Bifunctional compound and use thereof

Abstract

The present invention relates to a bifunctional Kras modulator (K-T or K-L-T) and the use thereof, wherein K represents a targeting group and is a modulator of a Kras protein (target protein), T is a ligand group of an E3 ubiquitin ligase, and L is a divalent linking group that chemically links the targeting group (K) to the ligand group (T). The bifunctional modulator or compound and a composition thereof disclosed in the present invention have pharmacological activity of degrading or inhibiting the target protein, and can be used for treating, inhibiting or preventing Kras-related diseases or disorders.

Description

A bifunctional compound and its use

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application number 202410177982.5, filed on February 8, 2024, Chinese patent application number 202410323566.1, filed on March 20, 2024, Chinese patent application number 202410554550.1, filed on May 7, 2024, and application number 202411117113.X, filed on August 14, 2024. The entire contents of the above Chinese patent applications are hereby incorporated into this application by reference. Technical Field

[0003] The present invention relates to a bifunctional compound with a KLT structure, or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, and use thereof in preparing a drug for treating, inhibiting or preventing Kras-related diseases. Background Art

[0004] The Kras (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family and is one of the most commonly mutated genes in human cancers. The protein it encodes is a small GTPase. The Kras gene participates in the kinase signaling pathway that controls gene transcription, thereby regulating cell growth and differentiation. Within cells, the Kras protein switches between inactive and active states. When bound to guanine diphosphate (GDP), Kras is inactive; when bound to guanine triphosphate (GTP), it becomes active and can activate downstream signaling pathways. Kras is inactive in most cells. Upon activation, it can activate downstream signaling pathways including the MAPK, PI3K, and Ral-GEF pathways. These signaling pathways play an important role in promoting cell survival, proliferation, and cytokine release, thereby influencing tumor development and progression.

[0005] In human cancers, Kras gene mutations occur in nearly 90% of pancreatic cancers, approximately 30% to 40% of colon cancers, approximately 17% of endometrial cancers, and approximately 15% to 20% of lung cancers (mostly non-small cell lung cancer (NSCLC)). It also occurs in cancer types such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. In other words, a high proportion of Kras gene mutations are present in many of the above cancers. Most Kras missense mutations occur in codon 12, resulting in the conversion of glycine to other amino acids. Based on the specific mutations present, G12C, G12D, G12R, and G12V are the most common Kras mutations in patients. In addition to wild-type Kras, Kras gene mutations also include Kras G12A, Kras G12S, Kras G13D, or Kras Q61H (Liu, Pingyu et al., Acta pharmaceutica Sinica. B (2019), 9(5), 871-879).

[0006] Taking anticancer drugs as an example, traditional small molecules inhibit target protease activity through targeted binding, inducing apoptosis in cancer cells. However, the target protein within tumor cells often regains its activity and acquires drug resistance through overexpression or new mutations. The shortcomings of traditional small molecule inhibitors have led to the gradual decline of small molecule drugs, and the development of small molecule drugs urgently needs to introduce revolutionary new technologies.

[0007] In the face of this phenomenon, researchers have found a new method, using small molecules to knock out functional target proteins, rather than simply inhibiting the activity of target proteins, protein degradation targeting chimera is a method for controlling this degradation pathway (reference Angew.Chem.Int.Ed.2016, 55, 807-810, J.Med.Chem.2018, 61, 444-452 etc.). The method is not a traditional enzyme inhibitor, but plays a role by inducing selective intracellular proteolysis. The heterobifunctional small molecule consisting of two active domains and a connector, one of the two active domains can be combined with E3 ubiquitin ligase, and the other can be combined with the target protein of degradation, and E3 ligase is recruited to the target protein to cause ubiquitination and subsequently by proteasome degradation target protein.

[0008] For diseases or conditions associated with various Kras mutations, small molecule agents that can target degradation for therapeutic purposes are of great significance. Summary of the Invention

[0009] The main technical problem solved by the present invention is to provide a bifunctional compound that can aggregate E3 ubiquitin ligase to the vicinity of a target protein for degradation, which can be used as a targeted ubiquitination regulator for a variety of polypeptides or proteins, thereby degrading or inhibiting the targeted polypeptide or protein. The bifunctional compound disclosed in the present invention, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, comprises a targeting group K of a Kras protein, a ligand group T of an E3 ubiquitin ligase, and an optional bivalent linking group (L) that chemically connects the targeting group (K) to the ligand group (T), thereby enabling the target protein (Kras G12A, G12C, G12D, G12V, G12R, G12S, G13D, Q61H and other mutant proteins or wild-type Kras protein (Wide Type, WT)) to be located near the E3 ubiquitin ligase, thereby affecting or enhancing the degradation of the protein.

[0010] The quantity and position of K and T described in the present invention are shown only as examples and are not intended to limit the compounds. In actual situations, those skilled in the art can adjust or change them as needed.

[0011] The bifunctional compound of the present invention comprises a targeting group K and a ligand group T of an E3 ubiquitin ligase, wherein K and T are covalently linked to form a protein degradation targeting chimera (represented by the general formula KT), or K and T are covalently linked to corresponding sites of a bivalent linking group L to form a protein degradation targeting chimera (represented by the general formula KLT); the targeting group K is represented by formula (IA), formula (IB) or formula (IC);

[0012] Among them, X 1 and X 2 are independently C or N;

[0013] Ring A is a carbocyclic ring or a carbon heterocyclic ring;

[0014] Y is -CH<, -CH2-CH<, -CH2-CH2-CH<, -N<, -NH-CH<, -CH2-N<, -CH2-CH2-N<, -CH2-NH-CH<, -O-CH< or -S-CH<; H in Y is optionally substituted by halogen, amino, hydroxy or C1-C4 alkyl;

[0015] Z is optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0016] R 1 Absent, or H, halogen, NH2 or optionally substituted C1-C4 alkyl;

[0017] R 2 is H, halogen, NH2 or optionally substituted C1-C4 alkyl;

[0018] Each R 3a and R 3b are independently halogen, 1 to 4 R 4 or R 6 Substituted C1-C4 alkyl, C2-C4 alkenyl, oxo (=O), -N(R 4 )2、-OR 4 、-C(O)OR 4 、-C(OR 4 )(R 4 )2、-C(O)R 4 、-C(O)R 5 、-C(O)(C1-C4 alkylene)-R 5 、-C(O)N(R 4 )2、-CN、-S(O)2R 6 、-P(O)(R 4 )2 or any 1-4 R 4 or R 6 substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or, two R 3a Or two adjacent R 3a Together with the carbon atoms to which they are attached, they form an optionally substituted carbocyclic or carboheterocyclic ring; or, two R atoms attached to the same carbon atom 3b Or two adjacent R 3b together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or carboheterocyclic ring;

[0019] Each R 4 are independently H, halogen, 1-4 R 6 Substituted C1-C5 alkyl, -C(O)R 6 、-N(R 6 )-C(O)R 6 、-N(R 6 )-S(O)2R 6 , -CH2-S-CH3, -S(O)2NH2, -S(O)2NH(C1-C4 alkyl), -S(O)2N(C1-C4 alkyl)2, -S(O)2(C1-C4 alkyl) or -P(O)(C1-C4 alkyl)2;

[0020] R 5 Choose 1-4 R 6 substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0021] Each R 6are each independently H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 heterocycloalkyl, hydroxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -O(C1-C4 alkyl), or -O(C1-C4 alkylene)-O(C1-C4 alkyl);

[0022] Each n1 is independently an integer from 0 to 4;

[0023] R C1 is H, halogen, optionally halogen-substituted alkoxy, optionally halogen-substituted C1-C4 alkyl, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, amino or hydroxy; or, R C1 , any R 3b together with the carbon atoms to which they are attached, form an optionally substituted carboheterocycle;

[0024] B is the following structure:

[0025] Wherein, E is oxygen (-O-), nitrogen (-NH-) or sulfur (-S-); R 7 and R 8 independently selected from hydrogen, halogen, hydroxy or cyano substituted C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkylamino, -OC(O)N(R 9 ) 2 、-(C1-C4 alkylene)-OC(O)N(R 9 )2, -(C1-C4 alkylene)-N(R 9 )-SO2-N(R 9 )2, -CO2R 9 、-CO2N(R 9 )2, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, =C(R 10 )2; Each R 9 are independently H or C1-C4 alkyl; each R 10 are independently H, halogen; n2 are each independently an integer of 0-3; n3 are an integer of 0-5;

[0026] M is C1-C4 alkylene, -(C1-C4 alkylene)-O-, or -(C1-C4 alkylene)-O-(C1-C4 alkylene)-.

[0027] In some embodiments, the targeting group K is Formula (I-a1), Formula (I-a2), Formula (I-a3), Formula (I-a4), or Formula (I-a5);

[0028] Wherein, the definitions of each group are as described above; R 3a and R 3b Can replace any substitutable position on the ring;

[0029] When the targeting group K is of formula (I-a5), n1 on the A ring (i.e. R 3a The number of substituents) is an integer from 0 to 4, and n1 (ie R 3b The number of substituents) is an integer from 1 to 4 (i.e., at least one R 3b With R C1 connection); R C2 O or -NR C3 -, R C3 is H or an optionally substituted C1-C4 alkyl group; Q is an optionally substituted C1-C4 alkylene group; the substituent may be halogen (F or Cl).

[0030] In other embodiments, the targeting group K is represented by formula (I-b1), formula (I-b2), formula (I-b3), formula (I-b4), or formula (I-b5);

[0031] Wherein, the definitions of each group are as described above; R 3a and R 3b Can replace any substitutable position on the ring;

[0032] When the targeting group K is of formula (I-b5), n1 on the A ring (i.e. R 3a The number of substituents) is an integer from 0 to 4, and n1 (ie R 3b The number of substituents) is an integer from 1 to 4 (i.e., at least one R 3b With R C1 connection); R C2 O or -NR C3 -, R C3 is H or an optionally substituted C1-C4 alkyl group; Q is an optionally substituted C1-C4 alkylene group; the substituent may be halogen (F or Cl).

[0033] In other embodiments, the targeting group K is represented by formula (I-c1), formula (I-c2), formula (I-c3), formula (I-c4), or formula (I-c5);

[0034] Wherein, the definitions of each group are as described above; R 3b Can replace any substitutable position on the ring;

[0035] When the targeting group K is of formula (I-c5), n1 is an integer of 1-4; R C2O or -NR C3 -, R C3 is H or an optionally substituted C1-C4 alkyl group; Q is an optionally substituted C1-C4 alkylene group; the substituent may be halogen (F or Cl).

[0036] In some embodiments, the targeting group K is of formula (IA), wherein Selected from the following structures:

[0037] Wherein, the definitions of each group are as described above; R 3a Any substitutable position on the A ring can be substituted.

[0038] In some embodiments, the targeting group K is of formula (IB), wherein Selected from the following structures: Wherein, the definitions of each group are as described above; R 3a Any substitutable position on the A ring can be substituted.

[0039] In some embodiments, R in the targeting group K 3a -C(O)N(R 4 )2,R 4 is a C1-C5 alkyl group (i.e., a C1, C2, C3, C4, or C5 alkyl group), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, etc. In some such embodiments, R 3a It is -C(O)N(CH3)2.

[0040] In some embodiments, R in the targeting group K 3a -C(O)R 5 , where R 5 Choose 1-4 R 6 Substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl. 5 You can choose from the following structures:

[0041] In some embodiments, the targeting group K is of formula (IC), wherein Select from the following structures:

[0042] In some embodiments, X 1 and X 2are independently C or N. In some embodiments, X 1 and X 2 In some embodiments, X 1 and X 2 In some embodiments, X 1 is C, and X 2 is N. In some embodiments, X 1 is N, and X 2 For C.

[0043] In some embodiments, R C1 is H. In some embodiments, R C1 is an alkoxy group (or lower alkoxy group) optionally substituted by halogen, in particular methoxy or fluoromethoxy (single fluorine substitution, difluorine substitution or trifluorine substitution). C1 is an optionally halogen-substituted C1-C4 alkyl group, in particular a methyl group or a fluoromethyl group (such as a trifluoromethyl group). C1 , any R 3b Together with the carbon atoms to which they are attached, they form an optionally substituted carboheterocycle, such as, but not limited to, the structures of Formula (I-a5), Formula (I-b5) or Formula (I-c5).

[0044] In some embodiments, R 1 In some embodiments, R 1 is H, halogen, NH2 or optionally substituted C1-C4 alkyl, especially halogen. In some embodiments, R 2 is H, halogen, NH2 or optionally substituted C1-C4 alkyl, especially halogen. In some embodiments, R 1 and R 2 All are halogens.

[0045] In some embodiments, Z is selected from the following structures: In some such embodiments, Z is further selected from the following structures:

[0046] In some embodiments, the bifunctional compound of the present invention is in the form of a prodrug, for example, the hydroxyl or amino group in Z as shown above is further replaced with an ester, ether or phosphate, etc. In some such embodiments, Z is selected from the following structures: Among them, Q Z (C1-C8 alkyl) C(O)-, (C1-C8 alkyl) C(O)O(C1-C4 alkylene)-, -CH2OP(O)(OQ 1)2、-P(O)(OQ 1 )2, -C(O)CH2NH2, (C1-C8 alkyl)-OC(O)O-(C1-C4 alkylene)-; Q 1 is H or C1-C8 alkyl.

[0047] In some embodiments, the targeting group K is of formula (IB), and the group B is selected from the following structures:

[0048] In some embodiments, the targeting group K is of formula (IA), wherein the formula (IA) is selected from the structures shown below: Among them, R 1 is a halogen (such as F or Cl).

[0049] In some embodiments, the targeting group K is of formula (IB), wherein the formula (IB) is selected from the structures shown below: Among them, R 1 is H or halogen (such as F or Cl).

[0050] In some embodiments, the targeting group K is of formula (IC), which is selected from the structures shown below: Among them, R 1 is a halogen (such as F or Cl), R C1 is H or methoxy.

[0051] In some embodiments, the bivalent linking group L of the present invention can be selectively composed of L 1 , L 2 , L 3 One or more components.

[0052] In some embodiments, the divalent linking group L has L 1 -L 2 -L 3 The bifunctional compound comprises a targeting group K and a ligand group T of E3 ubiquitin ligase, and K and T are respectively connected to a bivalent linking group L 1 , L 2 , L 3 The corresponding sites of the protein degradation targeting chimera are covalently linked to form the protein degradation targeting chimera, which is represented by the following general formula:

[0053] KL 1 -L 2 -L 3 -T.

[0054] In some embodiments, the bifunctional compound only includes a targeting group K and a ligand group T for the E3 ubiquitin ligase, ie, is displayed in the form of KT.

[0055] In some embodiments, the bifunctional compound includes only the targeting group K, the bivalent linking group L 1 and the ligand group T of E3 ubiquitin ligase, namely KL 1 -T format display.

[0056] In some embodiments, the bifunctional compound includes only the targeting group K, the bivalent linking group L 1 , L 2 and the ligand group T of E3 ubiquitin ligase, namely KL 1 -L 2 -T format display.

[0057] Furthermore, L 1 , L 2 , L 3 A bivalent group independently selected from one or a combination of several of substituted or unsubstituted hydrocarbon groups, hydrocarbonoxy groups, oxyalkyl groups, cycloalkyl groups, heterocycloalkyl groups, acylalkyl groups, alkylacyl groups, carbonylalkyl groups, alkylcarbonyl groups, amidealkyl groups, alkylamide groups, aryl groups, and oligopeptide groups having a double attachment site;

[0058] The hydrocarbon group includes a saturated hydrocarbon group, an unsaturated hydrocarbon group, an aromatic hydrocarbon group, an oxygen heterohydrocarbon group, an azo heterohydrocarbon group, a thio heterohydrocarbon group, a phosphorus heterohydrocarbon group, and a mixed heterohydrocarbon group of different heteroatoms, wherein the chain length of the hydrocarbon group or heterohydrocarbon group is 1 to 20 atoms, and when it is a heterohydrocarbon group, the heterohydrocarbon group contains 1 to 5 heteroatoms and the chemical valence of the heteroatoms is satisfied by hydrogen, oxygen, nitrogen, etc. in a corresponding bonding manner as required;

[0059] The heterocyclic ring in the heterocyclic hydrocarbon group includes substituted or unsubstituted monocyclic ring, spirocyclic ring or condensed ring.

[0060] In some embodiments, L 1 Selected from -O-, -NH-.

[0061] In some embodiments, L 1 Selected from the structures represented by formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), and (II-l):

[0062] wherein E' and G are independently selected from oxygen (-O-), nitrogen (-NH-), sulfur (-S-) or nitrogen-containing heterocycle; n = 0 to 10 (especially n = 0 to 5, for example, 0, 1, 2, 3, 4, 5); R 7 and R 8 are independently selected from hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, alkoxy, amino or amine. According to common knowledge in the art, when there is a chiral center in the structure, its stereo structure is independently selected from R-configuration, S-configuration, or a mixed configuration of R- and S-configurations. In some such embodiments, L 1 Is the formula (II-d), wherein E' is oxygen, G is

[0063] In some embodiments, in the bivalent linking group, L 1 You can choose from:

[0064] Among them, n=0-20, preferably n=0-5, more preferably 1-2.

[0065] In some embodiments, in the bivalent linking group, L 2 , L 3 Independently selected from: or does not exist;

[0066] Among them, p=0-15, preferably p=0-10, specifically, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; m=0-8, specifically, m can be 0, 1, 2, 3, 4, 5, 6, 7, 8; q=0-10, preferably q=0-5, specifically, q can be 0, 1, 2, 3, 4, 5.

[0067] In some such embodiments, L 2 and L 3 They may not exist at the same time.

[0068] In some such embodiments, L 2 and L 3 Can not exist at the same time.

[0069] In some embodiments, L 2 and L 3 Together they form the following structure: wherein each n is independently an integer from 0 to 5, for example, 0, 1, 2, 3, 4 or 5.

[0070] Furthermore, in some embodiments, the divalent linking group L is the following structure:

[0071] In some embodiments, the divalent linking group L may be absent.

[0072] In some embodiments, the ligand of the E3 ubiquitin ligase is selected from ligands that can bind to VHL (Von Hippel-Lindau), CRBN (Cereblon), MDM2, clAP, AhR, Nimbolide, CCW16, KB02, or KEAP1. When a chiral center is present in the structure, its stereostructure is independently selected from R-configuration, S-configuration, or a mixture of R- and S-configurations.

[0073] Furthermore, the ligand group T of the E3 ubiquitin ligase is selected from:

[0074] In some embodiments, the bifunctional compounds of the present invention include the compounds shown below or pharmaceutically acceptable salts, esters, stereoisomers, hydrates, solvates or prodrugs thereof;

[0075] Among them, K is selected from

[0076] T is selected from

[0077] In some embodiments, the bifunctional compounds of the present invention include the compounds shown below or pharmaceutically acceptable salts, esters, stereoisomers, hydrates, solvates or prodrugs thereof;

[0078] Among them, K is selected from

[0079] T is selected from

[0080] In some embodiments, the bifunctional compounds of the present invention include the compounds shown below or pharmaceutically acceptable salts, esters, stereoisomers, hydrates, solvates or prodrugs thereof;

[0081] K 1 -LT 1 Formula (III-d),

[0082] Among them, K 1 Selected from

[0083] L is selected from

[0084] T 1 Selected from

[0085] In some embodiments, the bifunctional compounds of the present invention include the compounds shown below or pharmaceutically acceptable salts, esters, stereoisomers, hydrates, solvates or prodrugs thereof;

[0086] Among them, R 3b are independently H or F, Q is -CH2- or -CH(CH3)-;

[0087] L'selected and,

[0088] T'selected

[0089] In some embodiments, the bifunctional compound includes a compound shown in Table 1 below, or a pharmaceutically acceptable salt, ester, stereoisomer, hydrate, solvate, or prodrug thereof.

[0090] Table 1

[0091] The above-mentioned compounds have good biological activity and can be used to treat Kras-related diseases. In some embodiments, the compounds provided herein can treat diseases related to Kras G12 A. In some embodiments, the compounds provided herein can treat diseases related to Kras G12 C. In some embodiments, the compounds provided herein can treat diseases related to Kras G12D. In some embodiments, the compounds provided herein can treat diseases related to Kras G12R. In some embodiments, the compounds provided herein can treat diseases related to Kras G12S. In some embodiments, the compounds provided herein can treat diseases related to Kras G12V. In some embodiments, the compounds provided herein can treat diseases related to Kras G13D. In some embodiments, the compounds provided herein can treat diseases related to Kras Q61H.

[0092] In some embodiments, the compounds provided herein can simultaneously inhibit two or more of the wild-type Kras, Kras G12A, Kras G12C, Kras G12D, Kras G12R, Kras G12S, Kras G12V, Kras G13D or Kras Q61H proteins.

[0093] In some embodiments, the compounds provided herein may be naturally abundant or isotopically substituted compounds, and the isotopes may be 1 H, D, T, 18 O. 17 O. 16 O. 15 N. 14 N. 13 C and 12 C, etc.

[0094] The present invention also provides a pharmaceutical composition comprising any of the above-mentioned compounds or pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof; and optionally at least one pharmaceutically acceptable excipient, carrier, or diluent.

[0095] Furthermore, the pharmaceutically acceptable excipients include one or more of a binder, a filler, a disintegrant, a lubricant and a glidant.

[0096] Furthermore, the pharmaceutically acceptable carrier includes one or more of creams, emulsions, gels, liposomes and nanoparticles.

[0097] Further, the composition is suitable for parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, intratracheal, rectal, subcutaneous and topical administration.

[0098] The present application also provides a use of any of the above-described compounds, or pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, or pharmaceutical compositions thereof, in the preparation of a medicament for treating, inhibiting, or preventing a hyperproliferative disorder. The present application also provides a method for treating, inhibiting, or preventing a hyperproliferative disorder, comprising administering an effective amount of the above-described compound and / or pharmaceutical composition to a subject, thereby treating the relevant disease.

[0099] In some embodiments, the hyperproliferative disorder is a malignancy or cancer associated with a gene comprising Kras wild type, G12D, G12A, G12C, G12R, G12S, G12V, G13D, Q61H mutations.

[0100] Further, the malignant tumor or cancer is selected from the group consisting of: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratoma;

[0101] Lung tumors or cancers: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma;

[0102] Gastrointestinal tumors or cancers: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucocorticoid tumor, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hematoma, leiomyoma);

[0103] Genitourinary tract tumors or cancers: kidney (adenocarcinoma, Wilms tumor (Nephroblastoma), lymphoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid, lipoma);

[0104] Liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0105] Biliary tract tumors or cancers: gallbladder cancer, ampulla cancer, bile duct cancer;

[0106] Bone tumors or cancers: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordal tumor, osteochondroma (osteochondroma), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0107] Nervous system tumors or cancers: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, epididymal tumors, germ cell tumors (pinealomas), glioblastomas, oligodendrogliomas, gliomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);

[0108] Gynecological tumors or cancers: uterus (endometrial cancer (serous bladder cancer, mucinous bladder cancer, unclassified carcinoma), granulosa cell tumor, serointerstitial cell tumor, dysplasia, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonal rhabdomyosarcoma));

[0109] Hematological tumors or cancers: leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma;

[0110] Dermatological tumors or cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse's dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0111] Adrenal gland tumor or cancer: neuroblastoma.

[0112] In some embodiments, the malignant tumor is one or more of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colorectal cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.

[0113] The present application also provides a kit comprising any of the above-mentioned compounds or pharmaceutically acceptable salts or esters or hydrates or solvates or stereoisomers, or any of the above-mentioned compositions, which can be used to prepare drugs for treating, inhibiting or preventing one or more Kras-related diseases.

[0114] The compounds provided herein, or pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, have excellent inhibitory or degradation effects on one or more Kras proteins and can be used in the preparation of drugs for treating, inhibiting, or preventing diseases associated with at least one Kras mutation.

[0115] It should be understood that within the scope of the present invention, the above-mentioned technical features and the technical features described in detail below (such as the specific implementation methods) can be combined with each other to form new or preferred technical solutions. Detailed description is omitted here. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Figure 1 shows the tumor volume change curves of mice in each group under the PK-59 model. DETAILED DESCRIPTION

[0117] In order to provide a clear and consistent understanding of the terms used in the specification of the present invention, some definitions are provided below. In addition, unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0118] When used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" can mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." Similarly, the word "another" can mean at least a second or many.

[0119] As used in this specification and claims, the words "comprising" (and any form of comprising, such as "including" and "comprising"), "having" (and any form of having, "having," "including," and "containing") are inclusive and open-ended and do not exclude additional, unrecited elements or process steps. The terms "about" or "approximately" are used to indicate that the value includes error for the equipment and method employed in determining the value.

[0120] As used herein, the terms "Kras protein" or "Kras-related diseases" include wild-type Kras and various mutant forms of Kras proteins, or diseases caused by wild-type Kras and various mutant forms of Kras proteins, wherein the various mutant forms of Kras proteins include Kras G12A, Kras G12C, Kras G12D, Kras G12R, Kras G12S, Kras G12V, Kras G13D, or Kras Q61H. The term "pan-KRAS" refers to multiple (e.g., two or more) KRAS isoforms or mutant forms of KRAS proteins, rather than a single KRAS isoform or mutant form of KRAS protein.

[0121] As used herein, the term "wild-type KRAS" refers to a non-mutated form of the mammalian KRAS protein. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116. The term "wild-type KRAS inhibitor" as used herein refers to a compound of the present invention, as shown in Formula (I) herein, which is capable of negatively regulating or inhibiting all or part of the enzymatic activity of wild-type KRAS. As used herein, "wild-type KRAS-associated disease or condition" refers to a disease or condition associated with wild-type KRAS or mediated by wild-type KRAS or having wild-type KRAS. A non-limiting example of a wild-type KRAS-associated disease or condition is a wild-type KRAS-associated cancer.

[0122] As used herein, the term "KRAS G12A" refers to a mutant form of the mammalian KRAS protein comprising an amino acid substitution of alanine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Ala. The term "KRAS G12A inhibitor" as used herein refers to a compound of the present invention represented by formula (I) as described herein, which is capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12A. As used herein, "KRAS G12A-associated disease or condition" refers to a disease or condition associated with, mediated by, or having a KRAS G12A mutation. A non-limiting example of a KRAS G12A-associated disease or condition is a KRAS G12A-associated cancer.

[0123] As used herein, the term "KRAS G12C" refers to a mutant form of the mammalian KRAS protein comprising an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Cys. The term "KRAS G12C inhibitor" as used herein refers to compounds of the present invention represented by formula (I) as described herein, which are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12C. The term "KRAS G12C-associated disease or condition" as used herein refers to a disease or condition associated with, mediated by, or having a KRAS G12C mutation. A non-limiting example of a KRAS G12C-associated disease or condition is a KRAS G12C-associated cancer.

[0124] As used herein, the term "KRAS G12D" refers to a mutant form of the mammalian KRAS protein comprising an amino acid substitution of aspartic acid for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Asp. As used herein, "KRAS G12D inhibitors" refer to compounds of the present invention, as represented by formula (I) herein, that are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12D. As used herein, the term "KRAS G12D-associated disease or condition" refers to a disease or condition associated with, mediated by, or having a KRAS G12D mutation. A non-limiting example of a KRAS G12D-associated disease or condition is a KRAS G12D-associated cancer.

[0125] As used herein, the term "KRAS G12R" refers to a mutant form of the mammalian KRAS protein comprising an amino acid substitution of arginine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Arg. As used herein, the term "KRAS G12R inhibitor" refers to compounds of the present invention represented by formula (I) as described herein, which are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12R. As used herein, the term "KRAS G12R-associated disease or condition" refers to a disease or condition associated with, mediated by, or having a KRAS G12R mutation. A non-limiting example of a KRAS G12R-associated disease or condition is a KRAS G12R-associated cancer.

[0126] As used herein, the term "KRAS G12S" refers to a mutant form of the mammalian KRAS protein comprising an amino acid substitution of serine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P011.16: variant p.Gly12Ser. The term "KRAS G12S inhibitor" as used herein refers to compounds of the present invention represented by formula (1) as described herein, which are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12S. The term "KRAS G12S-related disease or condition" as used herein refers to a disease or condition associated with or mediated by a KRAS G12S mutation or having a KRAS G12S mutation. A non-limiting example of a KRAS G12S-related disease or condition is a KRAS G12S-related cancer.

[0127] The term "KRAS G12V" as used herein refers to a mutant form of the mammalian KRAS protein comprising an amino acid substitution of valine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Val. The term "KRAS G12V inhibitor" as used herein refers to a compound represented by Formula (I) of the present invention, which is capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12V. The term "KRAS G12-related disease or condition" as used herein refers to a disease or condition associated with or mediated by a KRAS G12V mutation or having a KRAS G12V mutation. A non-limiting example of a KRAS G12V-related disease or condition is a KRAS G12V-related cancer.

[0128] As used herein, the term "KRAS G13D" refers to a mutant form of the mammalian KRAS protein comprising an aspartic acid to glycine amino acid substitution at amino acid position 13. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly13Asp. As used herein, the term "KRAS G13D inhibitor" refers to compounds of the present invention represented by Formula (I), as described herein, that negatively regulate or inhibit all or part of the enzymatic activity of KRAS G13D. As used herein, the term "KRAS G13D-associated disease or condition" refers to a disease or condition associated with or mediated by KRAS G13D or characterized by a KRAS G13D mutation. A non-limiting example of a KRAS G13D-associated disease or condition is a KRAS G13D-associated cancer.

[0129] As used herein, the term "KRAS Q61H" refers to a mutant form of the mammalian KRAS protein comprising a histidine to glutamine amino acid substitution at amino acid position 61. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gln61His. As used herein, the term "KRAS Q61H inhibitor" refers to compounds of the present invention represented by Formula (I), as described herein, that negatively regulate or inhibit all or part of the enzymatic activity of KRAS Q61H. As used herein, the term "KRAS Q61H-associated disease or condition" refers to a disease or condition associated with, mediated by, or characterized by a KRAS Q61H mutation. A non-limiting example of a KRAS Q61H-associated disease or condition is a KRAS Q61H-associated cancer.

[0130] The bifunctional compounds disclosed herein include a targeting group K for the Kras protein and a ligand group T for the E3 ubiquitin ligase. Unless otherwise indicated by the context, the terms K and T are used in an inclusive sense. For example, the term K includes all moieties that may target and recognize the Kras protein, which may be an independent molecule capable of targeting and recognition or a group generated by a molecule participating in a reaction. It may also be a molecule that includes a targeting and recognition molecule and is bound to other structures or a group generated by a molecule participating in a reaction. That is, K includes all molecules or groups that can be used partially or fully for targeting and recognizing the Kras protein. The term T includes all moieties that may be used as ligands for the E3 ubiquitin ligase. It may be an independent ligand capable of adapting to the E3 ubiquitin ligase or a molecule or group that includes a ligand molecule or group and also includes other structures. That is, T includes all molecules or groups that can be used partially or fully for adapting to the E3 ubiquitin ligase.

[0131] L disclosed in the present invention is a divalent linking group for chemically connecting a targeting group (K) to a ligand group (T). L disclosed in the present invention is all used to connect K and T, thereby playing the role of combining K and T together. In certain embodiments, K is directly connected to T, that is, L may not exist. In most cases, L exists, and the scope and specific structure of L provided in this application are not intended to be limiting, and it can be any structure that serves to connect K and T.

[0132] The term "pharmaceutically acceptable" as used herein means that the drugs, medicines, inert ingredients, etc. described by the term are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio.

[0133] "Pharmaceutically acceptable stereoisomers" of a compound refer to isomers resulting from different spatial arrangements of atoms in a molecule. Furthermore, isomers resulting from the same order of interconnection of atoms or groups of atoms in a molecule but different spatial arrangements are called stereoisomers, which are mainly divided into two categories: stereoisomers resulting from bond lengths, bond angles, the presence of double bonds or rings in the molecule, etc. are called configuration stereoisomers. Generally speaking, configuration stereoisomers cannot or are difficult to convert into each other. Stereoisomers resulting solely from the rotation of a single bond are called conformational stereoisomers, sometimes also called rotamers. When the rotation of a rotamer is hindered and cannot rotate, it becomes a "stereoisomer". For example, in a biphenyl structure, when there are large and different substituents at the α- and α'-positions, the single bond rotation between the two benzene rings cannot rotate freely due to the obstruction between the substituents, thus producing two stereoisomers.

[0134] A "pharmaceutically acceptable salt" of a compound refers to a salt of the compound that is pharmaceutically acceptable. Desirable salts of the compound (basic, acidic, or charged functional groups) retain or improve the biological activity and properties of the parent compound, as defined herein, and are not biologically undesirable. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts are prepared by reacting the compound (free acid or base) with an equistoichiometric amount of the base or acid in water or an organic solvent, or in a mixture of the two. Salts can be prepared in situ during the final isolation or purification of the pharmaceutical agent, or by reacting a purified compound of the invention in its free acid or base form with the desired corresponding base or acid and isolating the salt thus formed. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, which are referred to as "inner salts." The compounds of the invention encompass all acid, salt, base, and other ionic and non-ionic forms. For example, if the compound of the invention is an acid, the salt form of the compound is also encompassed. Likewise, if a compound of the present invention is a salt, the acid and / or base forms of the compound are also included.

[0135] The term "ester" used in the present invention refers to a group or fragment represented by the general formula RCOOR', which can usually be obtained by reacting a carboxylic acid with an alcohol (eliminating a molecule of water). Wherein, R is, for example, a lower alkyl or aryl group, such as methylene, ethylene, isopropylidene, phenylene, etc., but not limited thereto; R' is, for example, a lower alkyl or aryl group, such as methyl, ethyl, propyl, isopropyl, butyl, phenyl, etc., but not limited thereto. The term "ester alkyl" means that R' is an alkyl group, one end of the alkyl group is directly connected to the oxygen on the ester, and the other end is covalently bonded to at least one carbon or heteroatom in the compound or fragment.

[0136] The term "substituted" or "substituted" means that the parent compound or moiety has at least one substituent group. The term "unsubstituted" or "having no substituents" means that the parent compound or moiety has no substituents other than chemical saturation of undetermined valencies with hydrogen atoms. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents.

[0137] Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position in any given structure, the substituent is the same or different at each position.

[0138] As used herein, a "substituent" or "substituent group" refers to a group selected from halogen (F, Cl, Br or I), hydroxy, thiol, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphonyl or other organic moieties conventionally used and accepted in organic chemistry.

[0139] Ubiquitin (Ub) is a small molecule protein composed of 76 amino acids with a molecular weight of approximately 8.5 kDa. It is widely present in all eukaryotic cells and its sequence is highly conserved, differing only by three amino acids from yeast to humans. Ubiquitination refers to the process by which ubiquitin is covalently bound to a target protein under the catalysis of a series of enzymes. The ubiquitination process usually requires the coordinated action of three ubiquitin enzymes: E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase. Common E3 ubiquitin ligases include VHL (Von Hippel-Lindau), CRBN (Cereblon), MDM2, clAP, AhR, Nimbolide, CCW16, KB02, KEAP1, etc.

[0140] The terms "aryl" and "aromatic" used in the present invention refer to aromatic groups having "4n+2" (π) electrons in a conjugated monocyclic or polycyclic ring system (condensed or non-condensed), and having 6 to 14 ring atoms, wherein n is an integer from 1 to 3. The polycyclic ring system includes at least one aromatic ring. The aryl group can be directly connected or connected through a C1-C3 alkyl group (also referred to as an arylalkyl or aralkyl group). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthenyl, fluorenyl, phenanthrenyl, anthracenyl, etc. The term aryl includes unsubstituted aryl and substituted aryl.

[0141] The term "aromatic heterocycle" or "heteroaromatic ring" used in the present invention includes substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle and substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight or branched hydrocarbon group, halogen-substituted C1-4 straight or branched hydrocarbon group, F, Cl, Br, NO2, CN, methylenedioxy, cyclopropyl, cyclopropylmethylene, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl; the nitrogen-containing six-membered aromatic heterocycle and five-membered aromatic heterocycle can be monosubstituted or polysubstituted; the six-membered aromatic heterocycle can contain one nitrogen atom or multiple nitrogen atoms; the five-membered aromatic heterocycle can contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, S; the number of heteroatoms can be 1, 2 or 3; wherein the halogen includes F, Cl, and Br.

[0142] In some embodiments, the substituents of the substituted phenyl group, the substituted nitrogen-containing six-membered aromatic heterocycle, and the substituted or unsubstituted five-membered aromatic heterocycle may be selected from:

[0143] ( a ) C1-8 straight chain or branched hydrocarbon group, halogen-substituted C1-8 straight chain or branched hydrocarbon group, F, Cl, Br, NO2, CN, methylenedioxy, OR 1 SR 2 NR 3 R 1 NR 4 COR 2 、COOR 5 、CONR 6 R 3 NR 7 COOR 4 、SO2NR 8 R 5 、(CH2) n NR 9 R 6 、(CH2) n OR 10 , where the R 1 、R2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkynyl, substituted or unsubstituted 3-7 membered cyclic hydrocarbon group, substituted or unsubstituted 3-8 membered oxygen heterocyclic hydrocarbon group, substituted or unsubstituted 3-8 membered nitrogen heterocyclic hydrocarbon group, substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, OR a1 SR a2 NR a3 R b1 、COOR a4 、CONR a5 R b2 NR a6 COOR b3 、SO2NR a7 R b4 NR a8 COR b5 , where the R a1 、R a2 、R a3 、R b1 、R a4 、R a5 、R b2 、R a6 、R b3 、R a7 、R b4 、R a8 、R b5 independently selected from H, C1-4 straight or branched chain hydrocarbon group, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the 3-8 membered oxygen heterocyclic hydrocarbon group or nitrogen heterocyclic hydrocarbon group may contain one or more heteroatoms; n is selected from 1, 2 or 3;

[0144] (b) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted 3-8 membered oxygen heterocyclic hydrocarbon group, substituted or unsubstituted 3-8 membered nitrogen heterocyclic hydrocarbon group, wherein the substituent is selected from C1-5 straight chain or branched hydrocarbon group, F, Cl, Br, CN, OR a1 SR a2 NR a3 R b1 、COOR a4、CONR a5 R b2 NR a6 COOR b3 、SO2NR a7 R b4 NR a8 COR b5 , where the R a1 、R a2 、R a3 、R b1 、R a4 、R a5 、R b2 、R a6 、R b3 、R a7 、R b4 、R a8 、R b5 Independently selected from H, C1-4 straight or branched chain hydrocarbon group, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered oxygen heterocyclic hydrocarbon group or nitrogen heterocyclic hydrocarbon group may contain one heteroatom or multiple heteroatoms at the same time;

[0145] (c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, OR a1 SR a2 NR a3 R b1 、COOR a4 、CONR a5 R b2 NR a6 COOR b3 、SO2NR a7 R b4 NR a8 COR b5 , where the R a1 、R a2 、R a3 、R b1 、R a4 、R a5 、R b2 、R a6 、R b3 、R a7 、R b4 、R a8 、R b5Independently selected from H, C1-4 straight or branched chain hydrocarbon group, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the 3-8 membered oxygen heterocyclic hydrocarbon group or nitrogen heterocyclic hydrocarbon group may contain one heteroatom or multiple heteroatoms at the same time; the benzene ring, six-membered aromatic heterocycle or five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle and the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

[0146] In some embodiments, the substituted or unsubstituted aromatic fused ring or fused heterocycle, substituted or unsubstituted non-aromatic fused ring or fused heterocycle, include substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight chain or branched hydrocarbon group, halogen-substituted C1-4 straight chain or branched hydrocarbon group, F, Cl, Br, NO2, CN, methylenedioxy, OR s1 SR s2 NR s3 R t1 NR s4 COR t2 、COOR s5 、CONR s6 R t3 NR s7 COOR t4 、SO2NR s8 R t5 、(CH2) n NR s9 R t6 、(CH2) n OR s10 , where the R s1 、R s2 、R s3 、R t1 、R s4 、R t2 、R s5 、R s6 、R t3 、R s7 、R t4 、R s8 、R t5 、R s9 、R t6 、R s10Independently selected from H, C1-4 straight or branched chain hydrocarbon, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, benzo six-membered heterocycle or benzo five-membered heterocycle may be monosubstituted or polysubstituted; the benzo six-membered heterocycle or benzo five-membered heterocycle may contain one heteroatom or multiple heteroatoms, the heteroatom being selected from O, N or S; n is selected from 1, 2 or 3; wherein the halogen includes F, Cl, and Br.

[0147] The term "hydrocarbon group" includes, but is not limited to, saturated hydrocarbon groups, unsaturated hydrocarbon groups, aromatic hydrocarbon groups, oxygen heterohydrocarbon groups, nitrogen heterohydrocarbon groups, thio heterohydrocarbon groups, phosphorus heterohydrocarbon groups and mixed heterohydrocarbon groups of different heteroatoms, and the chain length of the hydrocarbon group or heterohydrocarbon group is 1 to 20 atoms, and when it is a heterohydrocarbon group, the heterohydrocarbon group contains 1 to 5 heteroatoms, and the chemical valence of the heteroatoms is satisfied by hydrogen, oxygen, nitrogen, etc. in a corresponding bonding manner as needed.

[0148] The terms "cyclyl," "alicyclic," "cycloalkyl," and equivalent expressions refer to groups comprising saturated or partially unsaturated carbocyclic rings within a monocyclic, spirocyclic (sharing one atom), or fused (sharing at least one bond) carbocyclic ring system, wherein the carbocyclic ring system has from 3 to 15 carbon atoms. The term "cycloalkyl" includes combinations of cyclyl and alkyl groups.

[0149] As used herein, the term "heterocycle" and equivalent expressions refer to a group containing a saturated or partially unsaturated carbocyclic ring in a monocyclic, spirocyclic (sharing one atom) or fused (sharing at least one bond) carbocyclic ring system, a group having 3 to 15 carbon atoms, including 1 to 6 heteroatoms (e.g., N, O, S, P) or a group containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2, SO, SO2, etc.). The heterocycloalkyl group can be attached to C or to a heteroatom (e.g., through a nitrogen atom). "Heterocycle" or "heterocyclic" includes heterocycloalkyl and heteroaryl. Examples of heterocyclic rings include, but are not limited to, acridinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, 4αH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, benzothiazolyl ... phenyl, 1H-indazolyl, 1H-indole ... phenanthiophene, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydrofuran ... Quinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 3,4-triazolyl, xanthenyl, etc. The term "heterocycle" includes unsubstituted heterocyclic groups and substituted heterocyclic groups. The term "heterocycloalkyl" refers to a combination of a heterocycle and an alkyl group.

[0150] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched carbon chain or a combination thereof, which can be fully saturated, monounsaturated or polyunsaturated, and can include monovalent, divalent and polyvalent groups. An alkyl group can include a specified number of carbons, for example, "C1-C10 alkyl" means an alkyl group containing one to ten carbons. In some embodiments, the alkyl group is fully saturated. In some embodiments, the alkyl group is monounsaturated. In some embodiments, the alkyl group is polyunsaturated. Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, homologues and isomers, such as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. An unsaturated alkyl group is an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers. The alkyl group may be an alkenyl. The alkyl group may be an alkynyl. The alkenyl group may include one or more double bonds. The alkynyl group may include one or more triple bonds.

[0151] The term "heteroalkyl" by itself or as part of another substituent means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, S, or Si), wherein the N or S may be optionally oxidized and the N may be optionally quaternized. The heteroatom may be located at any position of the heteroalkyl group. The heteroalkyl group may include one heteroatom, two optional heteroatoms, three optional heteroatoms, or four or more optional heteroatoms. Examples of typical heteroalkyl groups include, but are not limited to, -CH2CH2-O-CH3, -CH2CH2NH-CH3, -CH2CH2N(CH3)-CH3, -CH2-S-CH2CH3, -S(O)-CH3, -CH2CH2-S(O)2-CH3, -CH2CH2-O-CH3, -O-CH3, -O-CH2CH3, -CN, -CH=CH-N(CH3)-CH3, -CH2-NH-OCH3, etc.

[0152] The terms "cycloalkyl" and "heterocycloalkyl" refer to cyclic forms of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. In heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

[0153] The term "acyl" used in the present invention refers to the -C(=O)R residue left after dehydroxylation of a molecule of carbonic acid. a As used herein, the term "acyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on -C=O. As used herein, the term "amine" or "amino" refers to an unsubstituted or substituted fragment of the general formula -N-. The term "amide" refers to the structure -C(=O)N-, in which an amino group is directly linked to an acyl group. The term "acylalkyl" refers to a combination of an acyl group and a hydrocarbon group, i.e., a carbon atom on the acyl group is linked to a hydrocarbon group. The term "alkylamino" refers to a group formed by replacing the hydrogen atoms on an amino group with one or two alkyl groups. For example, "C1-C4 alkylamino" refers to an amino group substituted with an alkyl group, wherein the total number of carbon atoms in the alkyl substituent is 1-4, including but not limited to methylamino (-NHCH3), dimethylamino (-N(CH3)2), ethylamino (-NHCH2CH3), diethylamino (-N(CH2CH3)2), and the like.

[0154] The term "carbonyl" refers to a -C=O- fragment formed by carbon and oxygen atoms connected by a double bond. "Carbonyl" is a component of functional groups such as aldehydes, ketones, and acids.

[0155] The term "amidoalkyl" or "alkylamido" refers to a group consisting of a hydrocarbon group and an amide group. The term "acylalkyl" or "alkylacyl" refers to a group consisting of a hydrocarbon group and an acyl group. The term "carbonylalkyl" or "alkylcarbonyl" refers to a group consisting of a hydrocarbon group and a carbonyl group.

[0156] The term "alkoxy" or "lower alkoxy" refers to a structure in which an alkyl group is connected to an oxygen atom. Representative alkoxy groups include groups having 1 to about 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, etc. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "alkoxy" includes unsubstituted or substituted alkoxy groups, as well as perhalogenated alkoxy groups, etc. Similarly, the term "hydrocarbyl" or "oxyhydrocarbyl" refers to a group or structure in which a hydrocarbyl group is connected to an oxygen atom.

[0157] The term "alkylene" refers to a divalent alkyl group, that is, the residue after an alkane loses two hydrogen atoms, and can also be considered as a divalent alkyl group formed by losing another hydrogen on the basis of an alkyl group. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, usually having eight or fewer carbon atoms. Examples of the C1-C4 alkylene group may include, but are not limited to: methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene. The alkylene group may be straight-chain or branched, for example, the ethylene group may be -CH2CH2- or -CH(CH3)-. In the present invention, preferably, except for the methylene group, the divalent radicals of the other alkylene groups are not located on the same carbon atom.

[0158] Similarly, the term "heteroalkylene" (or "heteroalkylene") refers to a divalent group derived from a heteroalkyl group, wherein a heteroatom can occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). The terms "cycloalkylene" and "heterocycloalkylene" refer to divalent groups derived from cycloalkyl and heterocycloalkyl, respectively. In the present invention, unless explicitly stated, for alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene linking groups, the illustrated linking group (or structural formula) does not imply the direction of substitution of the linking group.

[0159] The term "spiro" or "spiro-complexed" refers to an organic compound that exhibits a twisted structure of two or more rings (ring system), wherein two or three rings are linked together by a common atom. Spirocyclic compounds can be completely carbocyclic (all carbon), such as spiro[5.5]undecane, or heterocyclic (having one or more non-carbon atoms), including but not limited to carbocyclic spiro compounds, heterocyclic spiro compounds, and polyspiro compounds.

[0160] The term "bridged ring" or "bridged" refers to a carbocyclic or heterocyclic moiety in which two or more atoms are shared in two or more ring structures, wherein the shared atoms are C, N, S, or other heteroatoms arranged in a chemically rational substitution pattern. Alternatively, a "bridged ring" compound also refers to a carbocyclic or heterocyclic structure in which an atom at any position in the main ring is bonded to a second atom on the main ring by a chemical bond or an atom other than a bond that does not actually comprise part of the main ring structure. The first and second atoms may be adjacent to each other in the main ring or non-adjacent to each other. Other carbocyclic or heterocyclic bridged ring structures are also contemplated, including bridged rings in which the bridging atom is C or a heteroatom arranged in a chemically rational substitution pattern, as known in the art.

[0161] The term "fused ring" or "fused ring" refers to a polycyclic ring system containing fused rings. Typically, a fused ring system contains 2 or 3 rings and / or up to 18 ring atoms. As described above, cycloalkyl, aryl, and heterocyclic groups can form fused ring systems. Thus, a fused ring system can be aromatic, partially aromatic, or non-aromatic and can contain heteroatoms. According to this definition, a spirocyclic ring system is not a fused polycyclic ring, but the fused polycyclic ring systems of the present invention can themselves have spirocyclic rings connected to them by individual ring atoms of the system. Examples of fused ring systems include, but are not limited to, naphthyl (e.g., 2-naphthyl), indenyl, phenanthrenyl, anthracenyl, pyrenyl, benzimidazole, benzothiazole, and the like.

[0162] According to common knowledge in the art, when the bifunctional compound of the present invention has a chiral center in its structure, its stereostructure is independently selected from R-configuration, S-configuration, or a mixed configuration of R- and S-configurations.

[0163] The "pharmaceutically acceptable salt" of a compound may be as described by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). Including but not limited to:

[0164] (1) Salts formed by adding an acid to a basic or positively charged functional group. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonic acid, etc. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, tert-butylacetic acid, β-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexyl Aminosulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, laurylsulfonic acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, muconic acid, etc.

[0165] (2) When acidic protons are present in the parent compound or are replaced by metal ions, a base may be added to obtain a salt. The metal ions include alkaline metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron, etc. Organic bases include, but are not limited to, N,N′-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, etc.

[0166] The present invention also provides a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises: a compound disclosed in the present invention or a pharmaceutically acceptable salt, ester, isomer or hydrate thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

[0167] Specifically, pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and glidants. Pharmaceutically acceptable carriers or diluents include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

[0168] A "pharmaceutical composition" refers to a composition comprising a compound as described herein and at least one component, depending on the mode of administration and dosage form requirements, comprising a pharmaceutically acceptable carrier, diluent, adjuvant, excipient or vehicle, such as a preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant and dispersant, etc.

[0169] The term "subject" refers to animals including mammals and humans, particularly humans.

[0170] The term "prodrug" or its equivalent refers to an agent that is converted directly or indirectly into an active form in vitro or in vivo (see, for example, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs." 360 pp. Elsevier, Amsterdam; Stella, V; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and Rewards, XVIII, 1470). p. Springer). Prodrugs can be used to alter the biodistribution of a particular drug (e.g., so that the agent does not normally enter a protease reaction site) or the pharmacokinetics. A variety of groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphates, etc. When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, by reduction, oxidation, or hydrolysis, or otherwise releases the active compound. As used herein, "prodrug" includes pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, as well as any crystalline forms of the above.

[0171] The term "peptide" or "oligopeptide" refers to a compound formed by dehydration condensation of two or more amino acid molecules linked together by amide bonds. Generally speaking, the number of amino acids constituting a peptide ranges from 2 (dipeptide) to 20 (eicosapeptide).

[0172] The term "residue" refers to the main part of a molecule after a certain group is removed, such as amino acid residues (such as the structure H2NCH2CO-, i.e. glycyl, which is the part after a hydroxyl group is removed from glycine) and peptide residues.

[0173] In other embodiments, the present invention provides methods for inhibiting, treating and / or preventing immune-related diseases, disorders and conditions, diseases with an inflammatory component, and disorders related thereto using at least one bifunctional compound provided herein or compositions thereof.

[0174] Other diseases, disorders, and conditions that can be treated or prevented in whole or in part by degrading Kras proteins are also candidate indications for the bifunctional compounds and compositions provided by the present invention.

[0175] The term "treating" refers to taking actions, after a disease, disorder, or condition, or symptoms thereof, have been diagnosed, observed, or to temporarily or permanently eliminate, alleviate, suppress, slow down, or ameliorate at least one underlying cause of the disease, disorder, or condition afflicting a subject, or a symptom associated with the disease, disorder, or condition afflicting a subject. Thus, treatment includes inhibiting (e.g., preventing or alleviating the development or further progression of) an active disease. Specifically, as used herein, the term "treating" is used to specifically refer to administering a therapeutic comprising a compound or composition according to the present invention to a patient already suffering from an infection. The term "treating" also relates to administering a compound or composition according to the present invention, optionally together with one or more anticancer agents, to alleviate or alleviate one or more symptoms associated with wild-type Kras or a Kras mutation; or to slow the development of one or more symptoms associated with wild-type Kras or a Kras mutation; or to reduce the severity of one or more symptoms associated with wild-type Kras or a Kras mutation; or to inhibit clinical manifestations associated with wild-type Kras or a Kras mutation; or to inhibit the manifestation of adverse symptoms associated with wild-type Kras or a Kras mutation.

[0176] The term "prevent" refers to preventing, inhibiting, suppressing, or reducing the risk of a subject developing a disease, disorder, condition, or the like (as determined, for example, by the absence of clinical symptoms) in some manner (e.g., in the case of a disease, disorder, condition, or symptom thereof), either temporarily or permanently, or in the case of a subject susceptible to a particular disease, disorder, or condition, delaying its onset. In certain instances, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its development into a harmful or other undesirable state. Specifically, the term "preventing" as used herein is used to refer to the administration of a compound or composition according to the present invention to prevent the occurrence of a disease associated with Kras.

[0177] As used herein, the term "Kras-associated disease" refers to any disease, disorder, or other pathological condition in which wild-type Kras or mutations of Kras are known to play a role. Thus, in some embodiments, the present application relates to treating or reducing the severity of one or more diseases in which mutations of the Kras protein are known to play a role. Specifically, the disease associated with wild-type Kras or mutations of the Kras protein is a hyperproliferative disease, such as a malignant tumor, preferably lung cancer, such as non-small cell lung cancer, pancreatic cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.

[0178] In some embodiments, the present invention further provides the use of a combination of the bifunctional compounds and compositions described herein with one or more additional agents. The one or more additional agents may have Kras modulating activity and / or they may act through different mechanisms of action. In some embodiments, such agents include agents used in radiation (e.g., localized radiotherapy or systemic radiotherapy) and / or other treatment modalities of non-pharmacological nature. When using combination therapy, the bifunctional compound and one additional agent may be in the form of a single composition or multiple compositions, and the treatment modality may be administered simultaneously, sequentially, or by some other regimen. For example, in some embodiments, an embodiment is provided in which a chemotherapy phase is performed after the radiation phase. Combination therapy may have an additive effect or a synergistic effect.

[0179] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, capsules, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions for oral administration may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavorings, colorants, and preservatives, to provide pharmaceutically acceptable formulations. Tablets, capsules, and the like typically contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier or excipient suitable for tablet manufacture. These carriers or excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0180] In some embodiments, the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.

[0181] In some embodiments, the pharmaceutical composition is contained in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector), while in other embodiments, it is contained in a multiple-use container (e.g., a multiple-use vial).

[0182] Preparation can also include carrier to protect composition from rapid degradation or disappearance from health, such as controlled release formulations, including liposomes, hydrogels and microencapsulated delivery systems. For example, time-delay materials can be used, such as independent glyceryl monostearate or glyceryl stearate, or used in combination with wax. Any drug delivery device can be used for sending bifunctional compounds, including implants (such as implantable pumps) and catheter systems, slow injection pumps and devices. All of these are well known to those skilled in the art.

[0183] Pharmaceutical compositions can also be in the form of sterile injectable aqueous or oily suspensions. The suspensions can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned herein. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butylene glycol. Acceptable diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) can be used to prepare injections. Prolonged absorption of specific injectable formulations can be achieved by including agents that delay absorption (e.g., aluminum monostearate or gelatin).

[0184] The bifunctional compounds and compositions provided herein can be administered to a subject in any suitable manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intracerebral (intraparenchymal and intraventricular); nasal; vaginal; sublingual; intraocular; rectal; topical (e.g., transdermal); oral, and inhalation. Depot injection, typically administered subcutaneously or intramuscularly, can also be used to release the bifunctional compounds disclosed herein over a defined period of time.

[0185] The present invention also provides a kit (or kit, combination product) comprising a bifunctional compound or composition. The kit is generally in the form of a physical structure that accommodates various components and can be used, for example, to implement the method provided herein. For example, the kit can include one or more bifunctional compounds disclosed herein (e.g., provided in a sterile container), which can be in the form of a pharmaceutical composition suitable for administration to a subject. The bifunctional compound can be provided in a ready-to-use form (e.g., tablet or capsule) or in a form that requires, for example, reconstitution or dilution (e.g., powder) before administration. When the bifunctional compound is in a form that requires the user to be reconstituted or diluted, the kit can also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc. that is packaged together with the bifunctional compound or packaged separately. When a combination therapy is employed, the kit can contain several therapeutic agents independently, or they can be combined in the kit. Each component of the kit can be encapsulated in a separate container, and all the various containers can be in a single package. The kit of the present invention can be designed to appropriately maintain the conditions required for the components contained therein (e.g., refrigerated or frozen).

[0186] In order to better understand the present invention and to more clearly show how to implement the present invention, the features of the embodiments according to the present invention are now described by way of examples.

[0187] Example

[0188] The present invention will be more readily understood by reference to the following examples, which are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way.

[0189] Unless otherwise defined or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Unless otherwise indicated, the materials and instruments used in this application are all commercially available.

[0190] Preparation example:

[0191] The compounds disclosed herein can be synthesized stepwise or modularly. Scheme A discloses the synthesis of some exemplary intermediates. Scheme B discloses the synthesis steps of exemplary compounds. Different intermediates or raw materials can be selected for each compound by referring to the synthesis of the exemplary compounds and the design of the compound itself.

[0192] Plan A

[0193] Synthesis of compound a:

[0194] Compound a-1 (24.5 g, 112.39 mmol, 1 eq) was dispersed in ethanol (300 mL), and potassium carbonate (34.17 g, 247.25 mmol, 2.2 eq) and methylhydrazine sulfate (28.80 g, 224.77 mmol, 2 eq) were added. The reaction solution was heated to 80°C and stirred at this temperature for 18 hours before cooling to room temperature. Ethyl acetate and water were added, stirred for 10 minutes, and the mixture was separated. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (EA / PE = 0%-5%) to obtain compound a-2 (17 g, yield 62.0%). 1 H NMR (400MHz, CD3OD) δ7.68 (d, J=5.4Hz, 1H), 7.51 (d, J=8.6Hz, 1H), 3.79 (s, 3H).

[0195] Compound a-2 (5 g, 20.49 mmol, 1 eq) was mixed with compound a-3 (14.36 g, 143.41 mmol, 7 e), and then DBU-LAC (an ionic liquid obtained by mixing DBU and lactic acid in equal moles, 5.45 g, 22.54 mmol, 1.1 eq) was added. The mixture was heated to 80 degrees and stirred at this temperature for 3 days. The reaction solution was cooled to room temperature, ethyl acetate and water were added, stirred for 10 minutes and separated into layers. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (EA / PE = 0%-25%) to obtain compound a-4 (3.86 g, yield 54.7%).

[0196] Compound a-4 (2.86 g, 8.31 mmol, 1 eq) was dispersed in ethanol (30 mL), and bromonitrile (4.40 g, 41.55 mmol, 5 eq) and sodium acetate (4.09 g, 49.86 mmol, 6 eq) were added. The reaction solution was heated to 85 degrees and stirred at this temperature for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added, stirred for 10 minutes and separated into layers. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (PE / DCM = 0%-20%) to obtain compound a-5 (1.5 g, yield 49.0%). 1 H NMR (400MHz, CDCl3) δ7.80 (d, J=8.4Hz, 1H), 7.56 (d, J=5.3Hz, 1H), 4.23 (q, J=7.2Hz, 2H), 4.14 (t, J=6.9Hz, 2H), 3.94 (s, 3H), 2.95 (t, J=6.8Hz, 2H), 1.31 (t, J=7.1Hz, 3H).

[0197] Compound a-5 (2 g, 5.42 mmol, 1 eq) was dispersed in toluene (30 mL), and acetaldehyde oxime (959.95 mg, 16.25 mmol, 3 eq) and indium trichloride (119.72 mg, 541.73 μmol, 0.1 eq) were added. The reaction mixture was heated to 110°C and stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-2%) to give compound a-6 (2 g, yield 95.3%). 1H NMR (400MHz, Chloroform-d) δ7.67 (d, J=5.1Hz, 1H), 7.41 (d, J=8.2Hz, 1H), 4.99 (s, 2H), 4.15 ( t, J=7.1Hz, 2H), 4.11-4.05 (m, 2H), 4.03 (s, 3H), 2.72 (t, J=7.1Hz, 2H), 1.22 (t, J=7.2Hz, 3H).

[0198] Compound a-6 (2 g, 5.17 mmol, 1 eq) was dispersed in ethanol (20 mL) and sodium ethoxide (537.19 mg, 10.33 mmol, 2 eq) was added under nitrogen. The reaction mixture was stirred at 25°C for 3 hours under a nitrogen atmosphere. Water was slowly added, and the pH was adjusted to 2 to 3 with 2N hydrochloric acid. The mixture was stirred for 10 minutes and then filtered. The filter cake was dried to obtain compound a-7 (1.4 g, 79.5% yield).

[0199] Compound a-7 (1.4 g, 4.10 mmol, 1 eq) was dispersed in a mixed solvent of dioxane (16 mL) and water (4 mL). Compound a-8 (1.90 g, 6.16 mmol, 1.5 eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2′-amino-1,1′-biphenyl-2-yl)palladium(II) (149.38 mg, 205.20 μmol, 0.05 eq), and potassium phosphate (2.61 g, 12.31 mmol, 3 eq) were added. The reaction solution was purged with nitrogen three times, heated to 90°C, and stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature, and then dichloromethane and water were added to the reaction solution. After stirring for 10 minutes, the layers were separated. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-2%) to obtain compound a-9 (1.7 g, yield 93.4%). 1 H NMR (400MHz, CDCl3) δ7.88 (s, 1H), 7.41 (d, J=10.7Hz, 1H), 7.22 (d, J=5.7Hz, 1H), 6.02 (s, 1H), 4 .05(s, 3H), 3.71(t, J=5.4Hz, 2H), 2.95(t, J=6.7Hz, 2H), 2.59(s, 2H), 1.77(s, 4H), 1.56(s, 9H).

[0200] Compound a-9 (1.7 g, 3.83 mmol, 1 eq) was dispersed in methanol (50 mL) and 0.5 g of palladium-carbon catalyst was added. The reaction solution was replaced with hydrogen three times and then heated to 50 degrees and stirred at this temperature for 24 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0% to 1%) to obtain compound a-10 (380 mg, yield 22.3%).

[0201] Compound a-10 (150 mg, 336.71 μmol, 1 eq) was dispersed in dichloromethane (0.5 mL), and 2M hydrochloric acid and ethyl acetate (0.5 mL) were added. The reaction mixture was stirred at 25°C for 15 minutes and then concentrated in vacuo to give compound a-11 (128 mg, yield 99.6%).

[0202] Compound a-11 (126 mg, 329.99 μmol, 1 eq) was dispersed in tetrahydrofuran (1 mL) and methanol (1 mL). Triethylamine (166.96 mg, 1.65 mmol, 5 eq) and acetic acid (19.8 mg, 330 μmol, 1 eq) were added and stirred for 10 minutes. Compound a-12 (94.76 mg, 395.99 μmol, 1.2 eq) and sodium cyanoborohydride (61.38 mg, 989.96 μmol, 3 eq) were then added. The reaction mixture was stirred at room temperature for 4 hours, then heated to 50°C and stirred overnight at this temperature. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was stirred for 10 minutes to separate the layers. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-10%) to obtain compound a-13 (160 mg, yield 85.3%).

[0203] Compound a-13 (160 mg, 281.35 μmol, 1 eq) was dispersed in dichloromethane (1 mL) and 2 M hydrochloric acid ethyl acetate solution (1.0 mL) was added. The reaction solution was stirred at 25 degrees for 1 hour and then concentrated in vacuo to give compound a (150 mg, yield 98.5%). m / z, (ESI + ):469.2.

[0204] Synthesis of compound b:

[0205] Compound a-11 (209.89 mg, 549.69 μmol, 1 eq) was dispersed in tetrahydrofuran (2 mL) and methanol (2 mL). Triethylamine (139.06 mg, 1.37 mmol, 2.5 eq) and acetic acid (109.46 mg, 549.69 μmol, 1 eq) were added and stirred for 10 minutes. Compound b-1 (140.68 mg, 659.63 μmol, 1.2 eq) and sodium cyanoborohydride (345.43 mg, 5.50 mmol, 10.0 eq) were then added. The reaction mixture was stirred at room temperature for 4 hours, then heated to 50°C and stirred overnight at this temperature. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was stirred for 10 minutes to separate the layers. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-10%) to obtain compound b-2 (237 mg, yield 79.5%).

[0206] Compound b-2 (237 mg, 436.75 μmol, 1 eq) was dispersed in dichloromethane (2 mL) and 2M hydrochloric acid ethyl acetate solution (1.0 mL) was added. The reaction mixture was stirred at 25 degrees for 1 hour and then concentrated in vacuo to give compound b (209 mg, yield 92.8%). m / z, (ESI + ):443.4.

[0207] Synthesis of compound c:

[0208] Compound a-11 (100 mg, 261.90 μmol, 1 eq) was dispersed in tetrahydrofuran (2 mL) and methanol (2 mL). Triethylamine (66.25 mg, 654.74 μmol, 2.5 eq) and acetic acid (109.46 mg, 261.90 μmol, 1 eq) were added and stirred for 10 minutes. Compound c-1 (79.62 mg, 314.27 μmol, 1.2 eq) and sodium cyanoborohydride (164.58 mg, 2.62 mmol, 10.0 eq) were then added. The reaction mixture was stirred at room temperature for 4 hours, then heated to 50°C and stirred overnight at this temperature. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was stirred for 10 minutes to separate the layers. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-10%) to obtain compound c-2 (126 mg, yield 82.6%).

[0209] Compound c-2 (126 mg, 216.23 μmol, 1 eq) was dispersed in dichloromethane (1 mL) and 2 M hydrochloric acid ethyl acetate solution (2.0 mL) was added. The reaction solution was stirred at 25 degrees for 1 hour and then concentrated in vacuo to obtain compound c (120 mg, yield 99.9%). m / z, (ESI + ):483.5.

[0210] Synthesis of compound d:

[0211] Compound a-11 (200 mg, 523.79 μmol, 1 eq) was dispersed in dichloroethane (10 mL), and triethylamine (159.01 mg, 1.57 mmol, 3 eq), tetraisopropyl titanate (297.73 mg, 1.05 mmol, 2 eq), and compound d-1 (114.80 mg, 576.17 μmol, 1.1 eq) were added. The mixture was heated to 50°C and stirred for 2 hours, followed by the addition of sodium acetate borohydride (333.04 mg, 1.57 mmol, 3 eq). The reaction mixture was stirred at 50°C for 3 hours, then cooled to room temperature, and dichloromethane and water were added. The mixture was stirred for 10 minutes and separated. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-7%) to obtain compound d-2 (100 mg, 36.1% yield).

[0212] Compound d-2 (100 mg, 189.17 μmol, 1 eq) was dispersed in dichloromethane (3 mL) and 2 M hydrochloric acid ethyl acetate solution (2.8 mL) was added. The reaction mixture was stirred at 25 degrees for 1 hour and then concentrated in vacuo to give compound d (90 mg, yield 94.9%). m / z, (ESI + ):429.5.

[0213] Synthesis of compound e:

[0214] The synthesis of compound e was carried out according to the synthesis steps of compound d, using compound e-1 as the starting material. m / z, (ESI + ):497.4.

[0215] Synthesis of compound f:

[0216] Compound a-7 (700 mg, 2.05 mmol, 1 eq) was dispersed in dioxane (10 mL), and compound f-1 (625.29 mg, 2.46 mmol, 1.2 eq), potassium acetate (652.53 mg, 6.16 mmol, 3 eq), and PdCl2(dppf) (151.44 mg, 205.20 μmol, 0.1 eq) were added. The reaction solution was purged with nitrogen three times, heated to 90°C under nitrogen protection, and stirred at this temperature for 3 hours, then cooled to room temperature. Water and dichloromethane were added to the reaction solution and stirred for 10 minutes, then allowed to stand and the organic phase was separated. The separated organic phase was concentrated in vacuo, and the residue was purified by column chromatography (MeOH / DCM = 0%-10%) to obtain compound f-2 (600 mg, yield 75.3%).

[0217] Compound a-12 (100 mg, 417.87 μmol, 1 eq) was dispersed in tetrahydrofuran (1.3 mL), cooled to 0 degrees under nitrogen protection, and then LDA (2M, 313.40 μL, 1.5 eq) was added dropwise. The reaction solution was stirred at 0 degrees for 30 minutes, and then compound f-3 (164.21 mg, 459.65 μmol, 1.1 eq) was added. The reaction solution was slowly warmed to room temperature and stirred at 25 degrees for 1 hour. Dichloromethane and water were slowly added to the reaction solution and stirred for 10 minutes, then allowed to stand and the organic phase was separated. The separated organic phase was washed with water, washed with brine, and then dried over anhydrous sodium sulfate. The liquid was filtered to obtain a filtrate, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-1%) to obtain compound f-4 (22 mg, yield 14.2%). m / z, (ESI - ):370.3.

[0218] Compound f-4 (22 mg, 59.24 μmol, 1 eq) was dispersed in a mixed solvent of dioxane (2 mL) and water (0.3 mL). Compound f-2 (34.50 mg, 88.86 μmol, 1.5 eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2′-amino-1,1′-biphenyl-2-yl)palladium(II) (8.62 mg, 11.85 μmol, 0.2 eq), and potassium phosphate (37.72 mg, 177.72 μmol, 3 eq) were added. The reaction solution was purged with nitrogen three times, heated to 60°C, and stirred at this temperature for 2 hours. The reaction mixture was cooled to room temperature, and then dichloromethane and water were added to the reaction solution. After stirring for 10 minutes, the layers were separated. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-3%) to give compound f-5 (10 mg, yield 34.9%).

[0219] Compound f-5 (10 mg, 20.68 μmol, 1 eq) was dispersed in a mixed solution of tetrahydrofuran (2 mL) and methanol (1 mL), and 10% palladium carbon catalyst (5 mg) was added. The reaction solution was replaced with hydrogen three times, then heated to 40 degrees in a hydrogen atmosphere and stirred at this temperature for 15 hours. The reaction was also cooled to room temperature and filtered. The filtrate was vacuum concentrated to give compound f-6 (8 mg, yield 79.7%). m / z, (ESI + ):486.5.

[0220] Compound f-6 (8.0 mg, 16.48 μmol, 1 eq) was dispersed in methanol, and a hydrochloric acid ethyl acetate solution (2 M, 164.76 μL, 20 eq) was added. The reaction mixture was stirred at 25 degrees for 30 minutes and then concentrated in vacuo to obtain f (7 mg, yield 98.7%). m / z, (ESI + ):386.5.

[0221] Synthesis of compound g:

[0222] The synthesis of compound g was carried out according to the synthesis steps of compound d, using compound g-1 as the starting material. m / z, (ESI + ):469.4.

[0223] Synthesis of compound h:

[0224] The synthesis of compound h was based on the synthesis steps of compound f, using compound g-1 as the starting material. m / z, (ESI + ):386.7.

[0225] Synthesis of compound i:

[0226] Compound c-1 (100 mg, 394.73 μmol, 1 eq) was dispersed in methanol (1 mL), and potassium carbonate (109.11 mg, 789.46 μmol, 2 eq) and compound i-1 (98.58 mg, 513.15 μmol, 1.3 eq) were added. The reaction solution was stirred at 25 degrees for 3 hours, then ethyl acetate and water were added and stirred for 10 minutes. The mixture was allowed to stand and the organic phase was separated. The separated organic phase was washed with water, then with brine, and then dried over anhydrous sodium sulfate. The liquid was filtered to obtain a filtrate, which was then concentrated in vacuo. The residue was purified by column chromatography (EA / PE = 0%-10%) to obtain compound i-2 (95 mg, yield 96.5%). 1H NMR (400MHz, CDCl3) δ3.38-3.30 (m, 4H), 3.02 (pd, J=8.4, 2.5Hz, 1H), 2.21 (td, J=9.3, 8.7, 3.9Hz, 3H), 2.00-1.91(m, 2H), 1.64-1.60(m, 2H), 1.58-1.54(m, 2H), 1.48(s, 9H).

[0227] Compound i-2 (85 mg, 340.89 μmol, 1 eq) was dispersed in DMF (2 mL), and compound a-7 (116.29 mg, 340.89 μmol, 1 eq), CuI (6.49 mg, 34.09 μmol, 0.1 eq), triphenylphosphine (17.88 mg, 68.18 μmol, 0.2 eq), PdCl2(PPh3)2 (23.93 mg, 34.09 μmol, 0.1 eq) and triethylamine (0.1 mL) were added. The reaction solution was replaced with nitrogen three times, heated to 50 degrees under nitrogen protection and stirred at this temperature for 4 hours. The reaction solution was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-2%) to give compound i-3 (140 mg, yield 80.6%). m / z, (ESI + ):510.4.

[0228] Compound i-3 (110 mg, 215.87 μmol, 1 eq) was dispersed in ethyl acetate (2 mL), and a 2M hydrochloric acid ethyl acetate solution (1 mL) was added. The reaction solution was stirred at 25 degrees for 1 hour and then concentrated to dryness in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-15%) to give compound i (50 mg, yield 51.9%). m / z, (ESI + ):410.8.

[0229] Synthesis of compound j:

[0230] Compound a-7 (300 mg, 879.42 μmol, 1 eq) was dispersed in dioxane (30 mL), and compound j-1 (378.66 mg, 1.76 mmol, 2.0 eq), Pd-PEPPSI-IHept C1(128.32 mg, 131.91 μmol, 0.15 eq) and cesium carbonate (859.59 mg, 2.64 mmol, 3.0 eq). The reaction solution was replaced with nitrogen three times, heated to 105 degrees under nitrogen protection and stirred for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added, stirred for 10 minutes, allowed to stand and the organic phase was separated. The separated organic phase was washed with water, washed with brine, and then dried over anhydrous sodium sulfate. The liquid was filtered to obtain a filtrate, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM=0%-4%) to obtain compound j-2 (380 mg, yield 90.9%). m / z, (ESI + ):476.4.

[0231] Compound j-2 (380 mg, 799.14 μmol, 1 eq) was dispersed in dichloromethane (6 mL), and dioxane hydrochloride solution (4 M, 11.99 mL, 60 eq) was added. The reaction solution was stirred at 25 degrees for 24 hours. The reaction solution was concentrated in vacuo to give compound j-3 (300 mg, yield 82.3%). m / z, (ESI + ):420.4.

[0232] Compound j-3 (75 mg, 164.52 μmol, 1 eq) was dispersed in DMF (4 mL), and compound j-4 (44.68 mg, 197.43 μmol, 1.2 eq), HATU (186.21 mg, 493.57 μmol, 3.0 eq) and DIPEA (106.31 mg, 822.61 μmol, 5.0 eq) were added. The reaction solution was stirred at 25 degrees for 0.5 hours, then ethyl acetate and water were added and stirred for 10 minutes, allowed to stand and the organic phase was separated. The separated organic phase was washed with water and brine, and then dried over anhydrous sodium sulfate. The liquid was filtered to obtain a filtrate, which was then concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-5%) to obtain compound j-5 (80 mg, yield 77.5%). m / z, (ESI + ):628.4.

[0233] Compound j-5 (80 mg, 127.45 μmol, 1 eq) was dispersed in dichloromethane (4 mL), and dioxane hydrochloride solution (4 M, 5 mL, 156.93 eq) was added. The reaction solution was stirred at 25 degrees for 1 hour. The reaction solution was concentrated in vacuo to give compound j (76 mg, yield 99.3%). m / z, (ESI + ):528.4.

[0234] Synthesis of compound k:

[0235] Compound k-1 (5 g, 32.22 mmol, 1 eq) was dispersed in DMF (15 mL), and compound k-2 (4.60 g, 38.66 mmol, 1.2 eq) was added. The reaction solution was cooled to 0°C under nitrogen, and then 60% sodium hydride (1.55 g, 38.66 mmol, 1.2 eq) was added. The reaction solution was stirred at 0°C for 3 hours, then warmed to room temperature, and then water and ethyl acetate were slowly added and stirred for 10 minutes. The mixture was allowed to stand and the layers were separated. The organic phase was washed with water and brine, and then dried over anhydrous sodium sulfate. The organic phase was filtered to obtain a filtrate, which was then concentrated in vacuo. The residue was purified by column chromatography (EA / PE = 0%-20%) to obtain compound k-3 (4.8 g, yield 77.1%).

[0236] Compound k-3 (4.8 g, 24.84 mmol, 1 eq) was dispersed in ethanol (20 mL), and compound k-4 (3.88 g, 27.32 mmol, 1.1 eq) and tris(triphenylphosphine)rhodium chloride (I) (2.30 g, 2.48 mmol, 0.1 eq) were added. The reaction solution was heated to 80 degrees and stirred at this temperature for 16 hours, then cooled to room temperature. Water and dichloromethane were added and stirred for 10 minutes, the mixture was allowed to stand and the organic phase was separated. The organic phase was washed with water and brine, and then dried over anhydrous sodium sulfate. The organic phase was filtered to obtain a filtrate, which was then concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-2%) to obtain compound k-5 (1.7 g, yield 20.4%).

[0237] Compound k-5 (1 g, 2.98 mmol, 1 eq) was dispersed in pyridine (5 mL), and compound k-6 (638.04 mg, 3.88 mmol, 1.3 eq) and lithium iodide (1.20 g, 8.95 mmol, 3 eq) were added. The reaction solution was heated to 100 degrees and stirred at this temperature for 16 hours, then cooled to room temperature. Water and dichloromethane were added and stirred for 10 minutes, the mixture was allowed to stand and the layers were separated. The organic phase was washed with water and brine, and then dried over anhydrous sodium sulfate. The organic phase was filtered to obtain a filtrate, which was then concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0%-2%) to obtain compound k-7 (0.4 g, yield 33.6%).

[0238] Compound k-7 (490 mg, 1.23 mmol, 1 eq) was dispersed in dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at 25°C for 30 minutes and then concentrated in vacuo to give compound k (240 mg, yield 58.3%).

[0239] Synthesis of compound 1:

[0240] The synthesis of compound 1 was carried out according to the synthesis steps of compound a-11, using compound 1-1 as the starting material. m / z, (ESI + ):382.3.

[0241] Synthesis of compound m:

[0242] Compound m-1 (125.05 mg, 439.71 μmol, 1.5 eq) was dispersed in dioxane (10 mL), and compound a-7 (100 mg, 293.14 μmol, 1 eq), Pd-PEPPSI-IHept C1 (142.47 mg, 146.57 μmol, 0.5 eq) and cesium carbonate (285.81 mg, 879.42 μmol, 3 eq). The reaction solution was replaced with nitrogen three times, heated to 100 degrees under nitrogen protection and stirred for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added, stirred for 10 minutes, allowed to stand and the organic phase was separated. The separated organic phase was washed with water, washed with brine, and then dried over anhydrous sodium sulfate. The liquid was filtered to obtain a filtrate, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM=0%-4%) to obtain compound m-2 (60 mg, yield 37.6%). m / z, (ESI + ):545.5.

[0243] Compound m-2 (60 mg, 110.17 μmol, 1 eq) was dispersed in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction solution was stirred at 25 degrees for 24 hours. The reaction solution was concentrated in vacuo to give compound m (60 mg, yield 97.5%). m / z, (ESI + ):445.5.

[0244] Synthesis of compound A:

[0245] Compound A-1 (240 mg, 853.16 μmol, 1 eq) was dispersed in dichloromethane (25 mL), and then a tetrahydrofuran solution of dimethylamine (2 M, 2.13 mL, 5.0 eq), DIPEA (330.79 mg, 2.56 mmol, 3.0 eq) and HATU (643.74 mg, 1.71 mmol, 2.0 eq) were added. The reaction solution was stirred at 25 degrees for 2 hours, and then dichloromethane and water were added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-5%) to obtain compound A-2 (263 mg, yield 99.9%). m / z, (ESI +):309.4.

[0246] Compound A-2 (263 mg, 852.86 μmol, 1 eq) was dispersed in dichloromethane (4 mL), and a hydrochloric acid ethyl acetate solution (4 M, 6.40 mL, 30 eq) was added. The reaction mixture was stirred at 25 degrees for 1 hour and concentrated in vacuo to obtain compound A-3 (208 mg, yield 99.7%). m / z, (ESI + ):209.2.

[0247] Compound A-3 (200 mg, 817.26 μmol, 1 eq) was dispersed in dichloromethane (30 mL), and the mixture was cooled to -40 degrees Celsius under nitrogen protection. Compound A-4 (270.00 mg, 817.26 μmol, 1 eq) and DIPEA (316.87 mg, 2.45 mmol, 3.0 eq) were added. The reaction solution was stirred at -40 degrees Celsius for 30 minutes, warmed to room temperature, and then dichloromethane and water were added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-2%) to obtain compound A-5 (400 mg, yield 97.5%). m / z, (ESI + ):503.4.

[0248] Compound A-5 (360 mg, 716.89 μmol, 1 eq) was dispersed in DMF (10 mL), and cesium carbonate (465.98 mg, 1.43 mmol, 2.0 eq), DABCO (80.41 mg, 716.89 μmol, 1 eq) and compound A-6 (465.39 mg, 2.15 mmol, 3.0 eq) were added. The reaction solution was stirred at 25 degrees for 4 hours, then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (EA / PE = 0%-100%) to obtain compound A-7 (300 mg, yield 61.4%). m / z, (ESI + ):683.5.

[0249] Compound A-7 (300 mg, 439.82 μmol, 1 eq) was dispersed in dioxane (15 mL), and compound A-8 (213.36 mg, 527.78 μmol, 1.2 eq), PdCl2(DPEphos) (2.89 mg, 87.96 μmol, 0.2 eq) and TMSOK (112.85 mg, 879.64 μmol, 2.0 eq) were added. The reaction solution was replaced with nitrogen three times, then heated to 80 degrees and stirred at this temperature for 3 hours. The reaction solution was cooled to room temperature, and then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-3%) to obtain compound A (220 mg, yield 56.0%). m / z, (ESI - ):891.6.

[0250] Synthesis of compound B:

[0251] The synthesis of compound B was carried out according to the synthesis steps of compound A, using compound B-1 as the starting material. m / z, (ESI + ):763.5.

[0252] Synthesis of compound C:

[0253] The synthesis of compound C was carried out according to the synthesis steps of compound A, using morpholine as the starting material. m / z, (ESI + ):822.8.

[0254] Synthesis of compound D:

[0255] Compound A-4 (676.92 mg, 2.05 mmol, 1 eq) was dispersed in dichloromethane (10 mL) and cooled to -40°C under nitrogen. Triethylamine (1.04 g, 10.24 mmol, 1.42 mL, 5 eq) and compound D-1 (400 mg, 2.05 mmol, 1 eq) were then added. The reaction mixture was slowly heated to 25°C and stirred at this temperature for 30 minutes. Dichloromethane and water were then added and stirred for 10 minutes. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to yield compound D-2 (800 mg, 79.8% yield).

[0256] Compound D-2 (60 mg, 122.67 μmol, 1 eq) was dispersed in DMF (2 mL), and cesium carbonate (119.90 mg, 368.00 μmol, 3 eq) and compound D-3 (15.85 mg, 122.67 μmol, 1 eq) were added. The reaction solution was heated to 100 degrees and stirred at this temperature for 1.5 hours, and then cooled to room temperature. Ethyl acetate and water were added to the reaction solution and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM=0%-2%) to obtain compound D-4 (50 mg, yield 70.1%). m / z, (ESI + ):583.1.

[0257] Compound D-4 (100 mg, 171.86 μmol, 1 eq) was dispersed in a mixed solvent of dioxane (0.8 mL) and water (0.2 mL). Compound A-8 (69.48 mg, 171.86 μmol, 1 eq), PdCl2(DPEphos) (12.3 mg, 17.1 μmol, 0.1 eq), and TMSOK (22.05 mg, 171.86 μmol, 1 eq) were added. The reaction solution was purged with nitrogen three times, then heated to 80°C and stirred at this temperature for 3 hours. The reaction solution was cooled to room temperature, and then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-5%) to obtain compound D-5 (70 mg, yield 51.3%).

[0258] Compound D-5 (70 mg, 88.24 μmol, 1 eq) was dispersed in a mixed solvent of tetrahydrofuran (0.6 mL) and water (0.3 mL), and lithium hydroxide (10.57 mg, 441.21 μmol, 5 eq) was added. The reaction solution was stirred at 25 degrees for 3 hours. The pH of the reaction solution was adjusted to about 2 with a 1M aqueous hydrochloric acid solution, and then dichloromethane was added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain compound D (25 mg, yield 36.4%). m / z, (ESI + ):779.4.

[0259] Synthesis of compound E:

[0260] The synthesis of compound E was carried out according to the synthesis steps of compound D, using compound E-1 as the starting material. m / z, (ESI + ):809.3.

[0261] Synthesis of compound F:

[0262] The synthesis of compound F was carried out according to the synthesis steps of compound D, using compound F-1 as the starting material. m / z, (ESI - ):801.3.

[0263] Synthesis of compound G:

[0264] The synthesis of compound G was carried out according to the synthesis steps of compound D, using compound G-1 as the starting material. m / z, (ESI - ):819.4.

[0265] Synthesis of compound H:

[0266] The synthesis of compound H was carried out according to the synthesis steps of compound D, using compound H-1 as the starting material. m / z, (ESI - ):813.4.

[0267] Synthesis of Compound I:

[0268] The synthesis of compound I was carried out according to the synthesis steps of compound E, using compound I-1 as the starting material. m / z, (ESI + ):776.4.

[0269] Synthesis of compound J:

[0270] The synthesis of compound J was carried out according to the synthesis steps of compound C, using compound I-1 as the starting material. m / z, (ESI + ):854.5.

[0271] Synthesis of compound K:

[0272] The synthesis of compound K was carried out according to the synthesis steps of compound J, using compound K-1 as the starting material. m / z, (ESI + ):688.4.

[0273] Synthesis of compound L:

[0274] Compound L-2 (90 mg, 686.12 μmol, 1 eq) was dispersed in acetonitrile (2 mL), and DIPEA (97.54 mg, 754.73 μmol, 1.1 eq) was added. The mixture was cooled to 0°C under nitrogen protection, and then compound L-1 (204.84 mg, 686.12 μmol, 1 eq) was added. The reaction solution was stirred at 0°C for 10 minutes, and then tert-butyl lithium (164.78 mg, 2.06 mmol, 3 eq) was added. The temperature was then slowly raised to 50°C and stirred at this temperature for 2 hours. The reaction mixture was also cooled to room temperature, and ethyl acetate and water were added, stirred for 10 minutes, and then allowed to stand. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was vacuum-dried to remove the solvent residue, and the residue was purified by column chromatography (MeOH / DCM = 0%-4%) to obtain compound L-3 (227 mg, yield 92.7%). m / z, (ESI + ):359.3.

[0275] Compound L-3 (220 mg, 616.59 μmol, 1 eq) was dispersed in a mixed solvent of tetrahydrofuran (1 mL) and water (0.5 mL), and Oxone (390.76 mg, 1.13 mmol, 1.83 eq) was added. The reaction solution was heated to 50 degrees and stirred at this temperature for 2 hours. The reaction was also cooled to room temperature, ethyl acetate and water were added, stirred for 10 minutes, and then allowed to stand. The organic phase was separated and dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was vacuum-dried to remove the solvent residue, and the residue was purified by column chromatography (MeOH / DCM = 0%-2%) to obtain compound L-4 (137 mg, yield 57.2%). m / z, (ESI + ):389.1.

[0276] Compound L-5 (183.88 mg, 1.80 mmol, 5 eq) was dispersed in tetrahydrofuran (2 mL), cooled to 0 degrees under nitrogen protection, and then sodium hydride (25.93 mg, 1.08 mmol, 3 eq) was added and stirred for 10 minutes, and finally compound L-4 (140.00 mg, 360.08 μmol, 1 eq). After the reaction solution was stirred at 0 degrees for 1 hour, saturated aqueous ammonium chloride solution and ethyl acetate were added in sequence and stirred for 10 minutes, and then allowed to stand. The organic phase was separated and dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was vacuum-dried to remove the solvent residue, and the residue was purified by column chromatography (MeOH / DCM=0%-5%) to obtain compound L-6 (110 mg, yield 74.4%). m / z, (ESI + ):411.2.

[0277] Compound L-6 (55 mg, 133.88 μmol, 1 eq) was dispersed in a mixed solvent of dioxane (2 mL) and water (0.5 mL), and potassium phosphate (85.25 mg, 401.63 μmol, 3 eq), compound 83-1 (82.34 mg, 160.65 μmol, 1.2 eq), and Cataxium A Pd G3 (9.75 mg, 13.39 μmol, 0.1 eq) were added. The reaction solution was purged with nitrogen three times, then heated to 90 degrees under nitrogen protection and stirred at that temperature for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added, stirred for 10 minutes, and then allowed to stand. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was vacuum-dried to remove the solvent residue, and the residue was purified by column chromatography (MeOH / DCM = 0%-4%) to obtain compound L (90 mg, yield 88.4%). m / z, (ESI + ):761.6.

[0278] Synthesis of compound M:

[0279] The synthesis of compound M followed the synthesis procedure of compound L, using compound M-1 as the starting material.

[0280] m / z, (ESI + ):824.2.

[0281] Plan B

[0282] Synthesis of compound 1:

[0283] Compound A (220 mg, 246.22 μmol, 1 eq) was dispersed in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of TBAF (1 M, 2.46 mL, 10 eq) was added. The reaction solution was stirred at 25 degrees for 4 hours, then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-3%) to obtain compound 1-1 (190 mg, yield 99.1%). m / z, (ESI + ):779.6.

[0284] Compound 1-1 (190 mg, 243.82 μmol, 1 eq) was dispersed in dichloromethane (10 mL) and Dess-martin oxidant (517.08 mg, 1.22 mmol, 5.0 eq) was added. The reaction solution was stirred at 25 degrees for 1.5 hours, then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-5%) to obtain compound 1-2 (180 mg, yield 61.7%). m / z, (ESI + ):777.7.

[0285] Compound 1-2 (60 mg, 77.20 μmol, 1 eq) was dispersed in 1,2-dichloroethane (5 mL), and compound a (58.48 mg, 115.79 μmol, 1.5 eq), tetraisopropyl titanate (43.88 mg, 154.39 μmol, 2 eq) and triethylamine (23.43 mg, 231.59 μmol, 3 eq) were added. The reaction solution was heated to 50 degrees and stirred at this temperature for 2 hours, then cooled to room temperature. Dichloromethane and water were added to the reaction solution and stirred for 10 minutes. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-7%) to obtain compound 1-3 (45 mg, yield 47.4%). m / z, (ESI - ):1227.8.

[0286] Compound 1-3 (45 mg, 36.59 μmol, 1 eq) was dispersed in dichloromethane (2 mL), and a hydrochloric acid ethyl acetate solution (2 M, 2 mL, 109.32 eq) was added. The reaction solution was stirred at 25°C for 5 minutes and then concentrated to dryness in vacuo. The residue was purified by preparative chromatography (0.05% NH in H2O / MeCN) to afford compound 1 (8 mg, 18.8% yield). 1H NMR (400MHz, CD3OD) δ0.56 (s, 2H), 0.76 (s, 2H), 0.94 (t, J=6.8Hz, 3H), 1.22 (dt, J=7.1, 3.6Hz, 3H), 1.69 (dd, J=20. 1, 9.8Hz, 7H), 1.99 (ddd, J=38.0, 21.6, 9.9Hz, 10H), 2.40 (dd, J=15.2, 7.3Hz, 3H), 2.55 (s, 4H), 2.90 (t, J=6.7Hz, 2H ), 3.12 (s, 3H), 3.39 (s, 3H), 3.64 (d, J = 7.6Hz, 1H), 4.05 (d, J = 2.7Hz, 5H), 4.30-4.37 (m, 3H), 4.41 (s, 1H), 6.76 (s, 1H), 7.07 (t, J=8.9Hz, 1H), 7.25 (dd, J=8.4, 5.0Hz, 1H), 7.38 (d, J=10.6Hz, 1H), 7.44 (d, J=5.7Hz, 1H), 8.03 (s, 1H). 19 F NMR (376MHz, CD3OD) δ-129.05--129.09(m, 1F), -123.11(s, 1F), -118.62--118.68(m, 1F).m / z(ESI + ):1129.31.

[0287] Compound 1 was separated by chiral SFC to give compound 1a and compound 1b.

[0288] Synthesis of compound 2:

[0289] The synthesis of compound 2 followed the synthetic steps of compound 1, using compound b and compound A as starting materials. 1H NMR (400MHz, CD3OD) δ0.61-0.70 (m, 2H). 0.80-0.87 (m, 2H), 1.22 (t, J = 7.1Hz, 1H), 1.26-1.30 (m, 3H), 1.49 (s, 1H), 1.65 (d, J = 7.0Hz, 2H), 1.93 (d t, J=12.3, 5.7Hz, 6H), 2.07 (d, J=5.9Hz, 1H), 2.22 (d, J=7.5Hz, 2H), 2.32 (s, 1H), 2.43 (d, J=4.7Hz, 3H), 2.90 (t, J=6.7Hz, 3H), 3.00 (d, J=4.2Hz, 2 H), 3.12 (d, J=3.9Hz, 4H), 3.16-3.19 (m, 1H), 3.52 (p, J=1.7Hz, 1H), 3.6 3(s, 1H), 4.03-4.09(m, 7H), 4.27-4.41(m, 4H), 4.47(d, J=11.6Hz, 1H), 4 .58 (d, J=5.4Hz, 3H), 6.76 (s, 1H), 7.08 (t, J=8.9Hz, 1H), 7.25 (dd, J=8.4 , 5.0Hz, 1H), 7.38 (d, J=10.6Hz, 1H), 7.43 (d, J=5.7Hz, 1H), 8.05 (s, 1H). 19 F NMR (376MHz, CD3OD) -129.16 (d, J=11.0Hz 1H), -123.01 (s, 1H), -118.57 (s, 1H).m / z (ESI + ):1103.23.

[0290] Synthesis of compound 3:

[0291] The synthesis of compound 3 followed the synthetic steps of compound 1, using compound c and compound A as starting materials. 1H NMR (400MHz, CD3OD) δ0.86-0.90 (m, 2H), 0.99-1.03 (m, 2H), 1.48 (s, 1H), 1.80 (dd, J=23.7, 12.8Hz, 3H), 1.96 (d, J=11.7 Hz, 4H), 2.20 (q, J=14.6Hz, 8H), 2.39 (d, J=29.8Hz, 4H), 2.90 (t, J=6.7Hz, 3H), 3.13 (s, 4H), 3.16-3.25 (m, 3H), 3.52 (p, J =1.6Hz, 1H), 3.66 (dd, J=12.7, 9.3Hz, 4H), 4.07 (d, J=5.0Hz, 7H), 4.31-4.41 (m, 4H), 4.48 (d, J=12.0Hz, 2H), 4.57 (d, J=6 .3Hz, 2H), 5.17 (s, 2H), 6.75 (s, 1H), 7.09 (t, J=8.9Hz, 1H), 7.26 (dd, J=8.4, 5.1Hz, 1H), 7.41-7.48 (m, 2H), 8.09 (s, 1H). 19 F NMR (376MHz, CD3OD) -129.07--128.86 (m 1F), -123.42 (d, J=7.9Hz 1F), -118.37 (t, J=7.0Hz 1F), -77.09 (s, 30F).m / z (ESI + ):1143.20.

[0292] Synthesis of compound 4:

[0293] The synthesis of compound 4 followed the synthetic procedure of compound 1, using compound d and compound A as starting materials. 1H NMR (400MHz, CD3OD) δ0.57 (s, 2H), 0.78 (s, 2H), 1.49-1.76 (m, 3H), 1.80-2.01 (m, 7H), 2.04-2.24 ( m, 2H), 2.36-2.71 (m, 7H), 2.91 (t, J=6.7Hz, 2H), 3.10 (s, 3H), 3.15-3.21 (m, 2H), 3.36 (s, 3H), 4.0 2-4.11 (m, 5H), 4.33 (s, 2H), 4.44 (d, J=4.8Hz, 2H), 4.59 (d, J=5.5Hz, 2H), 4.67 (s, 2H), 5.14 (s, 1H ), 6.76 (s, 1H), 7.07 (t, J=8.9Hz, 1H), 7.25 (dd, J=8.4, 5.0Hz, 1H), 7.35-7.44 (m, 2H), 8.04 (s, 1H). 19 F NMR (376MHz, CD3OD) δ-128.86 (m, 1F), -123.34 (s, 1F), -118.51 (s, 1F).m / z (ESI + ):1089.19.

[0294] Synthesis of compound 5:

[0295] The synthesis of compound 5 followed the synthetic steps of compound 1, using compound e as the starting material. 1 H NMR (400MHz, CD3OD) δ0.91 (t, J=9.7Hz, 2H), 1.01 (s, 2H), 1.32 (s, 4H), 1.52-1.85 (m, 7H), 1.86-2. 15 (m, 4H), 2.16-2.52 (m, 9H), 2.90 (t, J=6.7Hz, 3H), 3.08-3.24 (m, 6H), 3.38 (s, 6H), 3.68 (dd, J=31 .1, 10.1Hz, 5H), 4.07 (d, J=4.3Hz, 6H), 4.32-4.43 (m, 3H), 4.55-4.62 (m, 2H), 5.18 (s, 2H), 6.75 (s , 1H), 7.10 (t, J=8.9Hz, 1H), 7.26 (dd, J=8.4, 5.0Hz, 1H), 7.43-7.49 (m, 2H), 8.10 (d, J=1.5Hz, 1H). 19F NMR (376MHz, CD3OD) δ-128.95 (t, J=7.7Hz 1F), -123.25 (d, J=37.5Hz 1F), -118.47--118.04 (m 1F), -77.16 (s, 15F).m / z (ESI - ):1155.02.

[0296] Synthesis of compound 6:

[0297] The synthesis of compound 6 followed the synthetic steps of compound 1, using compound B as the starting material. 1 H NMR (400MHz, CD3OD) δ7.71 (d, J=9.9Hz, 1H), 7.45-7.31 (m, 2H), 7.31-7.22 (m, 1H), 7.03 (t , J=8.8Hz, 1H), 6.64 (s, 1H), 5.11 (s, 2H), 4.50 (s, 2H), 4.42-4.23 (m, 4H), 4.06-3.96 (m, 5 H), 3.81-3.53(m, 6H), 3.48-3.42(m, 2H), 3.21-3.13(m, 2H), 3.12-2.90(m, 8H), 2.84(t, J =6.8Hz, 2H), 2.60-2.45(m, 1H), 2.44-1.82(m, 13H), 1.01-0.91(m, 2H), 0.84-0.77(m, 2H). 19 F NMR (376MHz, CD3OD) δ-76.93, -117.97--118.19 (m), -118.62, -120.07 (d, J=10.4Hz), -124.82, -128.13, -128.80--129.18(m).m / z (ESI + ):1113.61.

[0298] Synthesis of compound 7:

[0299] Compound a-11 (100 mg, 261.90 μmol, 1 eq) was dispersed in DMF (3 mL), and compound 7-1 (63.87 mg, 314.27 μmol, 1.2 eq), DIPEA (135.39 mg, 1.05 mmol, 182.47 μL, 4 eq) and HATU (148.21 mg, 392.84 μmol, 1.5 eq) were added. The reaction solution was stirred at 25 degrees for 2 hours, then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-5%) to obtain compound 7-2 (110 mg, yield 79.2%). m / z, (ESI + ):531.4.

[0300] Compound 7-2 (110 mg, 207.32 μmol, 1 eq) was dispersed in dichloromethane (0.5 mL), and then 2M dioxane hydrochloride solution (0.5 mL) was added. The reaction mixture was stirred at 25°C for 1 hour and then concentrated in vacuo to give compound 7-3 (75 mg, yield 84.1%).

[0301] Compound D (25 mg, 32.08 μmol, 1 eq) was dispersed in dichloromethane (2 mL), and compound 7-3 (20.72 mg, 48.12 μmol, 1.5 eq), HATU (24.21 mg, 64.16 μmol, 2 eq) and DIPEA (20.73 mg, 160.41 μmol, 5 eq) were added. The reaction solution was stirred at 25 degrees for 2 hours, then ethyl acetate and water were added and stirred for 10 minutes. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was then purified by column chromatography (MeOH / DCM = 0%-5%) to obtain compound 7-4 (20 mg, yield 52.3%). m / z, (ESI + ):1191.5.

[0302] Compound 7-4 (20 mg, 16.78 μmol, 1 eq) was dispersed in dichloromethane (0.5 mL), and a 2 M hydrochloric acid ethyl acetate solution (0.5 mL) was added. The reaction solution was stirred at 25°C for 1 hour and then concentrated to dryness in vacuo. The residue was purified by preparative chromatography (0.05% NH3 in H2O / MeCN) to afford compound 7 (4.3 mg, 23.1% yield). 1H NMR (400MHz, CD3OD) δ7.98-7.90 (m, 1H), 7.36 (d, J=5.7Hz, 1H), 7.29 (d, J=10.8Hz, 1H), 7.22-7.16 (m, 1H), 7.07-7.01 (m, 1H), 6.77 (s, 1H), 5.09-4.96 (m, 2H), 4.70 (d, J=16.0Hz, 1H), 4.63 (s, 3H), 4.48 (s, 2H), 4.29 (dq, J=16.6, 8.5, 5.5Hz, 4H), 4.16-4.08 (m, 1H), 4.05-4.00 (m, 2 H), 3.99 (d, J=2.6Hz, 3H), 3.49-3.42 (m, 2H), 3.27-3.11 (m, 3H), 2.86 (td, J=6.8, 3.6Hz, 3H), 2.70 (d, J=13.4Hz, 1H), 2.61-2.53 (m, 4H), 2. 32 (dt, J=27.7, 8.8Hz, 3H), 2.19 (t, J=7.6Hz, 1H), 2.06-1.99 (m, 1H), 1.98-1.81 (m, 4H), 1.72 (d, J=12.4Hz, 1H), 1.65-1.47 (m, 3H).m / z (ESI + ):1092.91.

[0303] Synthesis of compound 8:

[0304] The synthesis of compound 8 followed the synthetic steps of compound 1, using compound C as the starting material. 1 H NMR (400MHz, CD3OD) δ0.54 (s, 2H), 0.73 (s, 2H), 1.26-1.33 (m, 3H), 1.64-2.73 (m, 1 5H), 2.35-2.62(m, 3H), 2.81-2.88(m, 3H), 2.97-3.09(m, 3H), 3.69-3.73(m, 6H), 4. 01-4.04(m, 8H), 4.28-4.40(m, 4H), 4.53(d, J=5.6Hz, 2H), 5.08(s, 2H), 6.73(s, 1H) , 7.04 (d, J=8.8Hz, 1H), 7.19-7.22 (m, 1H), 7.33-7.41 (m, 2H), 7.99 (s, 1H).m / z (ESI + ):1171.61.

[0305] Synthesis of compound 9:

[0306] The synthesis of compound 9 followed the synthetic steps of compound 1, using compound f as the starting material. 1 H NMR (400MHz, CD3OD) δ0.60 (s, 2H), 1.66 (s, 2H), 1.89 (s, 2H), 1.96-2.09 (m, 3H), 2.30-2.48 (m, 5H), 2. 65 (d, J=32.8Hz, 4H), 2.90 (t, J=6.8Hz, 2H), 3.11 (s, 3H), 3.38 (s, 3H), 3.79 (p, J=9.2Hz, 1H), 3.99-4.1 0 (m, 5H), 4.27-4.47 (m, 4H), 4.58 (t, J = 5.5Hz, 2H), 5.12 (s, 2H), 6.76 (s, 1H), 7.07 (dd, J = 9.4, 8.3Hz, 1H), 7.24 (dd, J=8.4, 5.1Hz, 1H), 7.32 (d, J=10.4Hz, 1H), 7.37 (d, J=5.9Hz, 1H), 8.04 (d, J=1.6Hz, 1H). 19 F NMR (376MHz, CD3OD) δ-127.29--127.24(m, 1F), -123.04(s, 1F), -118.65--118.63(m, 1F).m / z(ESI + ):1046.16.

[0307] Synthesis of compound 10:

[0308] The synthesis of compound 10 followed the synthetic steps of compound 1, using compound a-11 as the starting material. 1H NMR (400MHz, CD3OD) δ0.95 (dq, J=10.7, 7.0, 5.4Hz, 2H), 1.05 (dd, J=11.3, 5.2Hz, 2H), 2.27 (d, J=14.4Hz, 2H), 2.39 (q, J=7.5, 5 .7Hz, 3H), 2.93 (t, J=6.7Hz, 2H), 3.11 (s, 3H), 3.15-3.27 (m, 4H), 3.43-3.53 (m, 2H), 3.69 (s, 3H), 3.82 (d, J=12.1Hz, 1H), 4.00 -4.23(m, 4H), 4.33-4.47(m, 3H), 4.59(dd, J=28.3, 9.5Hz, 3H), 5.14-5.20(m, 2H), 6.75(s, 1 H), 7.07 (t, J=8.9Hz, 1H), 7.22-7.31 (m, 2H), 7.41 (d, J=10.8Hz, 1H), 8.10 (d, J=1.5Hz, 1H). 19 F NMR (376MHz, CD3OD) -128.95 (d, J=11.4Hz 1F). -122.59 (s, 1F), -118.08 (d, J=8.3Hz 1F), -76.98 (s, 12F).m / z (ESI + ):1006.08.

[0309] Synthesis of compound 11:

[0310] The synthesis of compound 11 followed the synthetic procedure of compound 7, using Boc-5-aminovaleric acid as the starting material. 1H NMR (400MHz, CD3OD) δ7.85 (dd, J=29.2, 1.5Hz, 1H), 7.31 (q, J=6.0Hz, 2H), 7.21 (ddd, J=9.7, 6.6, 5.2Hz, 2H), 7.07-7.00 (m, 1 H), 6.75 (d, J=15.5Hz, 1H), 4.69 (d, J=13.4Hz, 1H), 4.43 (t, J=5.5Hz, 2H), 4.29-4.18 (m, 4H), 4.13 (d, J=9.2Hz, 1H), 4.03 (d, J =6.7Hz, 2H), 3.95(s, 3H), 3.46-3.39(m, 2H), 3.23-3.13(m, 2H), 2.90-2.84(m, 2H), 2.75-2.65(m, 1H), 2.52(d, J=19.3Hz, 4H ), 2.34 (s, 6H), 2.26 (t, J = 5.6Hz, 2H), 1.88 (t, J = 12.1Hz, 2H), 1.75-1.63 (m, 8H), 0.72 (d, J = 3.9Hz, 2H), 0.52 (s, 2H).m / z (ESI + ):1105.41.

[0311] Synthesis of compound 12:

[0312] The synthesis of compound 12 followed the synthetic steps of compound 7, using Boc-β-alanine as the starting material. 1 H NMR (400MHz, CD3OD) δ1.29-1.33(m, 5H), 1.61-2.24(m, 18H), 2.36-2.41(m, 3H ), 2.55-2.89 (m, 11H), 2.97 (d, J = 11.2Hz, 1H), 3.07-3.13 (m, 2H), 3.21-3.24 ( m, 1H), 3.48-3.60 (m, 7H), 4.02-4.06 (m, 5H), 4.58 (d, J=13.6Hz, 1H), 4.63 (s, 1H), 7.15 (d, J=4.8Hz, 1H), 7.39-7.43 (m, 2H), 8.42 (t, J=4.8Hz, 1H).m / z (ESI + ):1105.41.

[0313] Synthesis of compound 13:

[0314] The synthesis of compound 13 followed the synthetic steps of compound 1, using compound g as the starting material. 1H NMR (400MHz, CD3OD) δ0.91 (s, 4H), 1.34 (d, J = 9.5Hz, 1H), 1.73 (d, J = 10.4Hz, 3H), 2.17 (d, J = 20.9Hz, 8H), 2.44 (d d, J=11.3, 5.6Hz, 3H), 2.91 (t, J=6.7Hz, 2H), 3.13 (s, 3H), 3.27 (t, J=11.9Hz, 4H), 3.37 (s, 4H), 3.44 (d, J=3.9Hz, 2H), 3.63(s, 2H), 3.94(s, 1H), 4.01-4.20(m, 8H), 4.33-4.42(m, 4H), 4.55(s, 2H), 5.17(s, 2H), 6.73(s, 1H), 7.0 6 (d, J=9.7Hz, 1H), 7.25 (dd, J=8.4, 5.0Hz, 1H), 7.40 (d, J=5.7Hz, 1H), 7.46 (dd, J=11.0, 1.2Hz, 1H), 8.10 (s, 1H). 19 F NMR (376MHz, CD3OD) -128.85 (d, J=23.2Hz, 1F), -123.85 (d, J=143.3Hz, 1F), -118.25 (s, 1F), -77.13 (s, 12F).m / z (ESI + ):1130.81.

[0315] Synthesis of compound 14:

[0316] The synthesis of compound 14 followed the synthetic steps of compound 7, using compound b as the starting material. 1H NMR (400MHz, CD3OD) δ7.98 (s, 1H), 7.39 (t, J=4.3Hz, 1H), 7.33 (d, J=10.7Hz, 1H), 7.20 (dd, J=8.4, 5.0Hz, 1H), 7.01 (td, J=9.0, 2.2Hz, 1H), 6.66 (d, J=5.3Hz, 1H), 5.07 (d, J=7.1Hz, 2H), 4.67-4.59 (m, 2H), 4.53 (t, J=5.3Hz, 2H), 4.34-4.29 (m, 2H), 4.28-4.22 (m, 2H), 4.0 1 (d, J=8.0Hz, 6H), 3.20-3.12 (m, 1H), 3.06 (d, J=10.8Hz, 2H), 2.92 (d, J=6.6Hz, 1H), 2.86 (t, J=6.7Hz, 3H), 2.53-2.44 (m, 2H), 2.37 (d d, J=8.7, 4.4Hz, 2H), 2.32 (s, 6H), 2.28 (s, 2H), 2.12 (s, 2H), 1.94-1.80 (m, 7H), 1.26-1.16 (m, 2H), 0.71 (s, 2H), 0.52 (s, 2H).m / z (ESI + ):1103.17.

[0317] Synthesis of compound 15:

[0318] The synthesis of compound 15 followed the synthetic steps of compound 7, using compound a as the starting material. 1H NMR (400MHz, CD3OD) δ7.99 (s, 1H), 7.41 (d, J=5.8Hz, 1H), 7.34 (d, J=10.7Hz, 1H), 7.21 (dd, J=8.4, 5.0Hz, 1H), 7.04 (dd, J=9.5, 8.3Hz, 1H), 6.67 (s, 1H ), 5.07 (s, 2H), 4.54 (t, J = 5.3Hz, 2H), 4.31 (d, J = 4.0Hz, 2H), 4.27 (d, J = 5. 5Hz, 2H), 4.02 (d, J=3.2Hz, 6H), 3.87 (d, J=6.4Hz, 1H), 3.80 (t, J=5.5Hz, 1H ), 3.71 (s, 1H), 3.64 (d, J = 6.5Hz, 1H), 3.08 (d, J = 10.8Hz, 2H), 2.96 (td, J = 9.7, 8.0, 5.7Hz, 1H), 2.86 (t, J=6.7Hz, 3H), 2.46 (d, J=5.5Hz, 2H), 2.40-2. 34 (m, 2H), 2.31 (s, 6H), 2.14 (d, J=8.9Hz, 2H), 1.92 (tt, J=24.3, 12.1Hz, 7H ), 1.77-1.67(m, 4H), 1.63(s, 2H), 0.72-0.68(m, 2H), 0.52(s, 2H).m / z(ESI + ):1126.97.

[0319] Synthesis of compound 70:

[0320] The synthesis of compound 70 followed the synthetic procedure of compound 15, using compound E as the starting material. 1H NMR (400MHz, CD3OD) δ8.03-7.98 (m, 1H), 7.41 (d, J=5.7Hz, 1H), 7.35 (dd, J=10.7, 2.2Hz, 1H), 7.21 (dd, J=8.4, 5.1Hz, 1H), 7.04 (t, J=8.9Hz, 1H), 6.70 (s, 1H), 5.12-5.05 (m, 2H), 4.64 (s, 2H), 4.53 (t, J=5.3Hz, 2H ), 4.32-4.27(m, 2H), 4.26-4.16(m, 2H), 4.02(d, J=2.8Hz, 6H), 3.88(s , 1H), 3.80 (s, 1H), 3.72 (d, J=6.1Hz, 1H), 3.67-3.60 (m, 1H), 3.26-3.19 (m, 2H), 3.10 (d, J=11.0Hz, 2H), 3.00 (dd, J=13.6, 4.5Hz, 2H), 2.86 ( td, J=6.8, 2.3Hz, 3H), 2.38 (q, J=6.0Hz, 2H), 2.28-2.20 (m, 1H), 2.15 (q, J=10.7, 9.1Hz, 4H), 2.03-1.82 (m, 10H), 1.80-1.60 (m, 7H).m / z (ESI + ):1159.31.

[0321] Synthesis of compound 71:

[0322] The synthesis of compound 71 followed the synthetic procedure of compound 70, using compound F as the starting material. 1H NMR (400MHz, CD3OD) δppm: 1.63-1.85 (m, 7H), 1.87-2.03 (m, 6H), 2.08 (d, J=6.8Hz, 3H), 2.21 (d, J=7.5Hz, 3H), 2.37- 2.47 (m, 2H), 2.59 (d, J=15.9Hz, 1H), 2.80-2.95 (m, 5H), 3.12-3.18 (m, 2H), 3.67 (s, 1H), 3.75 (s, 1H), 3.83 (s, 1H), 3. 91 (s, 2H), 4.06 (d, J = 3.1Hz, 4H), 4.31-4.41 (m, 3H), 4.56 (t, J = 5.3Hz, 2H), 4.67 (s, 5H), 5.11 (d, J = 15.3Hz, 4H), 6.7 3 (s, 1H), 7.08 (dd, J=9.4, 8.4Hz, 1H), 7.19-7.29 (m, 1H), 7.39 (d, J=10.7Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 8.06 (s, 1H). 19 F NMR (376MHz, CD3OD) δppm: -129.05--129.13(m, 1F), -123.26(s, 1F), -118.54--118.56(d, 1F).m / z(ESI + ):1153.34.

[0323] Synthesis of compound 72:

[0324] The synthesis of compound 72 followed the synthetic procedure of compound 70, using compound G as the starting material. 1H NMR (400MHz, CD3OD) δppm: 1.67 (dt, J=13.9, 5.6Hz, 4H), 1.73-1.78 (m, 2H), 1.84 (d, J=9.4Hz, 2H), 1.95 (s, 4H), 2.00-207 (m, 5H), 2.17-2.25 (m, 5 H), 2.42 (d, J=5.5Hz, 1H), 2.52 (d, J=15.9Hz, 1H), 2.79 (d, J=16.1Hz, 3H), 2.90 (t, J=6.7Hz, 3H), 3.06 (t, J=6.9Hz, 2H), 3.60 (dd, J=15.1, 6.7Hz, 2 H), 3.66-3.69 (m, 1H), 3.76 (d, J=3.5Hz, 1H), 3.84 (d, J=5.4Hz, 1H), 3.92 (d, J=5.1Hz, 1H), 4.06 (s, 3H), 4.35 (d, J=16.0Hz, 4H), 4.57 (s, 2H), 5.13 (s, 1H), 5.26 (s, 1H), 6.74 (s, 1H), 7.08 (t, J=8.9Hz, 1H), 7.25 (dd, J=8.4 , 5.0Hz, 1H), 7.40 (d, J=10.8Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 8.06 (s, 1H). 19 F NMR (376MHz, CD3OD) δppm: -129.06 (s, 1F), -123.16 (s, 1F), -118.60 (s, 1F).m / z (ESI + ):1170.98.

[0325] Synthesis of compound 73:

[0326] The synthesis of compound 73 followed the synthetic procedure of compound 70, using compound H as the starting material. 1H NMR (400MHz, CD3OD) δppm: 1.63-1.74 (m, 3H), 1.81 (dd, J=20.9, 11.4Hz, 3H), 1 .88-2.04(m, 4H), 2.09-2.26(m, 4H), 2.36-2.47(m, 2H), 2.57-2.66(m, 2H), 2. 81 (dd, J=16.6, 2.1Hz, 2H), 2.90 (t, J=6.7Hz, 2H), 2.96-3.09 (m, 2H), 3.13-3. 21(m, 2H), 3.38(d, J=2.7Hz, 1H), 3.41(s, 1H), 3.65-3.69(m, 1H), 3.75(s, 1H) , 3.84 (d, J = 14.7Hz, 3H), 3.89 (d, J = 4.9Hz, 1H), 4.06 (d, J = 3.1Hz, 5H), 4.33 (d , J=9.6Hz, 4H), 4.57 (t, J=5.3Hz, 2H), 4.69 (s, 3H), 5.06 (dt, J=6.2, 2.2Hz, 4H ), 5.12 (s, 1H), 6.72 (s, 1H), 7.08 (dd, J=9.4, 8.3Hz, 1H), 7.25 (dd, J=8.4, 5.0 Hz, 1H), 7.39 (d, J=10.7Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 8.04 (d, J=3.2Hz, 1H). 19 F NMR (376MHz, CD3OD) δppm: -129.06--129.10(m, 1F), -12303--123.05(d, 1F), -118.58--118.62(m, 1F).m / z(ESI + ):1164.93.

[0327] Synthesis of compound 74:

[0328] The synthesis of compound 74 followed the synthetic procedure of compound 1, using compound K as the starting material. 1H NMR (400MHz, CD3OD) δ9.17 (s, 1H), 7.67 (dd, J=9.1, 5.8Hz, 1H), 7.41 (d, J=5.7Hz, 1H), 7.34 (d, J=10.7Hz, 1H), 7.29 (d, J=2.6Hz, 1H), 7 .25 (t, J=9.4Hz, 1H), 7.05 (d, J=2.6Hz, 1H), 6.73 (s, 1H), 5.34 (d, J=16.1Hz, 1H), 5.21 (d, J=16.1Hz, 1H), 4.68-4.53 (m, 3H), 4.42 (dt, J =18.5, 8.3Hz, 4H), 4.02 (d, J = 2.7Hz, 6H), 3.34 (s, 3H), 3.07 (d, J = 10.0Hz, 5H), 3.01-2.92 (m, 1H), 2.86 (t, J = 6.7Hz, 2H), 2.83-2.76 (m, 1H), 2.58-2.40 (m, 8H), 2.18 (td, J=7.2, 2.9Hz, 1H), 2.06-1.82 (m, 9H), 1.70-1.53 ​​(m, 7H), 1.29 (s, 2H), 0.79 (t, J=7.4Hz, 3H).m / z (ESI + ):1094.12.

[0329] Synthesis of compound 75:

[0330] The synthesis of compound 75 followed the synthetic procedure of compound 74, using compound 75-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.80 (t, J=7.2Hz 3H), 0.91 (s, 2H), 1.01 (s, 2H), 2.08-2.32 (m, 12H), 2.45-2.56 (m, 1H), 2.86 (t, J=6.8Hz 2H), 2.97-3.06(m, 3H), 3.60-3.81(m, 13H), 4.02-4.06(s, 5H), 4.58-4.70(m, 5H), 7.06(s, 1H), 7.24-7.32(m, 2H), 7.40-7.47(m, 2H), 7.53(s, 1H), 7.67-7.70(m, 1H), 8.96(s, 1H), 9.24(s, 1H). 19 F NMR (376MHz, CD3OD) δ-138.39 (s, 1H), -129.11, (s, 1H), -121.07 (s, 1H), -76.95 (s, 12H).m / z (ESI + ):1009.38.

[0331] Synthesis of compound 76:

[0332] The synthesis of compound 76 followed the synthetic procedure of compound 74, using compound 76-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.80 (t, J=7.2Hz 3H), 0.89 (s, 2H), 0.99 (s, 2H), 1.94-2.58 (m, 17H), 2.86 (t, J=6.8Hz 2H), 2.95-3.13(m, 4H), 3.61-3.80(m, 5H), 4.02-4.06(s, 6H), 4.37-4.55(m, 7H), 5.20-5.38(m, 2H), 6.42(d, J=2.0Hz 1H), 7.06(d, J=2.8Hz 1H), 7.23-7.31(m, 2H), 7.40-7.43(m, 3H), 7.66-7.70(m, 1H), 9.24(s, 1H). 19 F NMR (376MHz, CD3OD) δ-138.59 (s, 1H), -128.94, (s, 1H), -120.95 (s, 1H), -77.21 (s, 9H).m / z (ESI + ):1023.52.

[0333] Synthesis of compound 77:

[0334] The synthesis of compound 77 followed the synthetic procedure of compound 74, using compound 77-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.80 (t, J=7.2Hz 3H), 0.89 (s, 2H), 0.94 (s, 2H), 1.94-2.59 (m, 18H), 2.86 (t, J=6.8Hz 2H), 2.95-3.07(m, 4H), 3.60-3.76(m, 5H), 4.03-4.06(s, 6H), 4.20-4.23(m, 1H), 4.38-4.54(m, 5H), 5.36-5.47(m, 2H), 7.04(d, J=2.8Hz 1H), 7.24-7.31(m, 2H), 7.40-7.43(m, 2H), 7.53-7.58(m, 2H), 7.66-7.70(m, 1H), 9.21(s, 1H). 19F NMR (376MHz, CD3OD) δ-138.48 (s, 1H), -128.94, (s, 1H), -121.04 (s, 1H), -77.06 (s, 12H).m / z (ESI + ):1023.44.

[0335] Synthesis of compound 78:

[0336] The synthesis of compound 78 followed the synthetic procedure of compound 70, using compound 78-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ7.90 (dd, J=9.1, 3.4Hz, 1H), 7.41 (d, J=5.7Hz, 1H), 7.35 (d, J=10.7Hz, 1H), 7.31-7.22 (m, 2H), 7.02 (dd, J=9.4, 8.3Hz, 1H), 6.69 (s, 1H), 5.12 (s, 2H), 4.63 (s, 4H), 4.52 (t, J=5.4Hz, 2H), 4.31 (d, J=5.6Hz , 2H), 4.28-4.17 (m, 2H), 4.02 (d, J=2.9Hz, 6H), 3.86 (d, J=5.9Hz, 1H), 3.80 (d, J=10.2Hz, 1H), 3.71 (t, J=5.7Hz, 1H), 3.62 (d, J=6.7Hz, 1H), 3.28-3.1 9(m, 2H), 3.14-3.08(m, 2H), 3.06-2.93(m, 2H), 2.86(t, J=6.7Hz, 3H), 2.37 (p, J=6.6, 6.0Hz, 2H), 2.25 (dd, J=6.7, 4.8Hz, 1H), 2.15 (d, J=9.0Hz, 4H), 2 .00(dq, J=12.3, 5.9Hz, 5H), 1.95-1.81(m, 5H), 1.77-1.60(m, 6H).m / z(ESI + ):1023.44.

[0337] Synthesis of compound 79:

[0338] The synthesis of compound 79 followed the synthetic procedure of compound 70, using compound 1 as the starting material. 1H NMR (400MHz, CD3OD) δ9.17 (d, J=2.9Hz, 1H), 7.43 (dd, J=9.2, 5.3Hz, 2H), 7.35 (d, J=10.7Hz, 1H), 7.06 (t, J=8.9Hz, 1H), 6.75 (s, 1H), 5 .24 (s, 3H), 4.63 (s, 1H), 4.57-4.50 (m, 2H), 4.41 (d, J=5.6Hz, 2H), 4.33-4.22 (m, 2H), 4.03 (d, J=3.2Hz, 6H), 3.87 (s, 1H), 3.80 (t, J=5. 5Hz, 1H), 3.70 (d, J=6.7Hz, 1H), 3.62 (d, J=6.2Hz, 1H), 3.34 (dd, J=5.5, 2.1Hz, 1H), 3.25-3.17 (m, 2H), 3.14-3.08 (m, 2H), 3.00 (qd, J=1 2.9, 11.3, 6.5Hz, 2H), 2.86 (t, J=6.7Hz, 3H), 2.43 (d, J=6.7Hz, 2H), 2.27-2.12 (m, 5H), 2.04-1.84 (m, 10H), 1.77-1.62 (m, 5H).m / z (ESI + ):1126.22.

[0339] Synthesis of compound 80:

[0340] The synthesis of compound 80 followed the synthetic procedure of compound 1, using compound J as the starting material. 1 H NMR (400MHz, CD3OD) δppm: 0.59 (d, J=14.6Hz, 2H), 0.80 (s, 2H), 1.33 (d, J=10.7Hz, 4H), 1.52-1.79 (m, 8H ), 1.86-2.14 (m, 10H), 2.46 (s, 2H), 2.59 (d, J=8.8Hz, 3H), 2.90 (t, J=6.7Hz, 4H), 3.01 (s, 1H), 3.09-3.26 (m, 3H), 4.06 (d, J = 3.9Hz, 5H), 4.44 (s, 3H), 4.59 (d, J = 8.3Hz, 2H), 4.67 (s, 3H), 4.76 (d, J = 13.4Hz, 1H), 5.28 (s, 2H), 6.79 (s, 1H), 7.09 (t, J=8.9Hz, 1H), 7.38 (d, J=10.7Hz, 1H), 7.41-7.51 (m, 2H), 9.19 (s, 1H). 19F NMR (376MHz, CD3OD) δppm: -139.77 (s, 1F), -129.05--129.12 (m, 1F), -117.78--117.82 (m, 1F).m / z (ESI + ):1204.80.

[0341] Synthesis of compound 81:

[0342] The synthesis of compound 81 followed the synthetic procedure of compound 79, using compound 81-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ9.15 (d, J=2.7Hz, 1H), 7.46-7.38 (m, 2H), 7.35 (d, J=10.7Hz, 1H), 7.06 (t, J=8.9Hz, 1H), 6.72 (s, 1H), 5.23 (s, 2H), 4. 63 (s, 4H), 4.58-4.52 (m, 2H), 4.40 (d, J=6.7Hz, 4H), 4.07-3.99 (m, 6H), 3.88 (d, J=6.1Hz, 1H), 3.86-3.80 (m, 1H), 3.70 (d, J=6.4Hz, 1H), 3.6 3(t, J=5.5Hz, 1H), 3.18-3.11 (m, 4H), 3.00 (q, J=13.7, 9.3Hz, 1H), 2.86 (t, J=6.7Hz, 3H), 2.43 (d, J=6.2Hz, 3H), 2.17-2.06 (m, 4H), 1.97-1. 89 (m, 5H), 1.77 (s, 3H), 1.63 (s, 2H), 1.48 (dd, J=12.4, 3.8Hz, 2H), 1.35-1.26 (m, 3H), 0.71 (t, J=2.9Hz, 2H), 0.50 (d, J=5.4Hz, 2H).m / z (ESI + ):1202.85.

[0343] Synthesis of compound 82:

[0344] The synthesis of compound 82 followed the synthetic procedure of compound 77, using compound 82-1 as the starting material. 1H NMR (400MHz, CD3OD) δ0.58 (s, 2H), 0.73-0.80 (m, 2H), 0.85 (t, J=7.4Hz, 3H), 1.69 (dd, J=23.8, 12.8Hz, 6H), 1.85-2.14 (m, 9 H), 2.23 (q, J=9.9, 7.8Hz, 3H), 2.44-2.63 (m, 5H), 2.90 (dd, J=7.8, 5.7Hz, 3H), 3.00 (d, J=11.7Hz, 1H), 3.10-3.17 (m, 2H), 3. 84-3.96 (m, 2H), 4.04-4.11 (m, 7H), 4.26-4.36 (m, 4H), 4.46 (q, J=11.1Hz, 2H), 4.67 (s, 1H), 7.09 (d, J=2.6Hz, 1H), 7.28 (t, J =9.4Hz, 1H), 7.33 (d, J = 2.6Hz, 1H), 7.38 (d, J = 10.7Hz, 1H), 7.44 (d, J = 5.8Hz, 1H), 7.71 (dd, J = 9.1, 5.9Hz, 1H), 9.17 (s, 1H). 19 F NMR (376MHz, CD3OD) δ-138.59 (s, 1F), -129.49--128.69 (m, 1F), -121.18 (t, J=8.1Hz, 1F).m / z (ESI + ):987.55.

[0345] Synthesis of compound 83:

[0346] The synthesis of compound 83 followed the synthetic procedure of compound 82, using compound 83-1 as the starting material. 1H NMR (400MHz, CD3OD) δ0.56 (s, 2H), 0.75 (s, 2H), 1.58-1.75 (m, 7H), 1.84-2.02 (m, 6H), 2.06 (d, J=10.7Hz, 3H), 2.25 (d, J=5.9Hz, 2H), 2.42 -2.60 (m, 5H), 2.82 (t, J = 8.0Hz, 1H), 2.90 (t, J = 6.7Hz, 2H), 2.96-3.04 (m, 1H), 3.10 (d, J = 11.0Hz, 2H), 3.50 (d, J = 1.0Hz, 1H), 3.85-3.97 (m , 2H), 4.06 (d, J=3.7Hz, 5H), 4.09 (dd, J=7.1, 2.9Hz, 2H), 4.27 (t, J=4.8Hz, 3H), 4.31-4.37 (m, 1H), 4.40 (d, J=11.0Hz, 1H), 4.49 (d, J=11. 1Hz, 1H), 7.25 (d, J=2.6Hz, 1H), 7.32-7.38 (m, 2H), 7.39 (d, J=6.1Hz, 1H), 7.44 (d, J=5.7Hz, 1H), 7.89 (dd, J=9.2, 5.7Hz, 1H), 9.12 (s, 1H). 19 F NMR (376MHz, CD3OD) δ-139.48 (s, 1F), -129.12 (dd, J=10.9, 6.0Hz, 1F), -111.80 (t, J=7.7Hz, 1F).m / z (ESI + ):983.51.

[0347] Synthesis of compound 84:

[0348] The synthesis of compound 84 followed the synthetic procedure of compound 1, using compound 82-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.89 (s, 2H), 1.01 (s, 2H), 1.18 (t, J = 7.2Hz 2H), 1.97-2.33 (m, 14H), 2.51-2.61 (m, 1H), 2.87 (t, J = 6.4Hz 2H), 2.93-3.09(m, 3H), 3.58-3.86(m, 8H), 4.02-4.06(s, 7H), 4.23-4.28(m, 4H), 4.36(d, J=11.6Hz 1H), 4.60(d, J=11.6Hz 1H), 7.07(t, J=8.8Hz1H), 7.23-7.26(m, 1H), 7.40-7.43(m, 2H), 8.11-8.12(m, 1H).19 F NMR (376MHz, CD3OD) δ-128.98 (q, J=5.6Hz 1H), -123.93, (s, 1H), -118.29 (t, J=6.8Hz 1H), -77.04 (s, 12H).m / z (ESI + ):1022.26.

[0349] Synthesis of compound 85:

[0350] The synthesis of compound 85 followed the synthetic procedure of compound 77, using compound 85-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.81 (t, J=7.3Hz, 2H), 0.87 (t, J=7.4Hz, 2H), 1.30-1.37 (m, 2H), 1.46 (dq, J=6.9, 3.6Hz, 1H), 1.82-2 .13 (m, 12H), 2.25 (dddd, J=17.8, 13.8, 7.2, 3.1Hz, 4H), 2.34-2.61 (m, 4H), 2.90 (t, J=6.7Hz, 3H), 3.05-3.28 (m, 5H), 4.06 ( d, J=3.8Hz, 7H), 4.44-4.58 (m, 2H), 4.67 (s, 1H), 4.74 (d, J=13.6Hz, 1H), 7.11 (dd, J=8.0, 2.6Hz, 1H), 7.29 (t, J=9.4Hz, 1H) , 7.34 (d, J=2.7Hz, 1H), 7.41 (d, J=10.8Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 7.71 (dd, J=9.0, 5.8Hz, 1H), 9.46 (d, J=20.3Hz, 1H). 19 F NMR (376MHz, CD3OD) δ-139.52 (d, J=212.9Hz, 1F), -129.00 (dd, J=11.6, 5.7Hz, 1F), -120.62--121.54 (m, 1F).m / z (ESI + ):999.42.

[0351] Synthesis of compound 86:

[0352] The synthesis of compound 86 followed the synthetic procedure of compound 84, using compound 85-1 as the starting material. 1H NMR (400MHz, CD3OD) δ1.22 (d, J=1.9Hz, 2H), 1.24 (d, J=1.3Hz, 2H), 1.69-1.80 (m, 4H), 1.85-1.94 (m, 7H), 2.22 (s, 1H), 2.30 (d, J=5.1Hz, 1H), 2.39 (t, J=7.4Hz, 2H), 3.16 (p, J=1.7Hz, 4H), 3.65 (dddd, J=23.7, 18.6, 7.7, 5.6Hz, 6H), 3.75-3.90 (m, 5H ), 3.94 (s, 1H), 4.03-4.11 (m, 8H), 4.14 (s, 1H), 4.25 (d, J = 15.4Hz, 1H), 4.65 (d, J = 15.4Hz, 2H), 5.25 (s, 2H), 7.08 (td, J = 8. 9, 8.5, 2.6Hz, 1H), 7.27 (ddd, J=10.6, 8.4, 5.1Hz, 1H), 7.39 (d, J=10.8Hz, 1H), 7.44 (d, J=5.7Hz, 1H), 8.39 (d, J=6.9Hz, 1H), 19 F NMR (376MHz, CD3OD) δ-129.05, (s, 1F), -124.28 (d, J=293.4Hz, 1F), -118.73 (s, 1F).m / z (ESI + ):1034.36.

[0353] Synthesis of compound 87:

[0354] The synthesis of compound 87 followed the synthetic procedure of compound 83, using compound 85-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.95-0.89 (m, 2H), 1.03 (d, J=3.4Hz, 2H), 1.88-2.46 (m, 15H), 2.58 (d, J=10.1H z, 1H), 2.90 (t, J=6.7Hz, 2H), 2.96-3.28 (m, 5H), 3.37-3.50 (m, 3H), 3.56-3.69 (m, 3H), 3.74-3.93 (m, 6H), 4.07 (d, J=5.1Hz, 6H), 4.41 (dd, J=30.0, 12.0Hz, 1H), 4.69 (dt, J=24.1, 11.6Hz, 2H), 7.29 (d, J=2 .6Hz, 1H), 7.33-7.41 (m, 2H), 7.42-7.48 (m, 2H), 7.90 (dt, J=9.3, 4.8Hz, 1H), 9.47 (d, J=12.5Hz, 1H).19 F NMR (376MHz, CD3OD) δ-140.43-138.98 (m, 1F), -128.95 (q, J=8.7, 7.9Hz, 1F), -111.74--111.02 (m, 1F), -77.06 (s, 9F).m / z (ESI + ):995.49.

[0355] Synthesis of compound 88:

[0356] The synthesis of compound 88 followed the synthetic procedure of compound 1, using compound L as the starting material. 1 H NMR (400MHz, CD3OD) δ7.89 (ddd, J=9.1, 5.7, 3.2Hz, 1H), 7.47-7.30 (m, 5H), 5.29 ( t, J=13.7Hz, 1H), 4.86-4.63(m, 4H), 4.52-4.13(m, 5H), 4.00-3.94(m, 1H), 3.84( dd, J=12.3, 9.9Hz, 1H), 3.79-3.72(m, 1H), 3.70-3.64(m, 1H), 3.60-3.49(m, 2H), 3.25-3.08(m, 3H), 2.90(t, J=6.7Hz, 3H), 2.42-1.77(m, 17H), 1.04-0.82(m, 6H). 19 F NMR (376MHz, CD3OD) δ-76.84 (s, 6F), -111.16 (d, J=131.9Hz, 1F), -128.98 (t, J=5.6Hz, 1F), -145.31 (s, 1F).m / z (ESI + ):1011.40.

[0357] Synthesis of compound 89:

[0358] The synthesis of compound 89 followed the synthetic procedure of compound 88, using compound 89-1 as the starting material. 1H NMR (400MHz, CD3OD) δppm 7.61 (dd, J=9.1, 5.8Hz, 1H), 7.37 (d, J=5.8Hz, 1H), 7.32 (d, J=10.8Hz, 1H), 7.25-7.15 ( m, 2H), 7.03 (d, J=2.7Hz, 1H), 4.38 (q, J=11.4Hz, 2H), 4.09-3.95 (m, 10H), 3.95-3.71 (m, 7H), 3.19-2.88(m, 5H), 2.88-2.64(m, 5H), 2.54-2.43(m, 1H), 2.40-2.29(m, 1H), 2.20-1 .98(m, 6H), 1.99-1.80(m, 5H), 1.80-1.61(m, 6H), 0.87-0.71(m, 5H), 0.70-0.45(m, 2H). 19 F NMR (376MHz, CD3OD) δppm -121.48 (t, J=8.0Hz, 1F), -129.05 (dd, J=10.6, 5.7Hz, 1F), -150.18 (s, 1F).m / z (ESI + ):1017.53.

[0359] Synthesis of compound 90:

[0360] The synthesis of compound 90 followed the synthetic procedure of compound 88, using compound 90-1 as the starting material. 1H NMR (400MHz, CD3OD) δ7.65 (dd, J=9.1, 5.8Hz, 1H), 7.41 (d, J=5.7Hz, 1H), 7.34 (d, J=10.7Hz, 1H), 7.27 (dd, J=2.7, 1.2Hz, 1H), 7.23 (td , J=9.4, 1.4Hz, 1H), 7.07 (dd, J=22.0, 2.6Hz, 1H), 5.38 (t, J=14.0Hz, 1H), 4.65 (s, 2H), 4.53 (d, J=3.8Hz, 2H), 4.41-4.36 (m, 2H), 4.04 ( s, 1H), 4.02 (s, 3H), 4.01 (s, 1H), 3.15-3.03 (m, 4H), 2.96 (t, J=11.8Hz, 1H), 2.85 (d, J=6.8Hz, 2H), 2.79 (q, J=7.9Hz, 1H), 2.59-2.34 ( m, 8H), 2.03 (d, J = 8.7Hz, 5H), 1.92-1.85 (m, 6H), 1.67-1.59 (m, 7H), 0.88 (t, J = 3.7Hz, 3H), 0.73 (s, 2H), 0.54 (d, J = 6.2Hz, 2H).m / z (ESI + ):999.47.

[0361] Synthesis of compound 91:

[0362] The synthesis of compound 91 followed the synthetic procedure of compound 80, using compound 91-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ9.09 (s, 1H), 7.48-7.39 (m, 3H), 7.11 (t, J=8.9Hz, 1H), 4.74- 4.39 (m, 5H), 4.17-3.95 (m, 9H), 3.76 (dd, J=15.1, 9.6Hz, 1H), 3.45 (dd, J=12.7, 9.6 Hz, 1H), 3.19-3.02 (m, 5H), 2.90 (t, J=6.7Hz, 2H), 2.41 (dt, J=15.6, 5.6Hz, 3H), 2. 26 (s, 2H), 2.16-1.85 (m, 13H), 1.59 (d, J=6.2Hz, 3H), 0.87 (dd, J=55.8, 4.9Hz, 5H). 19 F NMR (376MHz, CD3OD) δ-117.72 (d, J=8.0Hz, 1F), -128.97 (dd, J=11.5, 6.3Hz, 1F), -139.10 (s, 1F).m / z (ESI +):1003.86.

[0363] Synthesis of compound 92:

[0364] The synthesis of compound 92 followed the synthetic procedure of compound 83, using compound 92-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.92 (d, J=5.6Hz, 2H), 1.05 (s, 2H), 1.85 (d, J=13.5Hz, 1H), 191-2.33 (m, 17H), 2.34-2.46 (m, 2H), 2.50-2.64 (m, 3H), 3.02 (t, J=13.4Hz, 3H), 3.13-3.19 (m, 1H), 3.50-3.54 (m, 1H), 3.62-3.67 (m, 2H), 3.7 4-3.89 (m, 5H), 4.07 (d, J=4.6Hz, 6H), 4.54 (dt, J=9.3, 2.9Hz, 2H), 4.57-4.61 (m, 1H), 4.64 (q, J=6.7, 6.1Hz, 2H ), 7.30 (dd, J=8.8, 2.6Hz, 1H), 7.34-7.41 (m, 2H), 7.43-7.48 (m, 2H), 7.84-7.98 (m, 1H), 9.31 (d, J=27.7Hz, 1H). 19 F NMR (376MHz, CD3OD) δ-139.74 (d, J=81.0Hz, 1F).-128.97 (d, J=10.9Hz, 1F), -111.43 (d, J=45.9Hz, 1F), -77.06 (S, 15F).m / z (ESI + ):1009.45.

[0365] Synthesis of compound 93:

[0366] The synthesis of compound 93 followed the synthetic procedure of compound 92, using compound 93-1 as the starting material. 1H NMR (400MHz, CD3OD) δ0.54 (s, 2H), 0.75 (s, 2H), 0.85 (q, J=6.4Hz, 3H), 1.61-1.69 (m, 6H), 1 .79-2.06(m, 12H), 2.26-2.31(m, 2H), 2.47-2.58(m, 8H), 2.79-2.87(m, 3H), 2.94-3.09(m, 3H), 3.39-3.51(m, 1H), 3.79-3.87(m, 1H), 4.04(s, 5H), 4.41-4.69(m, 6H), 7.33-7.41(m, 3 H), 7.49-7.58 (m, 2H), 7.91-7.95 (m, 1H), 8.06 (d, J=8.0Hz, 1H), 9.27-9.28 (m, 1H).m / z (ESI + ):997.67.

[0367] Synthesis of compound 94:

[0368] The synthesis of compound 94 followed the synthetic procedure of compound 92, using compound 94-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm 9.30 (d, J=9.8Hz, 1H), 7.69-7.43 (m, 1H), 7.36 (d, J=10.7Hz, 1H), 7.26 (s, 1H ), 7.16-6.89(m, 3H), 4.74-4.34(m, 5H), 4.34-3.95(m, 7H), 3.94-3.75(m, 2H) , 3.76-3.34(m, 6H), 3.23-2.93(m, 7H), 2.92-2.80(m, 2H), 2.67-2.40(m, 4H) , 2.38-2.01(m, 6H), 2.03-1.73(m, 7H), 1.04-0.82(m, 4H), 0.82-0.71(m, 3H). 19 F NMR (376MHz, CD3OD) δppm-77.17 (s, 9F), -120.28--121.03 (m, 1F), -128.28--129.47 (m, 1F), -139.14--140.10 (m, 1F).m / z (ESI + ):999.60.

[0369] Synthesis of compound 95:

[0370] The synthesis of compound 95 followed the synthetic procedure of compound 92, using compound 95-1 as the starting material.1 H NMR (400MHz, CD3OD) δppm: 0.59 (s, 2H), 0.78 (s, 2H), 1.63-2.10 (m, 18H), 2.29 (s, 1H), 2.39-2.71 (m, 6H ), 2.85 (t, J=6.7Hz, 4H), 2.97 (d, J=11.9Hz, 1H), 3.06-3.15 (m, 2H), 3.40 (d, J=9.8Hz, 1H), 3.77 (d, J=1 3.3Hz, 1H), 4.01 (d, J=3.5Hz, 5H), 4.41 (d, J=12.5Hz, 3H), 4.59 (dd, J=23.9, 10.6Hz, 4H), 6.51 (d, J=2. 3Hz, 1H), 6.90 (d, J=2.3Hz, 1H), 7.34 (d, J=10.7Hz, 1H), 7.40 (d, J=5.7Hz, 1H), 9.20 (d, J=15.5Hz, 1H). 19 F NMR (376MHz, CD3OD) δppm: -55.61--55.62(d, 3F), -129.04--129.09(m, 1F), -141.24--141.32(m, 1F).m / z(ESI + ):1018.22.

[0371] Synthesis of compound 96:

[0372] The synthesis of compound 96 followed the synthetic procedure of compound 92, using compound 96-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm: 0.92 (s, 2H), 1.06 (s, 2H), 1.81-2.46 (m, 18H), 2.56 (dd, J=18.0, 9.2Hz, 3H ), 2.90 (t, J=6.7Hz, 2H), 3.00-3.23 (m, 5H), 3.48 (dd, J=19.6, 9.0Hz, 1H), 3.66 (dd, J=13.2, 9.7Hz, 2 H), 3.83 (dd, J=24.1, 10.9Hz, 4H), 4.07 (d, J=4.8Hz, 5H), 4.57 (dt, J=33.4, 9.6Hz, 4H), 4.76 (dd, J=1 9.2, 13.7Hz, 1H), 7.35-7.51 (m, 2H), 7.84 (d, J=4.9Hz, 1H), 7.87-7.93 (m, 2H), 9.41 (d, J=8.5Hz, 1H). 19F NMR (376MHz, CD3OD) δppm: -139.82--139.94(d, 1F), -128.92 -128.95(d, 1F), -57.92--57.94(d, 3F).m / z(ESI + ):1009.44.

[0373] Synthesis of compound 97:

[0374] The synthesis of compound 97 followed the synthetic procedure of compound 92, using compound 97-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.86 (td, J=7.3, 4.5Hz, 4H), 1.88 (s, 1H), 1.98-2.30 (m, 17H), 2.32-2.42 (m, 3H), 2.56 (t, J=9.1 Hz, 5H), 2.90 (t, J=6.7Hz, 3H), 3.06 (d, J=12.4Hz, 3H), 3.17 (q, J=1.6Hz, 1H), 3.52 (p, J=1.7Hz, 1H), 3.56-3.72 (m, 5H) , 3.84 (ddd, J=26.7, 15.5, 7.9Hz, 3H), 4.07 (d, J=3.9Hz, 7H), 4.46 (s, 2H), 4.60 (dq, J=15.3, 7.3Hz, 3H), 4.68-4.84 (m , 1H), 7.12 (t, J=2.7Hz, 1H), 7.27-7.39 (m, 2H), 7.43-7.52 (m, 2H), 7.74 (dd, J=9.0, 5.8Hz, 1H), 9.36 (d, J=5.6Hz, 1H). 19 F NMR (376MHz, CD3OD) -139.62 (d, J=57.2Hz, 1F). -129.08--128.91 (m, 1F), -121.01 (s, 1F), -77.03 (s, 18F).m / z (ESI + ):1015.61.

[0375] Synthesis of compound 98:

[0376] The synthesis of compound 98 followed the synthetic procedure of compound 92, using compound h as the starting material. 1H NMR (400MHz, CD3OD) δ9.35 (d, J=14.1Hz, 1H), 7.69 (dd, J=9.1, 5.8Hz, 1H), 7.39 (d, J=3.6Hz, 1H), 7.37 (s, 1H), 7.32 (d , J=2.6Hz, 1H), 7.27 (t, J=9.4Hz, 1H), 7.10 (t, J=2.2Hz, 1H), 4.74 (dd, J=34.7, 13.5Hz, 1H), 4.66-4.46 (m, 5H), 4.38-3 .95 (m, 12H), 3.87 (dd, J=13.6, 5.1Hz, 1H), 3.69-3.56 (m, 1H), 3.52-3.40 (m, 2H), 3.17-3.05 (m, 2H), 3.01-2.86 (m, 3H ), 2.64-2.16(m, 9H), 2.11-1.73(m, 10H), 1.74-1.49(m, 2H), 1.13-1.01(m, 2H), 0.97-0.90(m, 2H), 0.90-0.81(m, 3H). 19 F NMR (376MHz, CD3OD) δppm -77.10 (s, 9F), -128.98 (s, 1F), -129.09 (q, J=7.8, 6.8Hz, 1F), -139.43 (d, J=46.0Hz, 1F).m / z (ESI + ):1013.62.

[0377] Synthesis of compound 99:

[0378] The synthesis of compound 99 followed the synthetic procedure of compound 92, using compound 99-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm 9.13 (s, 1H), 7.77 (dd, J=9.1, 5.8Hz, 1H), 7.60 (d, J=2.4Hz, 1H), 7.39 (dd, J=8.2, 2.6Hz, 2H), 7.32 (t, J=9.3Hz, 1H), 7.22 (d, J=2.4Hz, 1H), 5.81 (s, 1H), 4.50 (d, J=24.5Hz, 4H), 4. 27-3.92(m, 8H), 3.88-3.52(m, 7H), 3.16-2.92(m, 4H), 2.84(t, J=6.7Hz, 2H), 2.65-2.38 (m, 4H), 2.38-1.82 (m, 16H), 1.06-0.91 (m, 2H), 0.89-0.83 (m, 2H), 0.80 (t, J=7.4Hz, 3H). 19F NMR (376MHz, CD3OD) δppm -77.02 (s, 12F), -121.39 (s, 1F), -128.89 (t, J=8.4Hz, 1F), -139.06 (s, 1F).m / z (ESI + ):1012.46.

[0379] Synthesis of compound 100:

[0380] The synthesis of compound 100 followed the synthetic procedure of compound 92, using compound 100-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ9.34 (d, J=7.2Hz, 1H), 7.72 (dd, J=9.0, 5.8Hz, 1H), 7.35 (d, J=2.7Hz, 1H), 7.30 (t, J=9.3Hz, 1 H), 7.12 (p, J=2.8Hz, 3H), 7.06 (d, J=7.5Hz, 1H), 5.37 (dd, J=12.3, 5.4Hz, 1H), 4.64-4.50 (m, 5H), 3.92-3.76 (m, 4H ), 3.66-3.59 (m, 2H), 3.54-3.50 (m, 1H), 3.47 (s, 3H), 2.97 (t, J=13.5Hz, 4H), 2.87-2.80 (m, 2H), 2.54 (p, J=9.8, 9. 2Hz, 4H), 2.38-2.00 (m, 18H), 1.86 (dq, J=12.9, 4.6Hz, 2H), 1.05 (s, 2H), 0.91 (s, 3H), 0.85 (td, J=7.3, 4.0Hz, 4H). 19 F NMR (376MHz, CD3OD) δ-77.12 (s, 12F), -120.98 (d, J=7.6Hz, 1F), -139.28 (d, J=57.2Hz, 1F).m / z (ESI + ):1010.74.

[0381] Synthesis of compound 101:

[0382] The synthesis of compound 101 followed the synthesis procedure of compound 89, using compound 92-1 as the starting material. 1H NMR (400 MHz, CD3OD) δ ppm 7.60 (dd, J=9.1, 5.8Hz, 1H), 7.44-7.30 (m, 2H), 7.23-7.13 (m, 2H), 7.03 (dd, J=23.2, 2.7Hz, 1H), 4.60 (s, 1H), 4.52-4.20 (m, 4H), 4.14-3.92 (m , 10H), 3.88-3.40 (m, 7H), 3.23-3.11 (m, 3H), 2.90-2.61 (m, 3H), 2.55- 1.79(m, 20H), 1.78-1.43(m, 2H), 0.98-0.89(m, 2H), 0.87-0.79(m, 5H). 19 F NMR (376MHz, CD3OD) δppm-121.25--121.54 (m, 1F), -129.01 (dd, J=11.4, 5.7Hz, 1F), -149.99 (d, J=65.0Hz, 1F).m / z (ESI + ):1043.54.

[0383] Synthesis of compound 102:

[0384] The synthesis of compound 102 followed the synthetic procedure of compound 100, using compound 102-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm 9.24 (d, J=8.9Hz, 1H), 7.71-7.61 (m, 2H), 7.52 (s, 2H), 7.28 (d, J=2.6Hz, 1H), 7.22 (t, J =9.4Hz, 1H), 7.04 (t, J = 2.5Hz, 1H), 5.12 (dd, J = 13.3, 5.1Hz, 1H), 4.62-4.36 (m, 9H), 3. 78(t, J=13.0Hz, 1H), 3.22-3.16(m, 2H), 2.95-2.69(m, 6H), 2.57-2.37(m, 5H), 2.35-2. 06 (m, 9H), 2.02-1.72 (m, 14H), 0.89-0.81 (m, 2H), 0.82-0.73 (m, 3H), 0.73-0.60 (m, 2H). 19 F NMR (376MHz, CD3OD) δppm -121.04 (t, J=7.9Hz, 1F), -139.09 (d, J=49.8Hz, 1F)..m / z (ESI + ):995.91.

[0385] Synthesis of compound 103:

[0386] The synthesis of compound 103 followed the synthetic procedure of compound 92, using compound i as the starting material. 1 H NMR (400MHz, CD3OD) δ9.30 (d, J=7.1Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.63 (d, J=5.5H z, 1H), 7.41 (d, J=9.4Hz, 1H), 7.34 (d, J=2.7Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 4.75-4.44 (m, 9H), 4.06 (t, J=6.7Hz, 2H), 4.02 (d, J=1.1Hz, 3H), 3.84 (t, J=13.2 Hz, 1H), 3.53-3.36 (m, 2H), 2.89 (t, J=6.7Hz, 2H), 2.57-1.79 (m, 18H), 1.00-0.71 (m, 8H). 19 F NMR (376MHz, CD3OD) δ-121.03 (t, J=7.8Hz, 1F), -122.80 (t, J=8.0Hz, 1F), -139.10 (d, J=52.2Hz, 1F).m / z (ESI + ):954.51.

[0387] Synthesis of compound 104:

[0388] The synthesis of compound 104 followed the synthetic procedure of compound 92, using compound j as the starting material. 1H NMR (400MHz, CD3OD) δppm: 0.59 (s, 2H), 0.84 (dt, J=14.6, 7.3Hz, 5H), 1.87 (d, J=11.7Hz, 6H), 1.93-2.08 (m, 4H), 2.21 (dd, J=12.2, 5 .1Hz, 1H), 2.33 (d, J=13.2Hz, 1H), 2.40 (s, 2H), 2.44-2.75 (m, 7H), 2.88 (t, ·6.6Hz, 2H), 3.14 (t, J=11.3Hz, 2H), 3.29 (d, J=10.4Hz, 2H), 3.48 (dd, J=21.5, 10.6Hz, 1H), 3.73 (s, 2H), 3.85 (t, J=14.8Hz, 1H), 3.97-4.02 (m, 5H), 4.04 (t, J=6.7Hz, 2H), 4.40-4.76 (m, 7H ), 7.05 (d, J=6.8Hz, 1H), 7.11 (s, 1H), 7.28 (t, J=9.3Hz, 1H), 7.31-7.38 (m, 2H), 7.71 (dd, J=9.2, 5.8Hz, 1H), 9.30 (d, J=9.2Hz, 1H). 19 F NMR (376MHz, CD3OD) δppm: -139.03--139.15(d, 1F), -130.66--130.71(m, 1F), -121.04--121.08(m, 1F).m / z(ESI + ):1072.34.

[0389] Synthesis of compound 105:

[0390] The synthesis of compound 105 followed the synthetic procedure of compound 104, using compound 105-1 as the starting material. 1H NMR (400MHz, CD3OD) δppm: 0.55 (s, 2H), 0.77 (d, J=4.6Hz, 2H), 0.85 (td, J=7.3, 5.3Hz, 3H), 1.91 (q, J=14.2, 12.1Hz, 5H), 2.06 (d, J=12.2Hz , 1H), 2.21 (dq, J=12.5, 5.4, 4.1Hz, 1H), 2.33 (d, J=13.3Hz, 1H), 2.47-2.61 (m, 8H), 2.64 (s, 2H), 2.89 (t, J=6.7Hz, 2H), 3.09-3.19 (m, 2H), 3.29 (d, J=12.0Hz, 2H), 3.61 (d, J=5.3Hz, 4H), 3.85 (t, J=13.9Hz, 1H), 3.99 (s, 3H), 4.04 (d, J=6.7Hz, 2H), 4.43-4.64 (m, 5H), 4.68 (s, 4H), 7.04 (d, J=6.8Hz, 1H), 7.12 (d, J=2.4Hz, 1H), 7.28 (t, J=9.3Hz, 1H), 7.31-7.37 (m, 2H), 7.71 (dd, J=9.1, 5.7Hz, 1H), 9.29 (d, J=6.6Hz, 1H). 19 F NMR (376MHz, CD3OD) δppm: -139.06--139.19(d, 1F), -130.60--130.65(m, 1F), -121.02--121.06(m, 1F).m / z(ESI + ):1032.51.

[0391] Synthesis of compound 106:

[0392] The synthesis of compound 106 followed the synthetic procedure of compound 101, using compound 106-1 as the starting material. 1 H NMR (400 MHz, CD3OD) δ ppm 7.67-7.57(m, 1H), 7.42-7.32(m, 2H), 7.28-7.16(m, 2H), 7.03(dd, J=14 .4, 2.6Hz, 1H), 4.53-4.28(m, 2H), 4.25-3.91(m, 9H), 3.89-3.31(m, 7H) , 3.24-2.91 (m, 5H), 2.84 (t, J=6.7Hz, 3H), 2.71-2.13 (m, 6H), 2.12-1.5 2(m, 14H), 1.17(d, J=20.1Hz, 3H), 1.00-0.89(m, 2H), 0.88-0.78(m, 5H).19 F NMR (376MHz, CD3OD) δppm -121.44 (dd, J=18.3, 9.4Hz, 1F), -129.05 (dd, J=11.5, 5.6Hz, 1F), -150.13 ((d, J=111.5Hz, 1F).m / z (ESI + ):1031.53.

[0393] Synthesis of compound 107:

[0394] The synthesis of compound 107 followed the synthetic procedure of compound 79, using compound K-1 as the starting material. 1 HNMR (400MHz, CD3OD) δ0.79-0.85 (m, 3H), 1.63-1.86 (m, 7H), 1.89-2.01 (m, 5H), 2.25 (dd, J=26.8, 16.5Hz, 8H), 2.51 (d, J=23.9Hz, 4H), 2. 90 (t, J=6.7Hz, 3H), 3.05 (d, J=10.3Hz, 2H), 3.14-3.19 (m, 2H), 3.61-3.76 (m, 3H), 3.88 (d, J=30.7Hz, 2H), 4.06 (d, J=2.9Hz, 6H), 4.32 (q, J =10.6Hz, 2H), 4.47 (t, J = 15.8Hz, 2H), 4.59 (d, J = 7.0Hz, 2H), 4.67 (s, 3H), 5.32 (d, J = 29.1Hz, 2H), 6.76 (d, J = 2.0Hz, 1H), 7.08 (d, J = 2.7Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.34 (d, J=2.7Hz, 1H), 7.39 (d, J=10.8Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 7.71 (dd, J=9.1, 5.8Hz, 1H), 9.22 (s, 1H). 19 F NMR (376MHz, CD3OD) δ-138.42 (s, 1F), -129.11 (d, J=14.3Hz, 1F), -121.13 (s, 1F).m / z (ESI + ):1124.13.

[0395] Synthesis of compound 108:

[0396] The synthesis of compound 108 followed the synthesis procedure of compound 81, using compound 108-1 as the starting material. 1H NMR (400MHz, CD3OD) δ9.20-9.11 (m, 1H), 7.47-7.40 (m, 2H), 7.38-7.32 (m, 1H), 7.06 (t, J=8.9Hz, 1H), 6.72 (s, 1H), 5.24 (s, 2 H), 4.61 (s, 13H), 4.55 (d, J=7.3Hz, 2H), 4.41 (s, 4H), 4.03 (d, J=2.7Hz, 4H), 3.91 (s, 1H), 3.84 (s, 1H), 3.72 (s, 1H), 3.64 (d, J =5.5Hz, 1H), 3.22-3.11(m, 1H), 3.01(d, J=12.2Hz, 1H), 2.87(td, J=6.7, 1.8Hz, 2H), 2.73(s, 2H), 2.42(s, 3H), 2.25-2.11(m , 3H), 1.99 (d, J=12.4Hz, 2H), 1.86 (q, J=17.6, 15.6Hz, 5H), 1.76-1.63 (m, 5H), 0.76-0.67 (m, 2H), 0.52-0.47 (m, 2H).m / z (ESI + ):1161.43.

[0397] Synthesis of compound 109:

[0398] The synthesis of compound 109 followed the synthesis procedure of compound 81, using compound 109-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm: 0.52 (d, J=4.9Hz, 2H), 0.67-0.74 (m, 2H), 1.34 (d, J=10.7Hz, 2H), 1.66-2.08 (m, 10H), 2.17-2. 26 (m, 5H), 2.43-2.63 (m, 4H), 2.84-2.94 (m, 4H), 2.99-3.14 (m, 4H), 3.18-3.28 (m, 2H), 3.71 (d, J=30.1Hz, 2H), 3.90 (d, J =27.6Hz, 2H), 4.06 (d, J = 3.2Hz, 5H), 4.44 (d, J = 21.4Hz, 4H), 4.65 (d, J = 26.2Hz, 4H), 5.19-5.43 (m, 2H), 6.73 (d, J = 1.7Hz , 1H), 7.25 (d, J=2.6Hz, 1H), 7.33-7.42 (m, 3H), 7.45 (d, J=5.7Hz, 1H), 7.90 (dd, J=9.1, 5.7Hz, 1H), 9.15 (d, J=1.9Hz, 1H). 19F NMR (376MHz, CD3OD) δppm: -151.04--151.45(d, 1F), -139.20--139.22(d, 1F), -12 9.01--129.08(m,1F),-125.84--126.33(m,1F),-111.66--111.72(m,1F).m / z(ESI + ): 1165.00.

[0399] Synthesis of compound 110:

[0400] The synthesis of compound 110 followed the synthesis procedure of compound 81, using compound 108-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.53 (s, 2H), 0.74 (s, 2H), 1.67-1.84 (m, 8H), 1.88-2.08 (m, 8H), 2.18 (d, J=8.9Hz, 2H), 2.34-2.53 (m, 6H), 2 .77 (s, 3H), 2.90 (t, J = 6.7Hz, 3H), 2.96-3.07 (m, 1H), 3.09-3.18 (m, 2H), 3.48 (d, J = 1.1Hz, 1H), 3.71 (d, J = 30.6Hz, 2H), 3.91 (d, J = 28.7Hz, 2H), 4.06 (d, J=3.3Hz, 5H), 4.39 (d, J=10.9Hz, 1H), 4.46 (d, J=11.3Hz, 3H), 4.59-4.64 (m, 2H), 5.20-5.44 (m, 2H), 6.74 (d, J=2.1Hz, 1H), 7.25 (d, J=2.5Hz, 1H), 7.33-7.41 (m, 3H), 7.45 (d, J=5.7Hz, 1H), 7.89 (dd, J=9.1, 5.7Hz, 1H), 9.15 (d, J=1.8Hz, 1H). 19 F NMR (376MHz, CD3OD) δ-139.23 (d, J=6.7Hz, 1F)).-129.11 (d, J=15.1Hz, 1F)), -111.75 (t, J=7.2Hz, 1F).m / z (ESI + ):1155.53.

[0401] Synthesis of compound 111:

[0402] The synthesis of compound 111 followed the synthesis procedure of compound 81, using compound 111-1 as the starting material. 1HNMR (400MHz, CD3OD) δppm: 0.48 (d, J=4.8Hz, 2H), 0.66 (d, J=4.8Hz, 2H), 1.06 (t, J=7.4Hz, 1H), 1.63-1.82 (m, 8H), 1.96 (ddd, J=36.5, 22.3, 12.0Hz, 6H), 2.18(d, J=9.8Hz, 2H), 2.35-2.43(m, 3H), 2.45-2.54(m, 3H), 2.90(t, J=6.7Hz, 3H), 2.97-3.05(m, 1H), 3.15(q, J=8.5, 8.0Hz, 4H), 3.71(d, J=30 .3Hz, 2H), 3.91 (d, J=28.2Hz, 2H), 4.06 (d, J=3.3Hz, 5H), 4.37 (d, J=2.6Hz , 2H), 4.45 (d, J=12.2Hz, 2H), 4.62 (d, J=9.3Hz, 2H), 4.68 (s, 1H), 5.21-5. 40 (m, 2H), 6.74 (d, J = 1.7Hz, 1H), 7.25 (d, J = 2.6Hz, 1H), 7.32-7.41 (m, 3H) , 7.45 (d, J=5.8Hz, 1H), 7.89 (dd, J=9.1, 5.7Hz, 1H), 9.15 (d, J=1.9Hz, 1H). 19 F NMR (376MHz, CD3OD) δppm: -215.76--216.03(m, 1F), -139.22--139.24(d, 1F), -129.04--129.12(m, 1F), -111.67--111.69(m, 1F).m / z(ESI + ):1146.97.

[0403] Synthesis of compound 112:

[0404] The synthesis of compound 112 followed the synthesis procedure of compound 88, using compound A-8 as the starting material. 1H NMR (400MHz, CD3OD) δ7.53-7.38 (m, 3H), 7.09 (t, J=8.9Hz, 1H), 5.21 (ddd, J=13.7, 6.6, 2.8Hz, 1H), 4.80 (dd, J=13 .5, 4.4Hz, 2H), 4.61 (d, J=13.4Hz, 2H), 4.47 (q, J=11.8Hz, 2H), 4.36 (dd, J=9.5, 4.7Hz, 1H), 4.22 (dd, J=12.4, 4.0 Hz, 1H), 4.09-4.00 (m, 6H), 3.86 (dd, J=12.4, 10.0Hz, 1H), 3.58-3.49 (m, 2H), 3.43 (d, J=11.0Hz, 3H), 3.26-3.14 ( m, 4H), 2.90 (t, J=6.7Hz, 2H), 2.64 (t, J=12.0Hz, 2H), 2.32 (s, 2H), 2.24-1.91 (m, 13H), 1.00 (s, 2H), 0.86 (s, 2H). 19 F NMR (376MHz, CD3O) δ-117.61 (s, 1F), -128.97 (t, J=8.4Hz, 1F), -145.93 (s, 1F).m / z (ESI + ):1017.81.

[0405] Synthesis of compound 113:

[0406] The synthesis of compound 113 followed the synthetic procedure of compound 92, using compound 113-1 as the starting material. 1H NMR (400MHz, CD3OD) δ0.84 (dd, J=7.6, 2.9Hz, 2H), 0.92 (d, J=9.3Hz, 2H), 1.80-1.98 (m, 2H), 2.01-2.15 (m, 6H), 2.2 7(d, J=37.7Hz, 10H), 2.4.-2.66(m, 6H), 2.90(t, J=6.7Hz, 2H), 2.98-3.24(m, 5H), 3.50-3.60(m, 1H), 3.62-3.74(m , 3H), 3.74-3.89 (m, 4H), 4.07 (d, J=3.1Hz, 6H), 4.29 (d, J=13.0Hz, 1H), 4.45-4.55 (m, 3H), 4.60 (q, J=6.4Hz, 3H), 7 .04 (d, J=2.6Hz, 1H), 7.25-7.36 (m, 2H), 7.46 (t, J=8.2Hz, 2H), 7.71 (dd, J=9.1, 6.0Hz, 1H), 7.93 (d, J=9.0Hz, 1H). 19 F NMR (376MHz, CD3OD) δ-129.00 (d, J=10.8Hz, 1F), -125.04 (d, J=43.1Hz, 1F), -120.93 (s, 1F) -117.33 (d, J=9.2Hz, 1F), -77.03 (s, 24F).m / z (ESI + ):1030.83.

[0407] Synthesis of compound 114:

[0408] The synthesis of compound 114 followed the synthetic procedure of compound 92, using compound k as the starting material. 1 HNMR (400MHz, CD3OD) δ0.78-0.82 (m, 3H), 0.87 (s, 2H), 1.00-1.04 (m, 4H), 1.40-1.49 (m, 3H), 1.59-2.53 (m, 19H), 2.64-2.91 (m, 4H), 3.09- 3.25 (m, 4H), 3.39-3.48 (m, 1H), 3.67-3.84 (m, 3H), 4.42-4.59 (m, 4H), 4.66-4.78 (m, 1H), 5.09 (s, 2H), 5.13-5.17 (m, 1H), 7.07 (t, J=3.2Hz 1H), 7.25(t, J=9.2Hz 1H), 7.30 (s, 1H), 7.66-7.69 (m, 1H), 7.85 (d, J=13.2Hz 2H), 9.29-9.30 (m, 1H). 19F NMR (376MHz, CD3OD) δ-139.09 (s, 1H), -120.96 (s, 1H), -77.22 (s, 12H).m / z (ESI + ):1023.90.

[0409] Synthesis of compound 115:

[0410] The synthesis of compound 115 followed the synthesis procedure of compound 81, using compound 81-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.57 (s, 2H), 0.78 (s, 2H), 1.56 (s, 2H), 1.73 (d, J = 26.6Hz, 5H), 1.87 (d, J = 13.2Hz, 4H), 1.96-2.09 (m, 5H), 2.29 (s, 2H), 2.53 (d, J = 45.6Hz, 5H), 2.91 (d, J = 6.7Hz, 3H), 3.17 (p, J = 1.7Hz, 1H), 3.60-3.79 (m, 5H), 3.88-4.02 (m, 2H), 4.07 (d , J=3.1Hz, 5H), 4.38 (d, J=11.0Hz, 1H), 4.48 (q, J=8.6, 6.2Hz, 3H), 4.64 (d, J=19.0Hz, 7H), 5.24 (d, J=16.1Hz, 1H), 5.37 (d, =16. 2Hz, 1H), 6.75 (s, 1H), 7.25 (d, J=2.5Hz, 1H), 7.33-7.43 (m, 3H), 7.45 (d, J=5.7Hz, 1H), 7.90 (dd, J=9.1, 5.7Hz, 1H), 9.16 (s, 1H). 19 F NMR (376MHz, CD3OD) δ-139.21 (s, 1F), -128.98 (s, 1F), -111.68 (d, J=7.7Hz, 1F), -75.25 (d, J=8.2Hz, 3F).m / z (ESI - ):1196.67.

[0411] Synthesis of compound 116:

[0412] The synthesis of compound 116 followed the synthesis procedure of compound 81, using compound A-8 as the starting material. 1HNMR (400MHz, CD3OD) δ9.15 (s, 1H), 7.46-7.37 (m, 3H), 7.06 (t, J=8.9Hz, 1H), 6.72 (s, 1H), 5.23 (d, J=8.9Hz, 2H), 4 .63 (s, 13H), 4.57-4.54 (m, 2H), 4.40 (d, J=10.1Hz, 4H), 4.03 (d, J=2.5Hz, 4H), 3.92 (s, 1H), 3.85 (s, 1H), 3.73 (s, 1 H), 3.66 (s, 1H), 3.05-3.02 (m, 1H), 2.91 (s, 1H), 2.88 (d, J=6.8Hz, 2H), 2.54 (s, 2H), 2.43 (s, 1H), 2.34 (q, J=7.8Hz , 2H), 2.19 (d, J=13.3Hz, 2H), 2.11 (s, 1H), 2.08-1.85 (m, 4H), 1.80-1.57 (m, 5H), 0.68 (s, 2H), 0.49 (s, 2H).m / z (ESI + ):1170.54.

[0413] Synthesis of compound 117:

[0414] The synthesis of compound 117 followed the synthetic procedure of compound 81, using compound 117-1 as the starting material. 1 HNMR (400MHz, CD3OD) δppm δ9.15 (s, 1H), 7.48-7.33 (m, 3H), 7.05 (t, J=8.9Hz, 1H), 6.71 (s, 1H) ,5.23(s,2H),4.63-4.48(m,3H),4.47-4.33(m,4H),4.10-3.98(m,5H),3.96-3.78(m,2H),3.76 -3.61(m, 2H), 3.52-3.37(m, 3H), 3.21-3.07(m, 1H), 2.85(t, J=6.7Hz, 2H), 2.81-2.37(m, 9H), 2.38-2.17(m, 6H), 2.16-1.86(m, 6H), 1.78-1.59(m, 4H), 0.82-0.70(m, 2H), 0.70-0.45(m, 2H). 19 F NMR (376MHz, CD3OD) δppm-100.51, -117.82, -128.95, -139.78.m / z (ESI + ):1184.80.

[0415] Synthesis of compound 118:

[0416] The synthesis of compound 118 followed the synthetic procedure of compound 81, using compound 118-1 as the starting material. 1 HNMR (400MHz, CD3OD) δppm 9.14 (s, 1H), 7.43-7.32 (m, 3H), 7.03 (t, J=9.0Hz, 1H), 6.69 (s, 1H), 5.21 (s, 2H), 4.66-4.32 (m, 10H), 4.05-3.77 (m, 7H), 3 .73-3.40(m, 6H), 2.99-2.56(m, 7H), 2.53-1.79(m, 14H), 1.76-1.51(m, 4H), 0.86-0.77(m, 2H), 0.75-0.53(m, 2H).m / z(ESI + ):1166.48.

[0417] Synthesis of compound 119:

[0418] The synthesis of compound 119 followed the synthetic procedure of compound 110, using compound 89-1 as the starting material. 1 HNMR (400MHz, CD3OD) δ7.88 (dd, J=9.1, 5.8Hz, 1H), 7.46 (d, J=5.7Hz, 1H), 7.41-7.32 (m, 3H), 7.28 (d, J=2.5Hz, 1H), 6.62 (s, 1 H), 5.15 (d, J=14.0Hz, 1H), 4.67 (s, 5H), 4.50 (s, 2H), 4.39 (d, J=10.9Hz, 1H), 4.28 (d, J=11.0Hz, 1H), 4.06 (t, J=2.1Hz, 10H), 3.98 (s, 1H), 3.91 (s, 1H), 3.76 (s, 1H), 3.68 (s, 1H), 3.48-3.45 (m, 1H), 3.19 (dd, J=11.5, 7.1Hz, 2H), 3.04 (d, J=12.4Hz, 2H), 2.90 (t, J=6.7Hz, 2H), 2.77 (s, 3H), 2.54-2.19 (m, 10H), 1.97 (d, J=23.5Hz, 4H), 1.80-1.67 (m, 6H), 0.71 (s, 2H), 0.51 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-111.83 (t, J=7.5Hz, 1F), -129.05 (d, J=8.2Hz, 1F), -150.50 (d, J=6.4Hz, 1F).m / z (ESI +):1185.09.

[0419] Synthesis of compound 120:

[0420] The synthesis of compound 120 followed the synthetic procedure of compound 88, using compound K-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ7.68 (dd, J=9.1, 5.8Hz, 1H), 7.48-7.42 (m, 2H), 7.33-7.24 (m, 2H), 7.12 (d, J=37.9Hz, 1H), 5.23 (d , J=14.1Hz, 1H), 4.79 (d, J=13.7Hz, 1H), 4.62 (d, J=14.2Hz, 1H), 4.53-4.37 (m, 3H), 4.22 (dt, J=12.3, 4.4Hz, 1H), 4.07 (d , J=4.4Hz, 7H), 3.82 (dt, J=28.4, 11.5Hz, 4H), 3.68-3.61 (m, 3H), 3.52 (q, J=2.8, 2.2Hz, 1H), 3.40-3.35 (m, 2H), 3.17-2. 98 (m, 4H), 2.90 (t, J=6.7Hz, 2H), 2.66-1.93 (m, 19H), 1.33 (d, J=10.5Hz, 2H), 1.04 (s, 2H), 0.90 (dd, J=14.2, 7.0Hz, 6H). 19 F NMR (376MHz, CD3OD) δ-77.05 (s, 12F), -120.84 (d, J=40.7Hz, 1F), -128.91 (d, J=9.2Hz, 1F), -145.02 (d, J=89.3Hz, 1F).m / z (ESI + ):1015.91.

[0421] Synthesis of compound 121:

[0422] The synthesis of compound 121 followed the synthetic procedure of compound 83, using compound 91-1 as the starting material. 1HNMR (400MHz, CD3OD) δ9.06 (d, J=18.1Hz, 1H), 7.90 (dd, J=9.2, 5.7Hz, 1H), 7.47-7.36 (m, 4H), 7.25 (dd, J=21.9, 2.6H z, 1H), 4.73-4.34 (m, 9H), 4.17 (t, J=13.1Hz, 1H), 4.10-3.98 (m, 8H), 3.79 (d, J=13.1Hz, 1H), 3.56 (s, 1H), 3.52 (d, J=3 .1Hz, 2H), 3.43 (s, 4H), 3.17 (s, 3H), 2.91 (t, J=6.7Hz, 2H), 2.58 (s, 2H), 2.44 (dd, J=15.2, 7.5Hz, 1H), 2.30 (s, 2H), 2 .03 (dq, J=30.5, 19.9, 16.6Hz, 12H), 1.61 (d, J=6.2Hz, 3H), 1.34 (d, J=8.3Hz, 1H), 0.97 (d, J=4.5Hz, 2H), 0.85 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-111.62 (t, J=7.7Hz, 1F), -128.76--129.21 (m, 1F), -138.69 (d, J=157.9Hz, 1F).m / z (ESI + ):997.84.

[0423] Synthesis of compound 122:

[0424] The synthesis of compound 122 followed the synthetic procedure of compound 83, using compound 122-1 as the starting material. 1H NMR (400MHz, CD3OD) δppm: 0.56 (s, 2H), 0.72-0.79 (m, 2H), 1.34 (d, J=10.7Hz, 2H), 1.60-1.80 (m, 8H), 1.84-2.11 (m, 9H), 2.18 (s, 1 H), 2.41-2.64 (m, 5H), 2.82 (q, J=7.9Hz, 1H), 2.90 (t, J=6.7Hz, 2H), 2.99 (t, J=11.7Hz, 1H), 3.10 (d, J=11.0Hz, 2H), 3.45 (s, 1H), 3. 84 (q, J=5.3, 4.8Hz, 2H), 4.06 (d, J=3.7Hz, 5H), 4.14 (t, J=4.3Hz, 2H), 4.23 (q, J=11.1, 8.5Hz, 2H), 4.34-4.47 (m, 2H), 4.50 (d, J=1 1.1Hz, 1H), 4.67 (s, 1H), 7.26 (d, J=2.6Hz, 1H), 7.31-7.42 (m, 3H), 7.44 (d, J=5.7Hz, 1H), 7.89 (dd, J=9.1, 5.7Hz, 1H), 9.06 (s, 1H). 19 F NMR (376MHz, CD3OD) δppm: -139.12 (s, 1F), -129.07--129.11 (m, 1F), -111.69--111.73 (m, 1F).m / z (ESI + ):997.74.

[0425] Synthesis of compound 123:

[0426] The synthesis of compound 123 followed the synthetic procedure of compound 100, using compound 123-1 as the starting material. 1H NMR (400MHz, CD3OD) δ9.30 (d, JJ=7.3Hz, 1H), 7.69 (dd, J=9.0, 5.8Hz, 1H), 7.33-7.23 (m, 2H), 7.08 (t, J=2.9Hz , 1H), 7.00-6.94 (m, 1H), 6.80-6.73 (m, 2H), 4.72 (dd, J=35.0, 13.7Hz, 1H), 4.62-4.41 (m, 4H), 3.87-3.81 (m, 2H ), 3.59 (dq, J=15.3, 7.4Hz, 3H), 3.26-3.20 (m, 3H), 3.10-2.95 (m, 3H), 2.50 (dq, J=16.3, 9.0, 7.2Hz, 3H), 2.36- 1.90 (m, 10H), 1.66 (p, J=8.0Hz, 3H), 1.47-1.24 (m, 7H), 1.01 (s, 2H), 0.88 (s, 2H), 0.81 (td, J=7.4, 3.7Hz, 3H). 19 F NMR (376MHz, CD3OD) δ-139.38 (s, 1H), -121.00 (s, 1H), -77.05 (s, 12H).m / z (ESI + ):886.72.

[0427] Synthesis of compound 124:

[0428] The synthesis of compound 124 followed the synthetic procedure of compound 100, using compound 124-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm 9.27 (d, J=8.5Hz, 1H), 7.78-7.62 (m, 2H), 7.50 (s, 1H), 7.42 (t, J=7.6Hz, 1H), 7.30 (d, J=2.6Hz , 1H), 7.25 (t, J=9.4Hz, 1H), 7.07 (t, J=2.4Hz, 1H), 5.14 (dd, J=13.3, 5.1Hz, 1H), 4.76-4.34 (m, 8H), 3.81 (dd, J=13.6, 11.1Hz, 1H), 3.64-3.50 (m, 1H), 3.21-3.05 (m, 4H), 2.95-2.72 (m, 4H), 2 .57-2.40(m, 4H), 2.39-2.10(m, 8H), 2.10-1.71(m, 16H), 0.99-0.85(m, 2H), 0.89-0.66(m, 5H). 19F NMR (376MHz, CD3OD) δppm-121.04 (t, J=7.4Hz, 1F), -139.12 (d, J=51.3Hz, 1F).m / z (ESI + ):995.74.

[0429] Synthesis of compound 125:

[0430] The synthesis of compound 125 followed the synthetic procedure of compound 114, using compound k as the starting material. 1 H NMR (400MHz, CD3OD) δ9.30 (d, J=6.1Hz, 1H), 7.94 (s, 2H), 7.69 (dd, J=9.0, 5.9Hz, 1H), 7.32 (d, J=2.7H z, 1H), 7.26 (t, J=9.4Hz, 1H), 7.08 (d, J=3.2Hz, 1H), 5.18 (dd, J=12.6, 5.3Hz, 1H), 4.77-4.49 (m, 8H), 3 .87-3.66(m, 6H), 3.49-3.41(m, 6H), 3.18(d, J=13.1Hz, 2H), 2.89-2.73(m, 3H), 2.60-1.74(m, 15H), 1. 60-1.46 (m, 2H), 1.30 (d, J=10.1Hz, 2H), 1.01 (s, 2H), 0.88 (s, 2H), 0.81 (q, J=5.5, 4.0Hz, 3H).m / z (ESI + ):1038.90.

[0431] Synthesis of compound 126:

[0432] The synthesis of compound 126 followed the synthetic procedure of compound 102, using compound 106-1 as the starting material. 1H NMR (400MHz, CD3OD) δppm 9.20 (d, J=4.0Hz, 1H), 7.72-7.61 (m, 2H), 7.52 (t, J=5.7Hz, 2H), 7.29 (d, J=2.6 Hz, 1H), 7.24 (t, J=9.4Hz, 1H), 7.07-7.01 (m, 1H), 5.14 (dd, J=13.3, 5.2Hz, 1H), 4.55-4.34(m, 5H), 4.25(t, J=13.1Hz, 1H), 3.70-3.55(m, 1H), 3.11-3.02(m, 2H) , 2.96-2.32(m, 13H), 2.29-1.49(m, 23H), 0.85-0.69(m, 5H), 0.61-0.45(m, 2H). 19 F NMR (376MHz, CD3OD) δppm -121.14 (t, J=10.6Hz, 1F), -139.15 (d, J=14.9Hz, 1F).m / z (ESI + ):983.85.

[0433] Synthesis of compound 127:

[0434] The synthesis of compound 127 followed the synthetic procedure of compound 119, using compound 81-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ7.87 (dd, J=9.1, 5.7Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 7.41 (d, J=10.8Hz, 1H), 7.37-7.31 (m, 2H), 7.27 (d, J=2 .6Hz, 1H), 6.61 (s, 1H), 5.26-5.04 (m, 2H), 4.66 (s, 4H), 4.50-4.40 (m, 3H), 4.26 (d, J=11.0Hz, 1H), 4.18-4.02 (m, 11H), 3.94 (d, J =27.7Hz, 2H), 3.74 (s, 1H), 3.66 (d, J = 2.9Hz, 1H), 3.45 (s, 1H), 3.17-3.11 (m, 1H), 2.89 (t, J = 6.7Hz, 2H), 2.30 (s, 4H), 2.12-1.82 (m, 11H), 1.79-1.66 (m, 5H), 1.59 (d, J=12.1Hz, 2H), 1.06 (t, J=7.3Hz, 1H), 0.92 (q, J=5.3, 4.5Hz, 1H), 0.74 (s, 2H), 0.55 (s, 2H). 19F NMR (376MHz, CD3OD) δ -75.21 (d, J=8.2Hz, 3F), -111.82 (t, J=7.4Hz, 1F), -128.97 (d, J=8.7Hz, 1F), -150.47 (s, 1F).

[0435] Synthesis of compound 135:

[0436] The synthesis of compound 135 followed the synthetic procedure of compound 81, using compound M as the starting material. 1 H NMR (400MHz, CD3OD) δppm: 0.60 (s, 2H), 0.82 (d, J=7.6Hz, 2H), 0.94 (t, J=7.1Hz, 3H), 1.57-1.80 (m, 7H), 1.82-2.3 2 (m, 17H), 2.40 (q, J=9.7, 7.4Hz, 3H), 2.59 (s, 2H), 2.90 (t, J=6.7Hz, 2H), 3.62-3.77 (m, 2H), 3.82-3.98 (m, 2H), 4. 06 (d, J=3.4Hz, 5H), 4.41-4.59 (m, 3H), 4.66 (s, 7H), 4.73 (d, J=8.9Hz, 2H), 6.38 (dd, J=15.3, 9.3Hz, 1H), 6.72 (d, J =5.1Hz, 1H), 7.06 (dd, =53.4, 2.7Hz, 1H), 7.17-7.34 (m, 2H), 7.37-7.51 (m, 2H), 7.68 (ddd, J=8.9, 5.9, 2.8Hz, 1H). 19 F NMR (376MHz, CD3OD) δppm: -144.35--144.66(t, 1F), -128.99(s, 1F), -121.05(s, 1F), -75.15--75.18(d, 3F).m / z(ESI + ):1230.44.

[0437] Synthesis of compound 152:

[0438] The synthesis of compound 152 followed the synthetic procedure of compound 88, using compound 95-1 as the starting material. 1H NMR (400MHz, CD3OD) δ0.92 (s, 2H), 1.03 (d, J=4.9Hz, 2H), 1.90-2.42 (m, 14H), 2.65 (d, J=3 5.0Hz, 1H), 2.90 (t, J=6.7Hz, 2H), 3.08 (dt, J=24.2, 13.4Hz, 4H), 3.65 (dd, J=23.9, 9.8Hz, 3H), 3.80 (dd, J=16.6, 8.8Hz, 4H), 3.99-4.12 (m, 6H), 4.16-4.28 (m, 1H), 4.31-4.43 (m, 1H) ), 4.50 (d, J = 5.4Hz, 3H), 6.52 (d, J = 34.6Hz, 1H), 6.91 (d, J = 2.3Hz, 1H), 7.41-7.53 (m, 2H). 19 F NMR (376MHz, CD3OD) δ-147.12 (d, J=17.6Hz, 1F), -128.90 (s, 1F), -77.07 (s, 9F), -55.88 (s, 3F).m / z (ESI + ):1020.62.

[0439] Synthesis of compound 155:

[0440] The synthesis of compound 155 followed the synthetic procedure of compound 88, using compound 155-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm: 0.58 (d, J=3.9Hz, 2H), 0.76 (s, 2H), 1.31-1.37 (m, 3H), 1.58-1.78 (m, 6H), 1.83-2.12 (m, 8H) ), 2.39-2.69 (m, 6H), 2.87 (dt, J=24.3, 7.4Hz, 3H), 2.98 (d, J=12.0Hz, 1H), 3.07-3.19 (m, 2H), 3.48-3.58 (m, 1H), 3.6 9-3.85 (m, 2H), 3.94 (ddd, J=28.1, 12.8, 10.7Hz, 1H), 4.03-4.09 (m, 5H), 4.10-4.19 (m, 1H), 4.35-4.54 (m, 4H), 6.01 ( t, J=13.7Hz, 1H), 7.24 (dd, J=34.9, 2.6Hz, 1H), 7.31-7.40 (m, 3H), 7.44 (d, J=5.7Hz, 1H), 7.87 (dd, J=9.1, 5.6Hz, 1H). 19F NMR (376MHz, CD3OD) δppm: -144.81--145.33(d, 1F), -129.04--129.09(m, 1F), -111.54--111.69(m, 1F), -100.05--103.27(m, 2F).m / z(ESI + ):1047.58.

[0441] Synthesis of compound 156:

[0442] The synthesis of compound 156 followed the synthetic procedure of compound 89, using compound 83-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ7.86 (dd, J=9.2, 5.7Hz, 1H), 7.44-7.39 (m, 2H), 7.36-7.30 (m, 2H), 7.28 (s, 1H), 4.84 (s, 3 H), 4.51 (s, 2H), 4.07 (d, J = 6.5Hz, 5H), 4.04 (d, J = 5.6Hz, 6H), 3.99 (d, J = 5.1Hz, 3H), 3.84 (q, J = 7.4, 6.7Hz, 2H), 3.79-3.69 (m, 2H), 3.62 (d, J=10.8Hz, 3H), 3.37 (d, J=13.7Hz, 1H), 3.26 (s, 2H), 2.99 (t, J=11.9Hz, 3H), 2.89 (s , 2H), 2.55 (s, 1H), 2.36-2.08 (m, 9H), 1.98 (d, J=41.9Hz, 4H), 1.06-0.98 (m, 2H), 0.91 (d, J=9.6Hz, 2H).m / z (ESI + ):1013.59.

[0443] Synthesis of compound 157:

[0444] The synthesis of compound 157 followed the synthetic procedure of compound 156, using compound 157-1 as the starting material. 1H NMR (400MHz, CD3OD) δ8.33 (s, 1H), 7.95 (dt, J=8.8, 4.6Hz, 1H), 7.57-7.48 (m, 2H), 7.44-7.38 (m, 2H), 6.45 ( ddd, J=13.2, 8.7, 4.8Hz, 1H), 6.12 (td, J=8.5, 3.8Hz, 1H), 5.49 (dd, J=13.6, 8.6Hz, 1H), 4.51 (t, J=8.8Hz, 2H ), 4.20-3.95 (m, 11H), 3.81 (dt, J = 18.5, 7.3Hz, 5H), 3.66 (d, J = 12.1Hz, 2H), 3.33 (d, J = 12.0Hz, 4H), 3.16-2 .95 (m, 3H), 2.87 (t, J = 6.7Hz, 2H), 2.39-1.91 (m, 12H), 1.02 (d, J = 4.7Hz, 2H), 0.91 (d, J = 6.2Hz, 2H).m / z (ESI + ):999.49.

[0445] Synthesis of compound 160:

[0446] The synthesis of compound 160 followed the synthetic procedure of compound 125, using compound L as the starting material. 1 H NMR (400MHz, CD3OD) δ7.81 (dd, J=9.3, 5.8Hz, 1H), 7.40 (d, J=5.7Hz, 1H), 7.37-7.22 (m, 3H), 7.23 (d, J=2.8 , 0.5H), 7.23 (d, J=2.4, 0.5H), 5.28-5.17 (m, 1H), 4.73-4.54 (m, 3H), 4.49-4.27 (m, 3H), 4.20-4.09 (m, 1H) , 4.06-3.94 (m, 8H), 3.82 (dt, J=12.6, 9.3Hz, 1H), 3.67 (s, 2H), 3.64-3.34 (m, 3H), 3.12-3.04 (m, 4H), 2.92 -2.79(m,3H),2.62-2.38(m,5H),2.31-2.20(m,3H),2.03-1.75(m,9H),0.71(s,2H),0.50(s,2H).m / z(ESI + ):1054.64.

[0447] Synthesis of compound 162:

[0448] The synthesis of compound 162 followed the synthetic procedure of compound 87, using compound 162-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ0.92 (d, J=7.8Hz, 2H), 1.04 (s, 2H), 1.34 (d, J=9.7Hz, 1H), 1.49 (dd, J=14.8, 7.3Hz, 2H), 1.99 (d, J=14.6Hz, 2H), 2.16(d, =49.9Hz, 10H), 2.31-2.44(m, 2H), 2.59(s, 1H), 2.94-3.24(m, 5H), 3.37-3.49(m, 4H), 3.52(dd, =3.5, 1.7Hz, 1H), 3.65 (d, J = 12.0Hz, 2H), 3.76 (dd, J = 16.6, 9.0Hz, 4H), 3.84-3.95 (m, 3H), 4.07 (d, J = 6.5Hz, 7H), 4.32- 4.78 (m, 4H), 7.25 (d, J = 2.3Hz, 1H), 7.29-7.37 (m, 2H), 7.40-7.50 (m, 2H), 7.82 (d, J = 7.8Hz, 1H), 9.47 (d, J = 6.3Hz, 1H). 19 F NMR (376MHz, CD3OD) δ -140.48--139.01 (m, 1F), -128.92 (t, J=8.7Hz, 1F), -112.23 (d, J=78.5Hz, 1F), -77.13 (s, 12F).m / z (ESI + ):994.56.

[0449] Synthesis of compound 163:

[0450] The synthesis of compound 163 followed the synthetic procedure of compound 160. 1H NMR (400MHz, CD3OD) δ7.84 (dd, J=9.2, 5.7Hz, 1H), 7.39-7.28 (m, 4H), 7.25 (d, J=2.6Hz, 0.5H), 7.17 (d, J=2.6H z, 0.5H), 5.17-5.28 (m, 1H), 4.75-4.64 (m, 4H), 4.27-4.29 (m, 4H), 4.18 (ddd, J=22.5, 12.4, 4.6Hz, 1H), 4.07- 3.92 (m, 7H), 3.89-3.66 (m, 3H), 3.57-3.52 (m, 1H), 3.38 (d, J = 5.7Hz, 4H), 3.22 (d, J = 12.2Hz, 2H), 2.91-2.73 ( m, 2H), 2.63 (s, 6H), 2.20 (s, 1H), 20.3-1.67 (m, 9H), 0.90 (t, J=7.2Hz, 1H), 0.78 (s, 2H), 0.59 (s, 2H).m / z (ESI + ):994.56.

[0451] Synthesis of compound 164:

[0452] The synthesis of compound 164 followed the synthetic procedure of compound 88, using compound m as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 7.94 (dd, J=9.2, 5.9Hz, 1H), 7.44 (t, J=9.0Hz, 1H), 7.37-7.29 (m, 2H), 7.15 (dd, J=26.9, 2.5Hz, 1H), 7 ... , 1H), 3.92(s, 3H), 3.90-3.86(m, 3H), 3.72-3.56(m, 8H), 3.31-3.22(m ,3H),2.88-2.72(m,5H),2.33-2.24(m,2H),2.11-2.02(m,2H),1.96-1 .88 (m, 2H), 1.76 (d, J=6.0Hz, 1H), 1.60 (d, J=9.3Hz, 1H), 1.39 (d, J=9.8Hz, 2H), 1.27 (s, 1H), 1.22 (s, 3H), 0.63 (s, 2H), 0.40 (s, 2H).m / z (ESI +):987.48.

[0453] Synthesis of compound 165:

[0454] The synthesis of compound 165 followed the synthetic procedure of compound 109, using compound 118-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm 9.12 (s, 1H), 7.85 (dd, J=9.1, 5.7Hz, 1H), 7.45-7.27 (m, 4H), 7.20 (d, J=2.6Hz, 1H), 6.69 (s, 1H), 6.62 (s, 0.5H), 6.40 (s, 0.5H), 5.40-5.13 (m, 2H), 4.67-4.31 (m, 7H), 4.06-3.96 (m, 5H), 3.86 (d, J=29.0Hz, 2H), 3 .66 (d, J=29.9Hz, 2H), 3.41 (s, 1H), 3.25-3.14 (m, 2H), 3.14-2.96 (m, 2H), 2.85 (t, J=6.7Hz, 2H), 2.74-2. 38(m, 8H), 2.38-2.14(m, 6H), 2.14-1.78(m, 8H), 1.78-1.58(m, 4H), 0.79-0.67(m, 2H), 0.63-0.42(m, 2H). 19 F NMR (376MHz, CD3OD) δppm -111.66 (t, J=7.0, 1F), -129.01 (q, J=8.3, 6.7Hz, 1F), -139.19 (s 1F), -141.87 (s, 1F).m / z (ESI + ):1160.68.

[0455] Synthesis of compound 166:

[0456] The synthesis of compound 166 followed the synthetic procedure of compound 109, using compound 117-1 as the starting material. 1H NMR (400MHz, CD3OD) δppm 9.11 (s, 1H), 7.85 (dd, J=9.2, 5.7Hz, 1H), 7.40 (d, J=5.7Hz, 1H), 7.36-7.27 (m, 3H), 7.20 (d, J=2. 5Hz, 1H), 6.69 (s, 1H), 5.38-5.13 (m, 2H), 4.61-4.54 (m, 2H), 4.51-4.33 (m, 4H), 4.09-3.96 (m, 5H ), 3.85 (d, J=29.2Hz, 2H), 3.75-3.55 (m, 2H), 3.41 (s, 1H), 3.18-3.06 (m, 2H), 3.06-2.75 (m, 4H), 2.60-2.36(m, 8H), 2.23-2.08(m, 6H), 2.08-1.54(m, 12H), 0.76-0.66(m, 2H), 0.55-0.40(m, 2H). 19 F NMR (376MHz, CD3OD) δppm -100.87 (s, 2F), -111.69 (q, J=7.6Hz, 1F), -129.09 (p, J=7.9Hz, 1F), -139.20 (d, J=6.4Hz, 1F).m / z (ESI + ):1178.66.

[0457] Synthesis of compound 167:

[0458] The synthesis of compound 167 followed the synthetic procedure of compound 110, using compound 167-1 as the starting material. 1H NMR (400MHz, CD3OD) δ9.14 (s, 1H), 7.86 (dd, J=9.2, 5.7Hz, 1H), 7.41 (d, J=5.7Hz, 1H), 7.38-7.28 (m, 3H), 7.23 (d, J=2.5 Hz, 1H), 6.70 (s, 1H), 5.36-5.32 (m, 1H), 5.24-5.19 (m, 1H), 4.60 (d, J=8.7Hz, 2H), 4.45 (s, 2H), 4.03 (t, J=6.8Hz, 2H), 4 .02 (s, 3H), 3.90 (s, 1H), 3.83 (s, 1H), 3.71 (s, 1H), 3.64 (s, 1H), 3.43 (d, J = 4.8Hz, 1H), 3.11 (d, J = 11.6Hz, 2H), 2.98 (t, J=6.8Hz, 1H), 2.86 (t, J=6.8Hz, 4H), 2.73 (s, 3H), 2.53-2.24 (m, 5H), 2.15 (d, J=9.2Hz, 2H), 2.05-1.63 (m, 20H).m / z (ESI + ):1191.81.

[0459] Synthesis of compound 168:

[0460] The synthesis of compound 168 followed the synthetic procedure of compound 70, using compound 95-1 as the starting material. 1 H NMR (400MHz, CD3OD) δppm: 1.63-1.87 (m, 7H), 1.90-2.09 (m, 8H), 2.10-2.31 (m, 7H), 2.39 (d, J=7.0Hz, 2H), 2.90 ( t, J=6.7Hz, 2H), 2.97-3.10 (m, 3H), 3.14-3.23 (m, 2H), 3.71 (d, J=29.5Hz, 2H), 3.89 (d, J=31.6Hz, 2H), 4.06 (d, J =2.7Hz, 5H), 4.22-4.41(m, 4H), 4.51-4.57(m, 2H), 4.64(s, 3H), 5.11(d, J=4.2Hz, 2H), 5.26-5.48(m, 2H), 6.39( d, J=2.3Hz, 1H), 6.71 (s, 1H), 6.93 (d, J=2.3Hz, 1H), 7.39 (d, J=10.7Hz, 1H), 7.45 (d, J=5.7Hz, 1H), 8.02 (s, 1H). 19F NMR (376MHz, CD3OD) δppm: -173.30--173.76(m, 1F), -129.02--129.09(m, 1F), -124.33(s, 1F), -53.39--56.38(m, 3F).m / z(ESI + ):1162.40.

[0461] Synthesis of compound 169:

[0462] The synthesis of compound 169 followed the synthetic procedure of compound 111, using compound 167-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ9.15 (s, 1H), 7.87 (dd, J=9.1, 5.7Hz, 1H), 7.42 (d, J=5.7Hz, 1H), 7.40-7.29 (m, 3H), 7.22 (d, J=2.3 Hz, 1H), 6.72 (s, 1H), 5.36-5.19 (m, 2H), 4.61 (s, 7H), 4.53-4.37 (m, 4H), 4.03 (d, J=3.3Hz, 5H), 3.93 (s, 1H), 3.86 (s, 1H) ), 3.72 (s, 1H), 3.65 (s, 1H), 3.42 (d, J = 5.7Hz, 1H), 3.12-3.01 (m, 3H), 2.87 (t, J = 6.7Hz, 2H), 2.75 (dd, J = 24.3, 13.0Hz, 1H), 2.61 (dd, J=25.3, 13.0Hz, 1H), 2.43 (d, J=10.9Hz, 4H), 2.22 (s, 3H), 2.01-1.56 (m, 13H), 1.37-1.34 (m, 1H).m / z (ESI + ):1182.78.

[0463] Synthesis of compound 170:

[0464] The synthesis of compound 170 followed the synthetic procedure of compound 98, using compound m as the starting material. 1H NMR (400MHz, CD3OD) δ9.26 (d, J=7.5Hz, 1H), 7.67 (dd, J=9.0, 5.8Hz, 1H), 7.35-7.20 (m, 3H), 7.08 (d, J=2.6Hz, 1H), 6.98 (d, J=6.8Hz, 1H), 4.69-4.38 (m, 10H), 4.01 (t, J=6.7Hz, 2H), 3.95 (s, 3H), 3 .84(dd, J=18.8, 13.6Hz, 1H), 3.71-3.46(m, 2H), 3.40-3.34(m, 2H), 3.03-2.82(m, 5H), 2.58-2.1 5(m, 7H), 2.06-1.60(m, 10H), 0.89(q, J=5.1, 4.1Hz, 1H), O.86-O.76(m, 5H), O.57(s, 2H).m / z(ESI + ):989.76.

[0465] Synthesis of compound 171:

[0466] The synthesis of compound 171 followed the synthetic procedure of compound 170, using compound 171-1 as the starting material. 1 H NMR (400MHz, CD3OD) δ9.26 (d, J=8.9Hz, 1H), 7.67 (dd, J=9.1, 5.8Hz, 1H), 7.35-7.20 (m, 3H), 7.08 (d, J=2.7Hz, 1H), 6.98 (d, J=6.9Hz, 1H), 4.65 (d, J=13.6Hz, 1H), 4.55 (d, J=9.O Hz, 8H), 4.49-4.42 (m, 3H), 4.17 (p, J=7.2Hz, 1H), 4.O1 (t, J=6.7Hz, 2H), 3.96 (s, 3H), 3 .84(dd, J=17.6, 13.6Hz, 1H), 3.52(td, J=8.5, 7.9, 4.2Hz, 1H), 3.47-3.35(m, 2H), 2.87( q, J=7.5, 6.7Hz, 4H), 2.50 (tq, J=13.7, 9.3, 6.4Hz, 4H), 2.29-2.14(m, 4H), 2.06-1.88(m , 4H), 1.81-1.63 (m, 9H), O.82 (td, J=7.3, 5.1Hz, 3H), O.78 (s, 2H), O.58 (s, 2H).m / z (ESI + ):1029.98.

[0467] Synthesis of compound 172:

[0468] The synthesis of compound 172 followed the synthetic procedure of compound 171, using compound L as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 10.22 (d, J=8.2Hz, 1H), 7.94 (ddd, J=9.3, 5.9, 1.3Hz, 1H), 7.45 (t, J=9.0Hz, 1H), 7. 36 (dd, J=2.6, 1.5Hz, 1H), 7.32 (d, J=12.7Hz, 1H), 7.15 (dd, J=27.4, 2.5Hz, 1H), 7.08 (d, J=7.2Hz, 1H), 4.98 (dq, J=7.1, 4.O Hz, 1H), 4.65 (dt, J=13.1, 4.O Hz, 1H), 4.54-4.44 (m, 1H), 4.28 (d, J=11.7Hz, 2H), 4.14-4.05 (m, 2H), 3.92 (s, 3H), 3.9 0-3.84(m, 3H), 3.71-3.55(m, 7H), 3.32-3.22(m, 3H), 2.91-2.65(m, 4H), 2.07(d, J=34.O Hz, 2H), 1.92-1.85 (m, 2H), 1.67-1.47 (m, 7H), 1.30-1.15 (m, 7H), O.66 (s, 2H), O.45 (s, 2H).m / z (ESI + ):1027.80.

[0469] Synthesis of compound 173:

[0470] Compound 88 (40 mg, 39.56 μmol, 1 eq) was dispersed in dichloromethane (5 mL), and DIPEA (15.34 mg, 118.68 μmol, 20.67 μL, 3 eq) was added. The reaction solution was cooled to 0°C under nitrogen, and then compound 173-1 (4.77 mg, 39.56 μmol, 1 eq) was added. The reaction solution was stirred at 0°C for half an hour, then slowly warmed to room temperature and concentrated in vacuo to remove the solvent. The residue was purified by column chromatography (MeOH / DCM = 0%-20%) to give compound 173 (17.6 mg, 39.8% yield). 1H NMR (400MHz, DMS0-d6) δ10.55 (s, 1H), 8.25-8.16 (m, 1H), 7.98 (t, J=2.1Hz, 1H ), 7.65 (t, J=9.0Hz, 1H), 7.60 (d, J=6.0Hz, 1H), 7.49 (d, J=2.4Hz, 0.5H), 7.43 (d, J=2.5Hz, 0.5H), 7.36 (d, J=10.8Hz, 1H), 5.02-4.92 (m, 1H), 4.72-4.64 (m, 1H), 4.49 (dd, J=15.5, 13.1Hz, 1H), 4.30 (dd, J=16.4, 9.5Hz, 3H), 4.22 (d, J=1. 0Hz, 0.5H), 4.19-4.09 (m, 1H), 4.06 (d, J=1.0Hz, 0.5H), 3.99 (s, 3H), 3.90 (dd , J=8.0, 5.4Hz, 2H), 3.68-3.51 (m, 2H), 2.93 (s, 2H), 2.84 (s, 1H), 2.75 (t, J=6. 7Hz, 2H), 2.28 (s, 2H), 2.12-1.91 (m, 4H), 1.79-1.77 (m, 4H), 1.55-1.43 (m, 6H ), 1.35 (d, J=3.1Hz, 9H), 1.27-1.23 (m, 9H), 0.63 (s, 2H), 0.41 (s, 2H).m / z (ESI + ):1095.65.

[0471] Effect embodiment:

[0472] Experiment 1: Protein degradation experiment:

[0473] Take the AsPc-1 (Cobioer, CBP60546) cell line in the logarithmic growth phase, inoculate it into a 6-well cell culture plate (Corning, 3516) at 1E6 / well, and place the culture plate in a 37°C, 5% carbon dioxide incubator for overnight incubation. The next day, the test compound was prepared into a 10mM stock solution with DMSO (Sigma, RNBF5902), and then diluted with complete culture medium to different concentrations of working solution, added to the corresponding well plate, and placed in a 37°C, 5% carbon dioxide incubator for continued culture. After 24 hours of compound treatment, remove the cell culture plate, wash the cells twice with pre-cooled PBS (Gibco, 14190250), and then add 80μL / well of PBS containing protease inhibitors (Invitrogen TM, AM2696) with RIPA (CST, 9806S) lysis buffer. Scrape the adherent cells with a cell scraper and transfer the cell lysate to a 1.5 mL centrifuge tube and place it on ice for 30 minutes. After lysis, centrifuge at 4 ° C, 12000 rpm for 10 minutes, transfer the supernatant to a new 1.5 mL centrifuge tube, place it on ice, and measure the protein concentration using a BCA protein detection kit (Thermo Fisher, 23225). Take 40 μL of cell lysate and mix it with 10 μL of 5×SDS (Beyotime, P0015L) loading buffer, and denature the protein in a 95 ° C water bath for 10 minutes. Add the denatured protein sample to the corresponding well of 4-20% Bis-Tris gel (GenScript, M00656) at 30 μg / well, first adjust the voltage to 80V and run for 30 minutes, then adjust it to 120V and run for 40 minutes, until the band runs to the appropriate position. After electrophoresis, the membrane was transferred using iBlot2 (Life Technologies, IB21001) at 20V for 7 minutes. After transfer, the membrane was blocked with 5% skim milk for 2 hours at room temperature and then rinsed three times with TBST (Thermo Scientific, 28360) buffer for 10 minutes each. A working solution of RAS G12D primary antibody (CST, 14429S) was prepared at a 1:1000 dilution in 5% skim milk and incubated overnight at 4°C. Following primary antibody incubation, the membrane was washed three times with TBST buffer at room temperature for 10 minutes each. A secondary antibody working solution was prepared with 5% skim milk and incubated for 1 hour at room temperature. After washing the membrane three times with TBST, the membrane was developed with ECL solution and imaged using a Biorad Chemi Doc gel imager. Band grayscale values ​​were analyzed using Image Lab.

[0474] The protein degradation rate was calculated according to the following formula: RAS G12D protein expression rate = (RAS G12D -化合物 / β-Actin -化合物 ) / (RAS G12D -DMSO / β-Actin -DMSO ) Degradation rate (%) = (1-RAS G12D protein expression rate) × 100

[0475] Compounds were tested for their ability to degrade KRAS G12V and KRAS G12C proteins in logarithmically growing NCI-H727 (Cobioer, CBP60182) and Miapaca2 (Cobioer, CBP60544) cell lines. The protein degradation assays were performed using the same procedures as previously described, using the corresponding primary antibodies against RAS G12V (CST, 14412S) and KRAS (CST, 71835S).

[0476] Table 2 shows the Ras protein degradation rates of different compounds at different concentrations on the AsPc-1 cell line, wherein "-" indicates that the Ras protein degradation rate of the compound of the present invention is less than or equal to 10%, "+" indicates that the Ras protein degradation rate of the compound of the present invention is greater than 10% and less than or equal to 30%, "++" indicates that the Ras protein degradation rate of the compound of the present invention is greater than 30% and less than or equal to 60%, "+++" indicates that the Ras protein degradation rate of the compound of the present invention is greater than 60% and less than or equal to 70%, "++++" indicates that the Ras protein degradation rate of the compound of the present invention is greater than 70% and less than or equal to 75%, and "+++++" indicates that the Ras protein degradation rate of the compound of the present invention is greater than 75%; "NT" means that no measurement was performed.

[0477] Table 2

[0478] Table 3 shows the degradation activity and Dmax of different compounds against KRAS G12D in AsPc-1 cells, KRAS G12V in NCI-H727 cells and KRAS G12C in Miapaca2 cells, wherein "+++++" indicates that the DC50 of the compound of the present invention is less than or equal to 1 nM, "++++" indicates that the DC50 of the compound is greater than 1 nM and less than or equal to 10 nM, "+++" indicates that the DC50 of the compound is greater than 10 nM and less than or equal to 50 nM, "++" indicates that the DC50 of the compound is greater than 50 nM and less than or equal to 100 nM, "+" indicates that the DC50 of the compound is greater than 100 nM and less than or equal to 300 nM, "-" indicates that the DC50 of the compound is greater than 300 nM and less than or equal to 1000 nM, "NO" indicates that the compound has no degradation activity within the detection range, and "NT" indicates that no determination was performed.

[0479] Table 3

[0480] Experiment 2: Cell proliferation experiment:

[0481] AsPc-1 (Cobioer, CBP60546), GP2D (Cobioer, CBP60683), Mia paca2 (Cobioer, CBP60136), NCI-H358 (Cobioer, CBP60544), and H727 (Cobioer, CBP60182) cells in logarithmic growth phase were plated at a density of 3.17E4 / ml and seeded into 96-well cell culture plates (Greiner, 655090) at a rate of 95 μL / well, resulting in 3E3 cells per well. The plates were then incubated overnight at 37°C in a 5% CO2 incubator. The next day, the test compounds were prepared in DMSO (Sigma, RNBF5902) to a 10 mM stock solution. These solutions were serially diluted and then prepared into working solutions of varying concentrations in complete culture medium. These solutions were then added to the corresponding wells of the plates and incubated in a 37°C incubator with 5% CO2. After 72 hours, the cell culture plate was removed and Cell Titer Glo (Promega, G7573) was added at 100 μL / well. After incubation at room temperature for 10 minutes, luminescence was detected by a microplate reader, and the inhibition percentage was calculated according to the following formula.

[0482] (“Highest signal” is the luminescence value measured in the DMSO control well, “lowest signal” is the luminescence value of each well measured on day 0, and “measured value” is the luminescence value measured after compound treatment)

[0483] IC50 values ​​were calculated by fitting the inhibition curves using a four-parameter equation using GraphPad Prism software. The results are shown in Table 4 below.

[0484] Table 4

[0485] Experiment 3: Pharmacokinetics in mice

[0486] Three male ICR mice were used for each compound pharmacokinetic experiment, and the pharmacokinetics of the compound were measured after intravenous injection (IV) or oral administration (PO). The compound injection solution was 5% DMSO + 5% Solutol + 90% (20% SBE-β-CD saline solution) for intravenous administration; the compound oral formulation was 5% DMSO + 5% Solutol + 90% (20% SBE-β-CD saline solution) for oral administration. Blood samples were collected at different time points and placed in a test tube containing an internal standard (IS). The samples were vortexed for 1 minute and centrifuged at 12000 rpm for 5 minutes at 4°C. The supernatant was used to detect the content of the compound by LC-MS / MS. The drug plasma data were fitted using a non-compartmental model (Phoenix WinNonlin). The experimental results are shown in Tables 5 and 6. "*" means that after oral administration of compound 173 (prodrug), the content of compound 88 (parent drug) was detected.

[0487] Table 5. Pharmacokinetic parameters of intravenous administration

[0488] Table 6. Pharmacokinetic parameters of oral administration

[0489] Experiment 4: Tumor model drug efficacy experiment

[0490] All studies were conducted in accordance with all applicable regulations and guidelines of the Institutional Animal Care and Use Committee (IACUC). Mice were maintained under pathogen-free conditions and provided with free access to food and water. Female Balb / c nude mice (Nu / Nu), 6-8 weeks old, were injected subcutaneously on the right hind flank with 5 × 10 6 A cell suspension of PK-59 cells (PBS and Matrigel matrix = 1:1) was prepared. The health of the mice was monitored daily, and caliper measurements were taken when tumors became apparent. The tumor volume was measured using the formula 0.5 × L × W. 2 , where L is the length of the tumor and W is the width of the tumor. When the average tumor volume reaches about 250 mm 3 Mice were randomly assigned to treatment groups. Animals were divided into at least six mice per group. Compound administration was performed in a vehicle consisting of 5% DMSO, 5% Solutol, and 90% saline solution of 20% SBE-β-CD. Animals were monitored daily, with body weight and tumor volume measured twice weekly. The dosage, schedule, and experimental results for the PK-59 cell subcutaneous xenograft tumor model are shown in Table 7. Tumor volume changes over 28 days are shown in Figure 1.

[0491] Table 7. Pharmacodynamic study of PK-59 cell subcutaneous xenograft tumor model Note: NA means not applicable, IV means intravenous injection, QW means once a week, TGI = (1-tumor volume of treatment group / tumor volume of control group) × 100%

[0492] Although the present invention has been described in detail with reference to the embodiments of the present invention, these embodiments are provided to illustrate rather than limit the present invention. Other embodiments that can be obtained according to the principles of the present invention all fall within the scope defined by the claims of the present invention.

Claims

1. A bifunctional compound having a KT or KLT structure, or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, wherein: K is the targeting group of Kras protein; T is the ligand group of E3 ubiquitin ligase; L is a bivalent linking group that chemically links the targeting group (K) to the ligand group (T); The targeting group K of the Kras protein has a structure shown in formula (IA), formula (IB) or formula (IC): Among them, X 1 and X 2 are independently C or N; Ring A is a carbocyclic ring or a carbon heterocyclic ring; Y is -CH<, -CH2-CH<, -CH2-CH2-CH<, -N<, -NH-CH<, -CH2-N<, -CH2-CH2-N<, -CH2-NH-CH<, -O-CH< or -S-CH<; H in Y is optionally substituted by halogen, amino, hydroxy or C1-C4 alkyl; Z is optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 1 Absent, or H, halogen, NH2 or optionally substituted C1-C4 alkyl; R 2 is H, halogen, NH2 or optionally substituted C1-C4 alkyl; Each R 3a and R 3b are independently halogen, 1 to 4 R 4 or R 6 Substituted C1-C4 alkyl or C2-C4 alkenyl, oxo (=O), -N(R 4 )2、-OR 4 、-C(O)OR 4 、-C(OR 4 )(R 4 )2、-C(O)R 4 、-C(O)R 5 、-C(O)(C1-C4 alkylene)-R 5 、-C(O)N(R 4 )2、-CN、-S(O)2R 6 、-P(O)(R 4 )2 or any 1-4 R 4 or R 6 substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or, two R 3a Or two adjacent R 3a Together with the carbon atoms to which they are attached, they form an optionally substituted carbocyclic or carboheterocyclic ring; or, two R atoms attached to the same carbon atom 3b Or two adjacent R 3b together with the carbon atoms to which they are attached, form an optionally substituted carbocyclic or carboheterocyclic ring; Each R 4 are independently H, halogen, 1-4 R 6 Substituted C1-C5 alkyl, -C(O)R 6 、-N(R 6 )-C(O)R 6 、-N(R 6 )-S(O)2R 6 , -CH2-S-CH3, -S(O)2NH2, -S(O)2NH(C1-C4 alkyl), -S(O)2N(C1-C4 alkyl)2, -S(O)2(C1-C4 alkyl) or -P(O)(C1-C4 alkyl)2; R 5 Choose 1-4 R 6 substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 6 are each independently H, halogen, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 heterocycloalkyl, hydroxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -O(C1-C4 alkyl), or -O(C1-C4 alkylene)-O(C1-C4 alkyl); Each n1 is independently an integer from 0 to 4; R C1 is H, halogen, optionally halogen-substituted alkoxy, optionally halogen-substituted C1-C4 alkyl, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, amino or hydroxy; or, R C1 , any R 3b together with the carbon atoms to which they are attached, form an optionally substituted carboheterocycle; B is the following structure: Wherein, E is oxygen (-O-), nitrogen (-NH-) or sulfur (-S-); R 7 and R 8 independently selected from hydrogen, halogen, hydroxy or cyano substituted C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkylamino, -OC(O)N(R 9 )2, -(C1-C4 alkylene)-OC(O)N(R 9 )2, -(C1-C4 alkylene)-N(R 9 )-SO2-N(R 9 )2, -CO2R 9 、-CO2N(R 9 )2, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, =C(R 10 )2; Each R 9 are independently H or C1-C4 alkyl; each R 10 are independently H, halogen; n2 are each independently an integer of 0-3; n3 are an integer of 0-5; M is C1-C4 alkylene, -(C1-C4 alkylene)-O-, or -(C1-C4 alkylene)-O-(C1-C4 alkylene)-.

2. The bifunctional compound according to claim 1, wherein The targeting group K has a structure represented by formula (IA), selected from the structure represented by formula (I-a1), formula (I-a2), formula (I-a3), formula (I-a4) or formula (I-a5): Among them, A ring, R 1 、R 2 、R 3a 、R 3b 、X 1 、X 2 , Z, Y, n1 as defined in claim 1; R 3a 、R 3b Each independently replaces any substitutable position on the ring; R C2 O or -NR C3 -, R C3 is H or an optionally substituted C1-C4 alkyl group; and Q is an optionally substituted C1-C4 alkylene group.

3. The bifunctional compound according to claim 1 or 2, wherein The targeting group K Selected from the following structures: Among them, R 3a and n1 as defined in claim 1; R 3 Substitution at any substitutable position.

4. The bifunctional compound according to claim 1, wherein The targeting group K has a structure represented by formula (IB), selected from the structure represented by formula (I-b1), formula (I-b2), formula (I-b3), formula (I-b4) or formula (I-b5): Among them, A ring, R 1 、R 2 、R 3a 、R 3b 、X 1 、X 2 , Z, B, Y, n1 as defined in claim 1; R 3a 、R 3b Each independently replaces any substitutable position on the ring; R C2 O or -NR C3 -, R C3 is H or an optionally substituted C1-C4 alkyl group; and Q is an optionally substituted C1-C4 alkylene group.

5. The bifunctional compound according to claim 4, wherein The targeting group K Selected from the following structures: Among them, R 3a and n1 as defined in claim 1; R 3a Substitution at any substitutable position.

6. The bifunctional compound according to claim 1, wherein The targeting group K has a structure represented by formula (IC), selected from the structure represented by formula (I-c1), formula (I-c2), formula (I-c3), formula (I-c4) or formula (I-c5): Among them, R 1 、R 2 、R 3a 、R 3b 、X 1 、X 2 , M, Z, B, Y, n1 as defined in claim 1; R 3b Substitute any substitutable position; R C2 O or -NR C 3. R C 3 is H or an optionally substituted C1-C4 alkyl group; Q is an optionally substituted C1-C4 alkylene group.

7. The bifunctional compound according to claim 6, wherein The targeting group K Selected from the following structures:

8. The bifunctional compound according to any one of claims 1 to 7, wherein Z is selected from the following structures: Especially selected Alternatively, Z is selected from the following structures: Among them, Q Z (C1-C8 alkyl) C(O)-, (C1-C8 alkyl) C(O)O(C1-C4 alkylene)-, -CH2OP(O)(OQ 1 )2、-P(O)(OQ 1 )2, -C(O)CH2NH2 or (C1-C8 alkyl)-OC(O)O-(C1-C4 alkylene)-; Q 1 is H or C1-C8 alkyl.

9. The bifunctional compound according to claim 4, wherein B is selected from the structure shown below:

10. The bifunctional compound according to claim 1, wherein The targeting group K is a formula (IA) selected from the following structures: Among them, R 1 It is a halogen.

11. The bifunctional compound according to claim 1, wherein The targeting group K is of formula (IB) and is selected from the following structures: Among them, R 1 is H or halogen.

12. The bifunctional compound according to claim 1, wherein The targeting group K is a formula (IC) selected from the following structures: Among them, R 1 is halogen, R C1 is H or methoxy.

13. The bifunctional compound according to any one of claims 1 to 12, wherein The ligand group T is selected from:

14. The bifunctional compound according to any one of claims 1 to 13, wherein The bifunctional compound has a structure shown in formula (III-a), formula (III-b) or formula (III-c): wherein the targeting group K and the ligand group T are as defined in any one of claims 1 to 13; Preferably, in formula (III-a) and formula (III-b), the targeting group K is selected from: The ligand group T is selected from Preferably, in formula (III-c), K is selected from The ligand group T is selected from 15. The bifunctional compound according to claim 1, wherein The bifunctional compound has a structure shown in formula (III-d): K 1 -LT 1 Formula (III-d), Among them, K 1 Selected from L is selected from T 1 Selected from 16. The bifunctional compound according to claim 1, wherein The bifunctional compound has a structure shown in formula (III-e): Among them, R 3b are independently H or F, Q is -CH2- or -CH(CH3)-; L'selected and, T'selected 17. A compound selected from the group consisting of compounds shown in Table 1 of the specification, or a pharmaceutically acceptable salt, ester, stereoisomer, hydrate, solvate or prodrug thereof.

18. A pharmaceutical composition comprising: At least one compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer or prodrug thereof; and optionally at least one pharmaceutically acceptable excipient, carrier or diluent; preferably, the pharmaceutically acceptable excipient comprises one or more of a binder, a filler, a disintegrant, a lubricant and a glidant; Preferably, the pharmaceutically acceptable carrier comprises one or more of creams, emulsions, gels, liposomes and nanoparticles; Preferably, the composition is suitable for oral administration or injection.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer or prodrug thereof, or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating, inhibiting or preventing a hyperproliferative disorder; Preferably, the hyperproliferative disorder is a Kras-associated malignancy or cancer; Preferably, the malignant tumor or cancer is selected from the group consisting of sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratoma; Lung tumors or cancers: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; Gastrointestinal tumors or cancers: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucocorticoid tumor, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hematoma, leiomyoma); Genitourinary tract tumors or cancers: kidney (adenocarcinoma, Wilms tumor (Nephroblastoma), lymphoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract tumors or cancers: gallbladder cancer, ampulla cancer, bile duct cancer; Bone tumors or cancers: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordal tumor, osteochondroma (osteochondroma), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system tumors or cancers: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, epididymal tumors, germ cell tumors (pinealomas), glioblastomas, oligodendrogliomas, gliomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecological tumors or cancers: uterus (endometrial cancer (serous bladder cancer, mucinous bladder cancer, unclassified carcinoma), granulosa cell tumor, serointerstitial cell tumor, dysplasia, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonal rhabdomyosarcoma)); Hematological tumors or cancers: leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma; Dermatological tumors or cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse's dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland tumors or cancer: neuroblastoma; Preferably, the malignant tumor or cancer is selected from one or more of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colorectal cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer or breast cancer.

20. Use of a kit for preparing a drug for treating, inhibiting or preventing a Kras-related disease, wherein: The kit comprises the compound or pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer or prodrug according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 18.

Images