 (m, 2H), 8.27-8.11 (m, 2H), 8.08-7.91 (m, 3H), 7.67-7.18 (m, 10H), 6.97 (s, 2H), 6.31-6.25 (m, 1H), 5.01 (s, 2H), 4.78-4.53 (m, 6H), 4.37-4.28 (m, 1H), 4.27-4.17 (m, 2H), 3.64-3.54 (m, 1H), 3.53-3.47 (m, 1H), 2.37-2.20 (m, 5H), 1.93-1.74 (m, 2H), 1.72-1.52 (m, 2H), 1.28-1.23 (m, 3H), 0.91-0.83 (m, 6H), 0.79-0.64 (m, 3H).

[0940] Example 2.53: synthesis of compound LP-53

[0941] Step one: synthesis of compound LP-53-a

[0942] Compound LP-44-f (1.24 g, 2.4 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (4 mL) was added. The mixture was continuously stirred at room temperature for 0.5 hours. The reaction solution was concentrated to obtain compound LP-53-a (1 g, yield 90%). ESI-MS (m / z): 464.6 [M+H] + .

[0943] Step two: synthesis of compound LP-53-b

[0944] Compound LP-53-a (1 g, 2.16 mmol), N,N-diisopropylethylamine (1.12 g, 8.6 mmol) and glycine tert-butyl ester (566 mg, 4.31 mmol) were dissolved in N,N-dimethylformamide (20 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.23 g, 3.24 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction, and it was extracted with ethyl acetate (30 mL) three times. The organic phases were combined and washed with water once and saturated brine once, dried, and concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 90 / 10) to obtain compound LP-53-b (1 g, yield 80%). ESI-MS (m / z): 577.5 [M+H] + .

[0945] Step three: synthesis of compound LP-53-c

[0946] Compound LP-53-b (1 g, 2.16 mmol) was dissolved in ethyl acetate (20 mL), and 10% palladium-carbon (0.1 g) was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction was filtered through diatomite, and concentrated to obtain compound LP-53-c (750 mg, yield 98%). ESI-MS (m / z): 443.5 [M+H] + .

[0947] Step four: synthesis of compound LP-53-d

[0948] Compound LP-53-c (600 mg, 1.36 mmol), N,N-diisopropylethylamine (700 mg, 5.42 mmol) and compound LP-44-c (566 mg, 4.31 mmol) were dissolved in N,N-dimethylformamide (20 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (773 mg, 2.03 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction, and it was extracted with ethyl acetate (30 mL) three times. The organic phases were combined and washed with water once and saturated brine once, dried, and concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 90 / 10) to obtain compound LP-53-d (330 mg, yield 35%). ESI-MS (m / z): 693.5 [M+H] + .

[0949] Step five: synthesis of compound LP-53-e

[0950] Compound LP-53-d (160 mg, 231 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added, and the mixture was continued to stir at room temperature for 0.5 h. The reaction solution was concentrated to give compound LP-53-e (145 mg, yield 99%). ESI-MS (m / z): 637.6 [M+H] + .

[0951] Step six: synthesis of compound LP-53

[0952] Compound LP-53-e (22 mg, 34 μmol), compound P-1 (15 mg, 31 μmol) and N,N- diisopropylethylamine (8 mg, 63 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (14 mg, 47 μmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-53 (10 mg, yield 29%). ESI-MS (m / z): 1091.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.43 - 11.35 (m, 1H), 9.10 (s, 2H), 8.59 - 8.48 (m, 1H), 8.37 - 8.30 (m, 2H), 8.18 - 8.05 (m, 4H), 7.94 - 7.89 (m, 1H), 7.68 - 7.63 (m, 1H), 7.52 - 7.44 (m, 1H), 7.37 - 7.28 (m, 1H), 7.25 - 7.17 (m, 2H), 6.27 (s, 1H), 4.76 - 4.56 (m, 5H), 4.26 - 4.13 (m, 2H), 3.88 - 3.82 (m, 1H), 3.78 - 3.73 (m, 1H), 3.40 (s, 3H), 2.39 - 2.29 (m, 10H), 1.95 - 1.88 (m, 1H), 1.85 - 1.75 (m, 3H), 1.72 - 1.64 (m, 2H), 1.60 - 1.54 (m, 1H), 1.40 - 1.32 (m, 6H), 1.29 - 1.21 (m, 2H), 0.85 - 0.79 (m, 12H), 0.76 - 0.65 (m, 3H).

[0953] Example 2.54: synthesis of compound LP-54

[0954] Step one: synthesis of compound LP-54-a

[0955] (2R,3S,4S,5R,6R)-2-(acetyloxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triacetate (5 g, 12 mmol) and 4-hydroxy-3-nitrobenzaldehyde (2.03 g, 12.2 mmol) were dissolved in acetonitrile (100 mL), silver oxide (1.46 g, 6.29 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was filtered through celite, concentrated. The residue was purified by column chromatography (PE / EA = 40 / 60) to give compound LP-54-a (3.5 g, yield 58%). ESI-MS (m / z): 498.5 [M+H] + .

[0956] Step two: synthesis of compound LP-54-b

[0957] Compound LP-54-a (3 g, 6.03 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL) and methanol (5 mL), sodium borohydride (228 mg, 6.03 mmol) was added slowly under ice bath. The mixture was allowed to warm to room temperature and stirred for 2 hours. To the reaction was added aqueous ammonium chloride solution (50 mL) to quench, extracted with ethyl acetate (50 mL) for three times, combined organic phase was washed with water once, saturated brine once, dried, concentrated. The residue was purified by column chromatography (PE / EA = 40 / 60) to give compound LP-54-b (750 mg, yield 25%). ESI-MS (m / z): 500.5 [M+H] + .

[0958] Step three: synthesis of compound LP-54-c

[0959] Compound LP-54-b (750 mg, 1.51 mmol) was dissolved in tetrahydrofuran (20 mL), palladium hydroxide on carbon (200 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere overnight. The reaction was filtered through celite, concentrated. The residue was purified by column chromatography (PE / EA = 20 / 80) to give compound LP-54-c (500 mg, yield 70%). ESI-MS (m / z): 470.5 [M+H] + .

[0960] Step four: synthesis of compound LP-54-d

[0961] Compound LP-54-c (7.30 g, 15.5 mmol) and 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (4.84 g, 15.5 mmol) were dissolved in dichloromethane (100 mL), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (5.77 g, 23.3 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was concentrated, and the residue was purified by column chromatography (PE / EA = 50 / 50) to give compound LP-54-d (4.89 g, yield 41%). ESI-MS (m / z): 763.5 [M+H] + .

[0962] Step five: synthesis of compound LP-54-e

[0963] Compound LP-54-d (200 mg, 262 μmol) and N,N-diisopropylethylamine (104 mg, 800 μmol) were dissolved in dichloromethane (10 mL), and bis(4-nitrophenyl) carbonate (105 mg, 523 μmol) was added. The mixture was stirred at 40 °C overnight. The reaction was concentrated, and the residue was purified by column chromatography (PE / EA = 50 / 50) to give compound LP-54-e (186 mg, yield 76%). ESI-MS (m / z): 928.5 [M+H] + .

[0964] Step six: synthesis of compound LP-54-f

[0965] Compound LP-54-e (108 mg, 116 μmol) and compound P-1 (50 mg, 105 μmol) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (27 mg, 211 μmol) was added. The mixture was stirred at room temperature overnight. The reaction was added to 20 mL of ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-54-f (123 mg, yield 92%). ESI-MS (m / z): 1261.7 [M+H] + .

[0966] Step seven: synthesis of compound LP-54-g

[0967] Compound LP-54-f (51 mg, 40 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL), and 1 N aqueous lithium hydroxide solution (0.2 mL) was added. The mixture was stirred in an ice bath for 2 hours. The reaction solution was added with acetic acid to pH = 7, concentrated, and the residue was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (alkali method) to obtain compound LP-54-g (20 mg, yield 50%). ESI-MS (m / z): 871.5 [M+H] + .

[0968] Step eight: synthesis of compound LP-54-h

[0969] Compound LP-54-g (10 mg, 11 μmol) and compound LP-46-a (7 mg, 17 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (5.5 mg, 42 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-54-h (12 mg, yield 92%). ESI-MS (m / z): 1137.5 [M+H] + .

[0970] Step nine: synthesis of compound LP-54

[0971] Compound LP-54-h (12 mg, 11 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was continuously stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and the residue was obtained by lyophilization to obtain compound LP-54 (20 mg, yield 84%). ESI-MS (m / z): 1037.5 [M+H] + ; 1H NMR (500 MHz, Methanol-d4) δ 8.62-8.54 (m, 1H), 8.33-8.27 (m, 1H), 8.23-8.18 (m, 1H), 8.17-8.11 (m, 1H), 7.78-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.48-7.42 (m, 1H), 7.28-7.22 (m, 1H), 7.14-7.08 (m, 1H), 6.90 (s, 2H), 5.10 (s, 2H), 4.98-4.90 (m, 3H), 4.85-4.79 (m, 3H), 4.78-4.70 (m, 2H), 4.64-4.58 (m, 1H), 3.93-3.90 (m, 1H), 3.90-3.83 (m, 1H), 3.80-3.76 (m, 2H), 3.67-3.59 (m, 3H), 3.55-3.48 (m, 2H), 3.46-3.36 (m, 2H), 2.66-2.55 (m, 2H), 2.22-2.14 (m, 1H), 1.90-1.72 (m, 2H), 1.62-1.57 (m, 1H), 1.40-1.31 (m, 5H), 0.91-0.88 (m, 1H), 0.84-0.75 (m, 3H).

[0972] Example 2.55: Synthesis of compound LP-55

[0973] Step one: Synthesis of compound LP-55-a

[0974] Compound LP-39-a (8 g, 16.7 mmol) and N-hydroxysuccinimide (3.84 g, 33.4 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N'-dicyclohexylcarbodiimide (6.88 g, 33.4 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography (PE / EA = 50 / 50) to obtain compound LP-55-a (9 g, yield 94%). ESI-MS (m / z): 577.5 [M+H] + .

[0975] Step two: Synthesis of compound LP-55-b

[0976] Glycine (1.29 g, 17.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), and compound LP-55-a (9 g, 15.6 mmol) and N,N-diisopropylethylamine (3.03 g, 23.4 mmol) were added. The mixture was stirred at 50 °C for 16 h. The reaction was concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-55-b (4 g, yield 48%). ESI-MS (m / z): 537.6 [M+H] + .

[0977] Step three: synthesis of compound LP-55-c

[0978] Compound LP-55-b (800 mg, 1.49 mmol) was dissolved in ethanol (10 mL), and 10% palladium carbon (0.2 g) was added. The mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction was filtered through celite, and concentrated to give compound LP-55-c (600 mg, yield 99%). ESI-MS (m / z): 403.3 [M+H] + .

[0979] Step four: synthesis of compound LP-55-d

[0980] Compound LP-55-c (300 mg, 745 μmol) and 2,5-dioxopyrrolidin-1-yl 1-(2,5-dihydro-2,5- dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16-tetraoxo-4-azanonadecan-19-oate (402 mg, 782 μmol) were dissolved in N,N-dimethylformamide (5 mL), and N-methylmorpholine (151 mg, 1.49 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was concentrated. The residue was purified by column chromatography (DCM / MeOH = 85 / 15) to give compound LP-55-d (75 mg, yield 13%). ESI-MS (m / z): 801.5 [M+H] + .

[0981] Step five: synthesis of compound LP-55-e

[0982] Compound LP-55-d (38 mg, 47 µmol) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (7.3 mg, 63 µmol), 3-(3-dimethylaminopropyl)-1- ethylcarbodiimide hydrochloride (38 mg, 47 µmol) were added. The mixture was stirred at room temperature for 1 hour. To the reaction was added compound P-1 (15 mg, 31 µmol) and N,N-diisopropylethylamine (12 mg, 90 µmol), the mixture was continued to stir at room temperature for 2 hours. The reaction was purified by preparative liquid chromatography (acid method) to give compound LP-55-e (8 mg, yield 20%). ESI-MS (m / z): 1255.5 [M+H] + .

[0983] Step six: synthesis of compound LP-55

[0984] Compound LP-55-e (8 mg, 6 µmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, the mixture was continued to stir at room temperature for 0.5 hour. The reaction was concentrated, the residue was obtained by lyophilization to give compound LP-55 (5 mg, yield 62%). ESI-MS (m / z): 1155.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.68-8.59 (m, 1H), 8.56-8.48 (m, 1H), 8.34-8.30 (m, 1H), 8.24-8.18 (m, 1H), 8.16-8.11 (m, 2H), 7.90-7.84 (m, 1H), 7.68-7.53 (m, 5H), 7.43-7.27 (m, 3H), 7.24-7.18 (m, 1H), 7.13-7.08 (m, 1H), 7.00 (s, 2H), 6.51-6.31 (m, 1H), 4.81-4.52 (m, 6H), 4.27-4.10 (m, 4H), 3.48-3.43 (m, 12H), 3.39-3.32 (m, 4H), 3.16-3.12 (m, 2H), 2.77-2.72 (m, 3H), 2.35-2.30 (m, 3H), 2.05-1.95 (m, 2H), 1.82-1.63 (m, 4H), 1.38-1.30 (m, 3H), 0.84-0.79 (m, 6H), 0.77-0.62 (m, 3H).

[0985] Example 2.56: synthesis of compound LP-56

[0986] Step one: synthesis of compound LP-56-a

[0987] (S)-2-((S)-2-amino-3-methylbutylamino)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (141 mg, 372 μmol), compound LP-44-c (100 mg, 372 μmol) and N,N- diisopropylethylamine (96 mg, 746 μmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (141 mg, 372 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-56-a (178 mg, yield 76%). ESI-MS (m / z): 630.5 [M+H] + .

[0988] Step two: synthesis of compound LP-56-b

[0989] Compound LP-56-a (100 mg, 158 μmol) and N,N-diisopropylethylamine (62 mg, 476 μmol) were dissolved in N,N-dimethylformamide (10 mL), and bis(4- nitrophenyl) carbonate (105 mg, 523 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate to give compound LP-56-b (120 mg, yield 95%). ESI-MS (m / z): 795.5 [M+H] + .

[0990] Step three: synthesis of compound LP-56

[0991] Compound LP-56-b (17 mg, 21 μmol) and compound P-l (10 mg, 21 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (10 mg, 88 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-56 (15 mg, yield 63%). ESI-MS (m / z): 1128.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.03 (s, 1H), 9.12 (s, 2H), 8.39 - 8.36 (m, 1H), 8.20 - 8.07 (m, 4H), 7.99 - 7.92 (m, 2H), 7.66 - 7.58 (m, 3H), 7.50 - 7.44 (m, 1H), 7.36 - 7.18 (m, 5H), 6.31 - 6.24 (m, 1H), 6.03 - 5.96 (m, 1H), 5.43 (s, 2H), 5.00 (s, 2H), 4.77 - 4.55 (m, 5H), 4.43 - 4.36 (m, 1H), 4.27 - 4.22 (m, 1H), 3.41 (s, 3H), 3.04 - 2.93 (m, 2H), 2.58 - 2.53 (m, 2H), 2.40 - 2.32 (m, 2H), 2.03 - 1.92 (m, 2H), 1.88 - 1.77 (m, 3H), 1.70 - 1.60 (m, 2H), 1.47 - 1.35 (m, 2H), 0.90 - 0.82 (m, 6H), 0.79 - 0.64 (m, 3H).

[0992] Example 2.57: Synthesis of compound LP-57

[0993] Step one: Synthesis of compound LP-57

[0994] Compound LP-41-b (15 mg, 28 μmol), compound LP-44-i (18 mg, 30 μmol) and N,N- diisopropylethylamine (7 mg, 55 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (9 mg, 30 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-57 (9 mg, 29% yield). ESI-MS (m / z): 1103.6 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.17 - 9.06 (m, 2H), 8.63 - 8.49 (m, 2H), 8.36 - 8.27 (m, 2H), 8.18 - 7.92 (m, 5H), 7.78 (d, J = 5.0 Hz, 1H), 7.53 (s, 1H), 7.35 - 7.27 (m, 1H), 5.65 - 5.46 (m, 1H), 4.73 - 4.44 (m, 4H), 4.29 - 4.13 (m, 3H), 3.74 - 3.67 (m, 3H), 3.41 (s, 3H), 2.33 - 2.18 (m, 8H), 2.02 - 1.91 (m, 2H), 1.82 - 1.75 (m, 2H), 1.74 - 1.57 (m, 2H), 1.56 - 1.43 (m, 2H), 1.36 - 1.30 (m, 6H), 1.15 - 1.05 (m, 2H), 0.98 - 0.89 (m, 4H), 0.85 - 0.76 (m, 12H).

[0995] Example 2.58: Synthesis of compound LP-58

[0996] Step one: Synthesis of compound LP-58

[0997] Compound LP-56-b (7 mg, 8 μmol) and compound P-23 (4 mg, 8 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (3 mg, 25 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to obtain compound LP-58 (8 mg, yield 85%). ESI-MS (m / z): 1138.5 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 12.44 - 12.34 (m, 1H), 10.10 - 9.95 (m, 1H), 9.12 (s, 2H), 8.41 - 8.32 (m, 1H), 8.29 - 8.07 (m, 4H), 7.96 (d, J = 8.6 Hz, 1H), 7.82 - 7.75 (m, 1H), 7.63 - 7.46 (m, 3H), 7.35 - 7.04 (m, 3H), 6.10 - 5.99 (m, 1H), 5.78 - 5.63 (m, 1H), 5.61 - 5.32 (m, 3H), 5.07 - 4.55 (m, 4H), 4.42 - 4.36 (m, 1H), 4.27 - 4.22 (m, 1H), 4.20 - 4.00 (m, 1H), 3.97 - 3.84 (m, 2H), 3.81 - 3.76 (m, 1H), 3.42 (s, 3H), 3.22 - 3.12 (m, 1H), 3.06 - 2.92 (m, 2H), 2.57 - 2.54 (m, 2H), 2.42 - 2.33 (m, 2H), 2.02 - 1.97 (m, 1H), 1.87 - 1.79 (m, 2H), 1.73 - 1.33 (m, 7H), 0.89 - 0.86 (m, 3H), 0.86 - 0.82 (m, 3H).

[0998] Example 2.59: Synthesis of compound LP-59

[0999] Step one: Synthesis of compound LP-59-a

[1000] Methyl ((2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl)amino)acetate (71 mg, 193 μmol) was dissolved in dichloromethane (5 mL), and trimethylsilyl chloride (428 mg, 3.94 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was dissolved in dichloromethane (5 mL), and compound P-19 (50 mg, 97 μmol) was added. The mixture was stirred at 60 °C overnight. The reaction was cooled to room temperature and concentrated to give the crude product compound LP-59-a (60 mg). ESI-MS (m / z): 824.5 [M+H] + .

[1001] Step two: Synthesis of compound LP-59-b

[1002] The crude product compound LP-59-a (60 mg) was dissolved in N,N- dimethylformamide (1 mL), diethylamine (0.2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (base method) to give compound LP-59-b (15 mg, yield 26%). ESI-MS (m / z): 602.4 [M+H] + .

[1003] Step three: synthesis of compound LP-59-c

[1004] N-Fluorenylmethoxycarbonyl-glycyl-glycine (2.00 g, 5.64 mmol), L-phenylalanine tert-butyl ester hydrochloride (1.6 g, 6.21 mmol) and N,N-diisopropylethylamine (1.46 g, 11 mmol) were dissolved in N,N-dimethylformamide (20 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.22 g, 8.47 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to 100 mL ethyl acetate, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to give compound LP-59-c (5.6 g, yield 98%). ESI-MS (m / z): 558.5 [M+H] + .

[1005] Step four: synthesis of compound LP-59-d

[1006] Compound LP-59-c (5.6 g, 5.52 mmol) was dissolved in N,N-dimethylformamide (50 mL), diethylamine (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was purified by column chromatography (DCM / MeOH = 90 / 10) to give compound LP-59-d (1 g, yield 54%). ESI-MS (m / z): 336.4 [M+H] + .

[1007] Step five: synthesis of compound LP-59-e

[1008] Compound LP-44-c (105 mg, 391 μmol), compound LP-59-d (131 mg, 391 μmol) and N,N-diisopropylethylamine (152 mg, 1.17 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (223 mg, 587 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added into ethyl acetate, washed with water for three times, saturated brine for once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 95 / 5) to obtain compound LP-59-e (290 mg, yield 75%). ESI-MS (m / z): 586.5 [M+H] + .

[1009] Step six: synthesis of compound LP-59-f

[1010] Compound LP-59-e (292 mg, 374 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound LP-59-f (230 mg, yield 95%). ESI-MS (m / z): 530.5 [M+H] + .

[1011] Step seven: synthesis of compound LP-59

[1012] Compound LP-59-f (11 mg, 20 μmol), compound LP-59-b (8 mg, 13 μmol) and N,N-diisopropylethylamine (7 mg, 55 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (6 mg, 20 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to obtain compound LP-59 (6 mg, yield 41%). ESI-MS (m / z): 1113.6 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 2H), 8.75 - 8.68 (m, 1H), 8.39 - 8.32 (m, 2H), 8.21 - 8.07 (m, 7H), 7.72 - 7.68 (m, 1H), 7.46 - 7.40 (m, 3H), 7.36 - 7.30 (m, 1H), 7.25 - 7.22 (m, 4H), 7.19 - 7.14 (m, 1H), 6.02 - 5.92 (m, 1H), 4.79 - 4.72 (m, 2H), 4.68 (s, 2H), 4.66 - 4.47 (m, 5H), 3.78 - 3.69 (m, 5H), 3.63 - 3.57 (m, 1H), 3.40 (s, 3H), 3.21 (s, 3H), 3.09 - 3.02 (m, 1H), 2.85 - 2.78 (m, 1H), 2.60 - 2.54 (m, 2H), 2.35 - 2.31 (m, 2H), 1.85 - 1.78 (m, 2H), 1.08 - 0.96 (m, 3H).

[1013] Example 2.60: Synthesis of compound LP-60

[1014] Step one: Synthesis of compound LP-60

[1015] Compound LP-53-e (7.6 mg, 12 μmol), compound P-24 (5 mg, 11 μmol) and N,N- diisopropylethylamine (3 mg, 22 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (5 mg, 16 μmol) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction solution was quenched by acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-60 (3 mg, yield 26%). ESI-MS (m / z): 1079.6 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.11 (s, 2H), 8.69 - 8.42 (m, 2H), 8.39 - 8.31 (m, 3H), 8.14 - 8.05 (m, 2H), 7.97 - 7.86 (m, 1H), 7.55 - 7.43 (m, 1H), 7.28 - 7.15 (m, 2H), 5.30 - 5.12 (m, 1H), 4.88 - 4.51 (m, 4H), 4.25 - 4.13 (m, 2H), 3.93 - 3.72 (m, 4H), 3.41 (s, 3H), 2.57 - 2.52 (m, 2H), 2.38 - 2.26 (m, 7H), 2.08 - 1.43 (m, 6H), 1.40 - 1.31 (m, 6H), 1.28 - 1.24 (m, 3H), 1.12 - 1.05 (m, 3H), 1.04 - 0.94 (m, 2H), 0.87 - 0.77 (m, 12H).

[1016] Example 2.61: Synthesis of compound LP-61

[1017] Step one: Synthesis of compound LP-61

[1018] Compound LP-59-f (12 mg, 22 μmol), compound LP-41-b (10 mg, 18 μmol) and N,N- diisopropylethylamine (25 mg, 46 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N,N',N'-tetramethyl-O-(N-succinimidyl)urea tetrafluoroborate (8 mg, 27 μmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction solution was quenched with acetic acid and purified by preparative liquid chromatography (acid method) to give compound LP-60 (2 mg, yield 9.3%). ESI-MS (m / z): 1053.6 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.09 (s, 2H), 8.58 - 8.55 (m, 1H), 8.34 - 8.27 (m, 1H), 8.22 - 8.03 (m, 6H), 7.81 - 7.78 (m, 1H), 7.56 - 7.51 (m, 1H), 7.35 - 7.28 (m, 1H), 7.26 - 7.15 (m, 5H), 6.11 - 5.68 (m, 1H), 4.78 - 4.16 (m, 6H), 3.78 - 3.52 (m, 12H), 2.58 - 2.55 (m, 2H), 2.34 - 2.31 (m, 3H), 1.86 - 1.78 (m, 2H), 1.03 - 0.88 (m, 6H).

[1019] Example 2.62: Synthesis of compound LP-62

[1020] Step one: Synthesis of compound LP-62

[1021] Compound LP-1-a (8 mg, 10 μmol) and compound P-23 (5 mg, 10 μmol) were dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (3 mg, 25 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by preparative liquid chromatography (acid method) to give compound LP-62 (4 mg, yield 32%). ESI-MS (m / z): 1081.5 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 10.06 - 9.90 (m, 1H), 8.65 - 8.33 (m, 1H), 8.21 - 8.03 (m, 3H), 7.84 - 7.72 (m, 2H), 7.61 - 7.42 (m, 3H), 7.37 - 7.04 (m, 4H), 6.99 (s, 2H), 6.12 - 5.77 (m, 2H), 5.54 - 5.28 (m, 2H), 5.07 - 4.89 (m, 2H), 4.68 - 4.32 (m, 4H), 4.23 - 4.15 (m, 2H), 3.41 - 3.33 (m, 3H), 3.13 - 2.90 (m, 4H), 2.22 - 2.06 (m, 3H), 2.00 - 1.88 (m, 1H), 1.69 - 1.28 (m, 13H), 0.85 - 0.79 (m, 6H).

[1022] Example 2.63: Synthesis of compound LP-63

[1023] Step one: Synthesis of compound LP-63-a

[1024] Compound L-alanine (7 g, 79 mmol) was dissolved in methanol (400 mL), potassium carbonate (29.3 g, 212 mmol), copper sulfate pentahydrate (196 mg, 786 μmol) and 1H-imidazole-1-sulfonyl azide hydrochloride (19.8 g, 94 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, 100 mL water was added, adjusted to pH = 1 with dilute hydrochloric acid, extracted with dichloromethane three times, the organic phase was combined, dried and concentrated to give compound LP-63-a (7.5 g, yield 83%).

[1025] Step two: Synthesis of compound LP-63-b

[1026] Compound LP-63-a (7.5 g, 65 mmol) and (4-aminophenyl)methanol (16 g, 130 mmol) were dissolved in a mixture of dichloromethane (150 mL) and methanol (75 mL), and 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (16.1 g, 65.2 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was concentrated, and the residue was purified by column chromatography (PE / EA = 50 / 50) to give compound LP-63-b (9.9 g, yield 69%). ESI-MS (m / z): 221.4 [M+H] + .

[1027] Step three: synthesis of compound LP-63-c

[1028] Compound LP-63-b (3 g, 13.6 mmol) and triethylamine (4.14 g, 40.9 mmol) were dissolved in tetrahydrofuran (75 mL), and bis(4-nitrophenyl) carbonate (4.56 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 hour, and 2-(methylsulfonyl)ethylamine (2.52 g, 20.4 mmol) was added, and stirring was continued for 1 hour. The reaction was concentrated, and 100 mL of ethyl acetate was added, which was washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 5 / 95) to give compound LP-63-c (4.2 g, yield 83%). ESI-MS (m / z): 370.4 [M+H] + .

[1029] Step four: synthesis of compound LP-63-d

[1030] Compound LP-63-c (1.9 g, 5.14 mmol) and paraformaldehyde (232 mg, 7.7 mmol) were dissolved in dichloromethane (70 mL), and trimethylsilyl chloride (5.59 g, 51 mmol) was added. The mixture was stirred at room temperature for 2 ho...

Claims

1. An antibody-drug conjugate compound of Formula I: ###0001### or a pharmaceutically acceptable salt or solvate thereof. wherein, Ab is an antibody or an antigen binding fragment thereof, or an antigen ligand; P is a Cyclin K protein degrader fragment; L is a fragment covalently linking Ab and P; q is the number of L-P conjugation on Ab, q is selected from any value between 1.0-16.

0.

2. The antibody-drug conjugate compound of claim 1, wherein, P is a structural unit of formula II, P is linked to L via an oxygen atom, a sulfur atom or a nitrogen atom contained therein: wherein, R cy selected from: wherein, each independently represents a single bond or a double bond; W 1 each independently represents CR, N or a bond; W 2 each independently represents CR 0 , N, NR a , S or O; W 3 each independently represents C or N, but at most 2 W 3 is simultaneously N; W 4 each independently represents CR 1 , N, NR a , S or O; W 5 each independently represents CR or N, and at most 2 W 5 is simultaneously N; R 4 represents a phenyl ring or a 5-6 membered heteroaromatic ring, each of which can be optionally substituted with 0, 1, or 2 R; R, R 0 and R 1 each independently represents hydrogen, halogen, nitro, cyano, -R a , -OR a , -SR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , -C1-C6alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, which alkyl, alkenyl or alkynyl can be optionally substituted with 0 to 3 substituents selected from -OR a , -SR a , -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b ; wherein R a in said -NR b C(O)R b may optionally be substituted with 0, 1 or 2 substituents selected from -(C0-C3alkylene)OR a , -(C0-C3alkylene)SR a , -(C0-C3alkylene)NR a R b ; R L and R L’ each independently represent hydrogen, fluorine, C1-C6alkyl or C3-C6cycloalkyl, R L and R L’ may form together with the carbon atom to which they are attached a 3-6 membered ring; R 2 represents halogen, -R a , -OR a , -SR a , nitro, cyano, -NR a R b , -NR a C(O)R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)2R a , -S(O)R a , -S(O)2NR a R b , -P(O)R a R b , -(C2-C6)alkenyl, -(C2-C6)alkynyl; R 3 Represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 quinone heteroaryl, -NR M R N -NHR M -OR M -SR M ; When R 3 Represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C 10 When the alkyl or 3-10 membered heterocyclic alkyl group is used, it may optionally be substituted by 0, 1, 2, or 3 substituents selected from the following: oxo, nitro, halogen, cyano, -R. a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -(C0-C6 alkylene)NR a C(O)R b -(C0-C6 alkylene)C(O)R a -(C0-C6 alkylene)C(O)OR a -(C0-C6 alkylene)C(O)NR a R b -(C0-C6 alkylene)S(O)2R a -(C0-C6 alkylene)S(O)R a -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)P(O)R a R b ; When R 3 Indicates C6-C 10 When aryl or 5-10-membered heteroaryl, it may optionally be substituted by 0, 1, 2, or 3 substituents selected from the following: nitro, halogen, cyano, -R. a -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a -(C0-C6 alkylene)NR a R b -(C0-C6 alkylene)NR a C(O)R b -(C0-C6 alkylene)C(O)R a -(C0-C6 alkylene)C(O)OR a -(C0-C6 alkylene)C(O)NR a R b -(C0-C6 alkylene)S(O)2R a -(C0-C6 alkylene)S(O)R a -(C0-C6 alkylene)S(O)2NR a R b -(C0-C6 alkylene)P(O)R a R b ; R 3 represents -NR M R N R M R M R M R M R N each independently represents C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); each of R M and R N is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR a C(O)R b , -(C0-C6alkylene)C(O)R a , -(C0-C6alkylene)C(O)OR a , -(C0-C6alkylene)C(O)NR a R b , -(C0-C6alkylene)S(O)2R a , -(C0-C6alkylene)S(O)R a , -(C0-C6alkylene)S(O)2NR a R b , -(C0-C6alkylene)P(O)R a R b ; wherein, when R M or R N represents -(C0-C6alkylene)(3-10 membered heterocycloalkyl) containing a N atom and the substituent is on the N atom, the C atom on the N atom vicinal to the substituent can be further substituted with oxo; wherein R a , R b each independently represent hydrogen, C1-C6alkyl or C3-C8cycloalkyl, which alkyl or cycloalkyl groups can each be optionally substituted with 0, 1, 2, 3 halogen atoms; the above-mentioned alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl can each be optionally substituted with 0, 1, 2, 3 halogen atoms.

3. The antibody-drug conjugate compound of claim 2, wherein, R cy selected from the group consisting of: or W 1 , W 2 , W 3 , W 4 , W 5 , R 4 as defined in claim 2.

4. The antibody-drug conjugate compound of claim 3, wherein, R cy selected from the group consisting of: wherein each X independently represents NR a , O or S; W 1 each independently represents CR or N; W 2 each independently represents CR 0 or N; W 4 each independently represents CR 1 or N; W 5 each independently represents CR or N, at most 2 W 5 may be N simultaneously; the remaining groups are as defined in claim 2.

5. The antibody-drug conjugate compound of claim 4, wherein, R cy selected from the group consisting of: R, R 1 As defined in claim 2.

6. The antibody-drug conjugate compound of claim 1, wherein, P is a structural unit of the formula III-a, III-b, III-c, III-d, P being attached to L via an oxygen atom, a sulfur atom or a nitrogen atom contained therein: wherein R cy , R 2 and R 3 are as defined in claim 2.

7. The antibody-drug conjugate compound of claim 1, wherein, P is a structural unit of the formula IV, P is bonded to L via an oxygen atom, a sulfur atom or a nitrogen atom contained therein: Among them, R 41 Selected from: C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl group may optionally be substituted with 1, 2, or 3 of the following groups: H, CN, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, -NR M R N -NHR M -OR M -SR M ; R cy , R 2 , R M and R N as defined in claim 2.

8. The antibody-drug conjugate compound of claim 1, wherein, P is a structural unit of the formula V, P is bonded to L via an oxygen atom, a sulfur atom or a nitrogen atom contained therein: Among them, R 51 Selected from: C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl; R cy and R 3 as defined in claim 2.

9. The antibody-drug conjugate compound of claim 1, wherein, P is a structural unit of the formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, P being attached to L via an oxygen atom, a sulfur atom or a nitrogen atom contained therein: wherein R 61 each is independently selected from a 5-12 membered heteroaromatic ring or a 6-12 membered aromatic ring, which aromatic and heteroaromatic rings can be optionally substituted with 1, 2, or 3 of H, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl; R 62 each independently is selected from: H or C1-C4alkyl; R 63 each independently is selected from the group consisting of H, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C6cycloalkyl.

10. The antibody-drug conjugate compound of any of the preceding claims, wherein, R 3 represents -NR M R N represents -NHR M represents -OR M represents -SR M R M and R N each independently represents C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); R M and R N each is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR a C(O)R b , -(C0-C6alkylene)C(O)R a , -(C0-C6alkylene)C(O)OR a , -(C0-C6alkylene)C(O)NR a R b , -(C0-C6alkylene)S(O)2R a , -(C0-C6alkylene)S(O)R a , -(C0-C6alkylene)S(O)2NR a R b , -(C0-C6alkylene)P(O)R a R b ; wherein, when R M or R N represents -(C0-C6alkylene)(3-10 membered heterocycloalkyl) containing a N atom and the substituent is on the N atom, the C atom on the N atom vicinal to the N atom can be further substituted with oxo.

11. The antibody-drug conjugate compound of any of the preceding claims, wherein, R and R 1 each independently represent hydrogen, halogen, cyano, -R a , -(C0-C2alkylene)OH, -(C0-C2alkylene)NH2, R a as defined in claim 2.

12. The antibody-drug conjugate compound of any of the preceding claims, wherein, R 2 represents halogen, -R a , nitro, cyano, -S(O)2R a , (C2-C6)alkenyl, (C2-C6)alkynyl.

13. The antibody-drug conjugate compound of any one of the preceding claims, wherein, R 2 represents halogen, trifluoromethyl, cyano, -S(O)2Me, vinyl, ethynyl.

14. The antibody-drug conjugate compound of any of the preceding claims, wherein, R cy selected from the group consisting of: or R 3 represents -NR M R N , -NHR M , -OR M , -SR M , R M and R N each independently represents C1-C6alkyl, -(C0-C6alkylene)(C3-C 10 cycloalkyl), -(C0-C6alkylene)(3-10 membered heterocycloalkyl), -(C0-C6alkylene)(C6-C 10 aryl), -(C0-C6alkylene)(5-10 membered heteroaryl); R M and R N each is optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of oxo, nitro, halogen, cyano, -R a , -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , -(C0-C6alkylene)NR a R b , -(C0-C6alkylene)NR a C(O)R b , -(C0-C6alkylene)C(O)R a , -(C0-C6alkylene)C(O)OR a , -(C0-C6alkylene)C(O)NR a R b , -(C0-C6alkylene)S(O)2R a , -(C0-C6alkylene)S(O)R a , -(C0-C6alkylene)S(O)2NR a R b , -(C0-C6alkylene)P(O)R a R b ; wherein, when R M or R N represents -(C0-C6alkylene)(3-10 membered heterocycloalkyl) containing a N atom and the substituent is on the N atom, the C atom on the N atom vicinal to the N atom can be further substituted with oxo; the remaining groups are as defined in the cited claim.

15. The antibody-drug conjugate compound of any of the preceding claims, wherein, R cy selected from the group consisting of: wherein each X independently represents NR a , O or S; W 1 each independently represents CR or N; W 2 each independently represents CR 0 or N; W 4 each independently represents CR 1 or N; W 5 each independently represents CR or N, at most 2 W 5 may be N simultaneously; R 2 represents halogen, -R a , nitro, cyano, -S(O)2R a , (C2-C6)alkenyl, (C2-C6)alkynyl; the remaining groups are as defined in the cited claim.

16. The antibody-drug conjugate compound of any of the preceding claims, wherein, P is a fragment of Formula II-a, Formula II-b, Formula II- c. a structural unit of the formula II-d, P is attached to L via an oxygen atom, a sulfur atom or a nitrogen atom contained in P; R and R 1 each independently represent hydrogen, halogen, cyano, -R a , -(C0-C2alkylene)OH, -(C0-C2alkylene)NH2; R 2 represents halogen, trifluoromethyl, cyano, -S(O)2Me, vinyl, ethynyl; the remaining groups are as defined in the cited claim.

17. The antibody-drug conjugate compound of any of the preceding claims, wherein, P is selected from the group consisting of fragments of the following structures, P is attached to L via an oxygen atom or a nitrogen atom contained therein:

18. The antibody-drug conjugate compound of any of the preceding claims, wherein, - P is selected from the following structures:

19. The antibody-drug conjugate compound of any of the preceding claims, wherein, P is selected from the group consisting of fragments of the following structures, P is attached to L via an oxygen or nitrogen atom contained therein:

20. The antibody-drug conjugate compound of any of the preceding claims, wherein, - P is selected from the following structures:

21. The antibody-drug conjugate compound of any of the preceding claims, wherein, L is -L1-L2-L3-L4-L5-, wherein L1 links Ab, L5 links P, but when L5 is a direct bond, L4 links P, wherein: L1is selected from: Preferably, L1is selected from: or L2is selected from: wherein each E is independently selected from a direct bond, an alkyne bond, a phenyl group, a 5-6 membered heteroaryl group, an amide group, said phenyl and 5-6 membered heteroaryl groups can be optionally substituted with 0, 1 or 2 of the following substituents: F, Cl, methyl, methoxy, each a1 is independently selected from 1, 2, 3, 4, 5 and 6, each a2 is independently selected from 0, 1, 2, 3, 4, 5 and 6, each a3 is independently selected from 1, 2, 3, 4, 5 and 6, R x1 are each independently selected from H, methyl or -CH2CH2N(Me)2, R x2 are each independently selected from H or methyl, R x3 each independently selected from -NH2, -OH, -OMe, -NHMe, -N(Me)2, or - NHCH2COOH; L3is absent or present, when L3is absent, it is a direct bond; when L3is present, L3is selected from: -M-L 3a - or -L 3a - M-, wherein each M is independently selected from the group consisting of a direct bond, wherein L 3a each is independently selected from: a direct bond, each b1 is independently selected from 1, 2, 3, 4 and 5, each b2 is independently selected from 0, 1, 2, 3, 4 and 5, each b3 is independently selected from 1, 2, 3, 4 and 5, each b4 is independently selected from 0, 1, 2 and 3, R y1 each independently selected from H, methyl, -CH2CH2N(Me)2, or HL, R y2 each independently selected from H, methyl, -CH2CH2N(Me)2, or HL, R y3 are each independently selected from H, methyl or -CH2CH2N(Me)2, R y4 are each independently selected from H, methyl or -CH2CH2N(Me)2, R y5 each independently selected from H, C1-C4alkyl or HL, HL is selected from: wherein cl is selected from 0, 1 or 2; c2 is selected from 2-20; c3 is selected from 1-20; R y6 is selected from H, methyl or acetyl; L4 is selected from a direct bond, a short peptide consisting of 2-5 amino acid residues, or an amide consisting of an amino acid residue and a carboxylic acid / amine; L5is selected from: a direct bond, R w1 each independently is selected from the group consisting of -CH2NH-HL, -CH2N(Me)-HL, -CH2CH2NH-HL, -CH2CH2N(Me)-HL, wherein d1 is selected from 0, 1 or 2, d2 is selected from 1-20; R w2 are each independently selected from: H, Me, -CH2CH2N(Me)2, or -CH2CH2SO2Me; R w3 are each independently selected from: H, Me, -CH2CH2N(Me)2, -CH2CH2SO2Me, or -CH2CH2OCH2CH2OH; R w4 are each independently selected from: H, Me, -CH2CH2N(Me)2, -CH2CH2SO2Me, or -CH2CH2OCH2CH2OH; R w5 are each independently selected from: H, Me, or -CH2CH2N(Me)2; R w6 are each independently selected from: H, Me, or -CH2CH2N(Me)2; W 1 each independently selected from W 2 -L w1 -L w2 or -L w3 -L w4 wherein L w1 is a short peptide consisting of 2 to 5 amino acid residues; L w2 is H, CrC4alkyl, (CrC4alkyl)-acyl, HL, HL being defined as above; L w3 is a carboxylic acid / amine and an amide consisting of 1 to 3 amino acid residues; L w4 is -NH(CrC4alkyl), -N(CrC4alkyl)2, wherein R e is H or C1-C4 alkyl, each of e1or e3is an integer from 1 to 20; each d is independently selected from 0, 1 or 2.

22. The antibody-drug conjugate compound of claim 21, wherein, L4 is selected from a direct bond.

23. The antibody-drug conjugate compound of claim 21, wherein, L4 is selected from an amide consisting of an amino acid residue and a carboxylic acid residue, or an amide consisting of an amino acid residue and an amine residue.

24. The antibody-drug conjugate compound of claim 21, wherein, L4 is wherein p is selected from 2, 3, 4 or 5; R p each is independently optionally selected from H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)Me, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2) p1 N(R z )2, -(CH2)3NHCOMe, -(CH2)3NHCONH2, -(CH2)4NHCONH2, wherein p1 is selected from 1, 2, 3, 4; R z each is independently optionally selected from H, C1-C4 alkyl or HL.

25. The antibody-drug conjugate compound of claim 21, wherein, L4 is wherein r is selected from 1 or 2; R p as defined in claim 24.

26. The antibody-drug conjugate compound of any of the preceding claims, wherein, L4 is selected from: R z each independently selected from H, C1-C4alkyl or HL.

27. The antibody-drug conjugate compound of any of the preceding claims, wherein, L4 is selected from:

28. The antibody-drug conjugate compound of any of the preceding claims, wherein, L4 is selected from:

29. The antibody-drug conjugate compound of claim 21, L5 is selected from: a direct bond.

30. The antibody-drug conjugate compound of claim 21, L5 is selected from: wherein R w6 each is independently selected from H or methyl; each d is independently selected from 1 or 2; W 2 -L w1 -L w2 or -L w3 -L w4 , wherein L w1 is L w1 the N-terminus of L w2 is connected, p is selected from 2, 3, 4 or 5; R p each independently is optionally selected from: H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)Me, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3N(Me)2, -(CH2)3NHCOMe, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)4N(Me)2, -(CH2)4N(Et)2, -(CH2)4N(nPr)2, -(CH2)4NHCONH2; L w2 H, methyl, acetyl, HL; L w3 for L w3 the left and L w4 are connected, wherein r is selected from 1 or 2; R p each independently is optionally selected from: H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)Me, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3N(Me)2, -(CH2)3NHCOMe, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)4N(Me)2, -(CH2)4N(Et)2, -(CH2)4N(nPr)2, -(CH2)4NHCONH2; L w4 -NHMe, -N(Me)2, wherein each of e1, e2 or e3 is optionally an integer from 1-20.

31. The antibody-drug conjugate compound of any of the preceding claims, wherein, L5 is selected from:

32. The antibody-drug conjugate compound of any of the preceding claims, wherein, L5 is selected from:

33. The antibody-drug conjugate compound of any of the preceding claims, wherein, - L4-L5- is selected from:

34. The antibody-drug conjugate compound of any of the preceding claims, wherein, - L4-L5- is selected from:

35. The antibody-drug conjugate compound of any of the preceding claims, wherein, - L1-L2- is selected from:

36. The antibody-drug conjugate compound of any of the preceding claims, wherein, - L3- is selected from: a direct bond, 37. The antibody-drug conjugate compound of any of the preceding claims, wherein, - L- is selected from the following structures or hydrolytic ring opening structures of the following structures:

38. The antibody-drug conjugate compound of any of the preceding claims, wherein, L5may be attached to a substituent of R cy or a substituent of R 3 or a substituent of R 41 .

39. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-2a or I-2b:

40. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-2a-1 or I-2b-1:

41. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-2a-2 or I-2b-2:

42. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-3a, I-3b, I-3c, I-3d, I-3e, I-3f, I-3g, or I-3h:

43. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-4a or I-4b:

44. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-5a or I-5b:

45. The antibody-drug conjugate compound of any of the preceding claims, having a structure according to Formula I-6a, I-6b, I-6c, I-6d, I-6e, or I-6f:

46. The antibody-drug conjugate compound of any of the preceding claims, selected from the following structures or the hydrolytic ring-opened structures of the following structures:

47. The antibody-drug conjugate compound of any of the preceding claims, selected from the following structures or the hydrolytic ring-opened structures of the following structures:

48. The antibody-drug conjugate compound of any of the preceding claims, selected from the following structures:

49. The antibody-drug conjugate compound of any of the preceding claims, selected from the following structures:

50. The antibody-drug conjugate compound of any of the preceding claims, wherein, q is selected from any value between 1.0-16.0; preferably, q is selected from any value between 2.0-16.0; preferably, q is selected from any value between 1.0-8.0; preferably, q is selected from any value between 4.0-8.0; preferably, q is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; preferably, q is selected from 1, 2, 3, 4, 5, 6, 7 or 8; preferably, q is selected from 2, 4, 6 or 8; preferably, q is selected from 4, 5, 6, 7, 8; preferably, q is selected from 4, 6, 8.

51. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is a ligand that binds to a target antigen, said target being a target that is highly expressed on tumor cells, while being lowly expressed or not expressed on normal cells.

52. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an antibody or antigen ligand, the target of which is, for example, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ANGPTL4, ASLG659, Axl, B7H3, B7H4, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCL5, CCR5, CCR7, CD123, CD138, CD142, CD147, CD166, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD46, CD47, CD49D (ITGA4), CD56, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH3, CDH6, CDH11, CD11b, CEA, CEACAM5, CEACAM6, CLDN18.2, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTGF, CTSD, CTSS, CXCL11, CXCL10, CXCR5, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRH1, FGF2, FGFR2, FGFR3, FLT3, FOLR-alpha, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSMA, PTK7, RNF43, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STC2, STEAP1, STEAP2, TCF4, TENB2, TGF, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A.

53. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-antigen antibody or antigen-binding fragment thereof, the antigen target of which is selected from the group consisting of HER2, TROP2, EGFR, HER3, B7H3, FGFR2b, B7H4, Nectin4, FOLR1, CD30, CD79b, CD19, CD33, 5T4, CLDN18.

2.

54. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an antibody or antigen-binding fragment thereof, the antibody selected from the group consisting of adalimumab, aducanumab, alemtuzumab, altumomab, amivantamab, atezolizumab, anetumab, avelumab, bapineuzumab, basiliximab, bectumomab, bermekimab, besilesomab, bevacizumab, bezlotoxumab, brentuximab, brodalumab, catumaxomab, cemiplimab, cetuximab, cinpanemab, clivatuzumab, crenezumab, daclizumab, daratumumab, denosumab, dinutuximab, dostarlimab, durvalumab, edrecolomab, elotuzumab, emapalumab, enfortumab, epcoritamab, epratuzumab, etaracizumab, gemtuzumab, glofitamab, girentuximab, gosuranemab, ibritumomab, inebilizumab, infliximab, inotuzumab, ipilimumab, isatuximab, ixekizumab, J591, labetuzumab, lecanemab, loncastuximab, mirzotamab, mogamulizumab, mosunetuzumab, necitumumab, nimotuzumab, natalizumab, naratuximab, naxitamab, nivolumab, ocrelizumab, ofatumumab, olaratumab, oregovomab, panitumumab, pembrolizumab, pertuzumab, polatuzumab, prasinezumab, racotumomab, ramucirumab, rituximab, sacituzumab, semorinemab, siltuximab, solanezumab, tacatuzumab, tafasitamab, teprotumumab, tilavonemab, tocilizumab, tositumomab, trastuzumab, ustekinumab,vedolizumab, votumumab, zagotenemab, zanidatamab, zalutumumab, zanolimumab.

55. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-HER2 antibody or antigen-binding fragment thereof, the antibody preferably being Trastuzumab, Pertuzumab, Zanidatamab.

56. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-TROP2 antibody or antigen-binding fragment thereof, the antibody preferably being Sacituzumab.

57. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-HER3 antibody or antigen-binding fragment thereof, the antibody preferably being Patritumab.

58. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-Nectin4 antibody or antigen-binding fragment thereof, the antibody preferably being Enfortumab.

59. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-B7H3 antibody or antigen-binding fragment thereof, the antibody preferably being Mirzotamab.

60. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is an anti-EGFR antibody or antigen-binding fragment thereof, the antibody preferably being Cetuximab.

61. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is a bifunctional antibody or antigen-binding fragment thereof, the antigen targets of which include a combination of any 2 or more of the above targets.

62. The antibody-drug conjugate compound of any of the preceding claims, wherein, Ab is a bifunctional antibody or antigen-binding fragment thereof, the combination of antigen targets of which is selected from the group consisting of: EGFR / c-Met, EGFR / HER3, FOLR1 / TRPV6, HER2 / TROP2, HER2 / HER2, EGFR / MUC1, HER3 / TROP2.

63. A pharmaceutical composition comprising the antibody-drug conjugate compound of any one of the preceding claims, and optionally a pharmaceutically acceptable salt, carrier, diluent or excipient.

64. Use of the antibody-drug conjugate compound of claims 1-62 or the pharmaceutical composition of claim 63 in the manufacture of a medicament for preventing or treating a cancer-related disease or disorder.

65. Use of the antibody-drug conjugate compound of claims 1-62 or the pharmaceutical composition of claim 63 for preventing or treating a cancer-related disease or disorder.

66. A method for preventing or treating a cancer-related disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody-drug conjugate compound of claims 1-62 or the pharmaceutical composition of claim 63.

67. The use of claim 64 or 65, or the method of claim 66, wherein the cancer is a solid tumor or a hematological tumor, in particular selected from the group consisting of esophageal cancer, lung cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, ovarian cancer, uterine cancer, liver cancer, kidney cancer, head and neck cancer, brain tumor, urothelial cancer, skin cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, leukemia or lymphoma.

68. L-P Intermediates, which can be used to prepare antibody-drug conjugate compounds with Ab by a coupling reaction, said L-P Intermediates have the following structure, or a stereoisomer thereof: wherein, Ab is an antibody or antigen-binding fragment thereof, or an antigen ligand.

69. An L-P intermediate that can be used to prepare an antibody-drug conjugate compound with an Ab by a coupling reaction, the L-P intermediate having the structure: wherein, Ab is an antibody or antigen-binding fragment thereof, or an antigen ligand.

70. An L-P intermediate that can be used to prepare an antibody-drug conjugate compound with an Ab by a coupling reaction, the L-P intermediate having the structure: wherein Ab is an antibody or antigen-binding fragment thereof, or an antigen ligand.

71. A method of preparing an antibody-drug conjugate compound comprising the step of conjugating Ab to the L-P intermediate of any one of claims 68-70, wherein, Ab is an antibody or antigen binding fragment thereof, or an antigen ligand. Ab is an antibody or antigen binding fragment thereof, or an antigen ligand. Ab is an antibody

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