Agents for degrading WEE1 protein kinase and uses thereof

Abstract

Compounds or pharma- ceutically acceptable salts thereof that degrade WEE1 protein kinase, and their use in the treatment of proliferative diseases.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine. The present invention provides a compound or a pharmaceutically acceptable salt thereof that degrades WEE1 protein kinase, and its use in the treatment of proliferative diseases. The present invention further provides a composition comprising the compound or a pharmaceutically acceptable salt thereof and, optionally, a pharmaceutically acceptable carrier. [Background technology]

[0002] The cell cycle refers to the entire process of cell division, including interphase (including DNA synthesis prophase (G1 phase), DNA synthesis S phase, and DNA synthesis anaphase (G2 phase)) and mitosis (M phase, which includes prophase, metaphase, anaphase, telophase, and cytoplasmic mitosis). Cell cycle checkpoints are key points that regulate the cell cycle, and their main function is to ensure that all events within the cycle (e.g., DNA replication and chromosome allocation) are completed in an orderly and high-quality manner. The main cell checkpoints are: 1) the G1 / S checkpoint, which verifies and controls the cell's transition from the quiescent G1 phase to the DNA synthesis phase; 2) the S phase checkpoint, which verifies whether DNA replication is complete; 3) the G2 / M checkpoint, which verifies and controls the cell's transition to the mitotic phase; and 4) the metaphase-anaphase checkpoint, which verifies whether the spindle is properly assembled. If there is an abnormality in a particular process of the cell division cycle, such as DNA damage, the checkpoint senses it in time and initiates repair.

[0003] Damaged DNA is normally repaired at the G1 / S phase checkpoint. The P53 protein can repair DNA damage and prevent cells from entering the S phase. If the damage is irreversible, the P53 protein can trigger apoptosis. In normal cells, the P53 protein is maintained at low levels. However, many tumor cells have P53 mutations that cause defects in the G1 / S checkpoint.

[0004] In cells with p53 mutations (e.g., tumor cells), cell division cycle control (e.g., cell cycle arrest or cell elimination) depends on the G2 / M checkpoint. WEE1 protein kinase is a key gene for G2 / M phase arrest. WEE1 protein kinase is highly expressed in many tumors. Inhibition or downregulation of WEE1 protein kinase can lead to "mitotic catastrophe" and tumor cell apoptosis. WEE1 kinase inhibitors, such as AZD1775, have achieved some therapeutic efficacy in anti-cancer treatment, but still suffer from drawbacks such as low cellular activity, high clinical toxicity, and poor patient tolerance.

[0005] The ubiquitin-proteasome pathway is a key protein degradation pathway in cells and is highly specific and selective. Proteolysis targeting chimeras (PROTACs) are compounds in which a ligand for a protein of interest (POI) and a ligand for an E3 ubiquitin ligase are linked via a linker. In other words, one end of the PROTAC molecule can bind to the target protein, and the other end can bind to the E3 ubiquitin ligase, thereby recruiting the E3 ubiquitin ligase to the target protein. The E3 ubiquitin ligase can then "tag" the target protein with multiple ubiquitin proteins (also known as ubiquitination). The tagged target protein (ubiquitinated target protein) is then recognized and degraded by the proteasome. In this process, the target protein's ligand does not need to occupy the binding site for a long time, and the PROTAC only needs to occupy the target protein site and the E3 ubiquitin ligase site for a short time, resulting in instantaneous ubiquitination of the target protein. PROTACs are also recyclable and not degraded by the proteasome.

[0006] However, compared with the drug-like properties of small molecule inhibitors, many PROTAC drugs suffer from drawbacks such as poor water solubility, poor membrane permeability, poor metabolic stability, and poor oral bioavailability.

[0007] Hydrolysis of WEE1 protein can effectively block downstream signal transduction. Elimination of WEE1 protein can advantageously eliminate WEE1 kinase activity and any protein interaction or scaffolding function of WEE1, which has broad prospects for tumor therapy.

[0008] The compounds according to the present invention or pharmaceutically acceptable salts thereof can effectively decompose WEE1 protein kinase, and also have improved water solubility, membrane permeability, metabolic stability, and oral bioavailability. Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention provides chimeras that target protein degradation. [Means for solving the problem]

[0010] In a first embodiment, the present invention provides a compound represented by structural formula (I), or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof: (I):WLD where: W is a WEE1 kinase binding ligand having the following structure: [ka] where: [ka] represents an optionally substituted cyclic group; A 1 is selected from O=, halogen, hydroxyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C1-C6 alkoxy, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl groups; X 2 Whenever present, CR 2 ' or N, R 2', whenever present, means: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, L is a linker having the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] where: [ka] represents the binding site, D is an E3 ubiquitin ligase binding ligand having the following structure: [ka] where: [ka] represents an optionally substituted cyclic group; Y 1 Whenever exists, CT 1 or N, independently selected from T 1 is selected from hydrogen or deuterium, L is attached to W and / or D through one or more bonds.

[0011] In a second aspect of the first embodiment, W is [ka] and where: A 2 is selected from O=, halogen, hydroxyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C1-C6 alkoxy, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl groups; B 3 is, at each occurrence, independently selected from C, CH, CD or N; B 4 is, at each occurrence, independently selected from C, CH, CD or N; or B 3 -B 4 is -C=C-, [ka] represents a single bond or a double bond, X 2 Whenever present, CR 2 ' or N, R 2 ', each time present, shall be replaced by the following: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 3is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 4 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 3 and R 4 together with the atoms to which it is attached, form a monocyclic, bicyclic, or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, of which 0, 1, 2, 3, or 4 are heteroatoms selected from N, O, and S, and the remainder are carbon atoms, and the ring system is optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups.

[0012] In a third aspect of the first embodiment, W is [ka] and A 2 is selected from O=, halogen, hydroxyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C1-C6 alkoxy, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl groups; B 3 each occurrence is independently selected from C, CH, CD or N; or R 4 B 3 -NR 3 is -N=N-, [ka] represents a single bond or a double bond, R 1is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 3 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 4 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 3 and R 4 together with the atoms to which it is attached, form a monocyclic, bicyclic, or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, of which 0, 1, 2, 3, or 4 are heteroatoms selected from N, O, and S, and the remainder are carbon atoms, and the ring system is optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups.

[0013] In a fourth aspect of the first embodiment, W is [ka] and where: R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 3is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 4 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 3 and R 4 together with the atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; or -(R 4 N-NR 3 )- is -N=N-.

[0014] In a fifth aspect of the first embodiment, W is [ka] and where: A 1 is selected from O=, halogen, hydroxyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C1-C6 alkoxy, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl groups; B 1 is, at each occurrence, independently selected from C, CH, CD or N; B 2 is, at each occurrence, independently selected from C, CH, CD or N; or B 1 -B 2 represents -(C=C)-, -(N=C)- or -(C=N)-; X 2 Whenever present, CR 2 ' or N, R 2 ', whenever present, means: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 5 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 6is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 7 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 5 , R 6 and R 7 two of which, together with the atom to which they are attached, form a monocyclic, bicyclic, or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, of which 0, 1, 2, 3, or 4 are heteroatoms selected from N, O, and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups.

[0015] In a sixth aspect of the first embodiment, W is [ka] and where: X 2 Whenever present, CR 2 ' or N, R 2 ', whenever present, means: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, X 6 is, each occurrence, independently selected from C or N; X 7 is, each occurrence, independently selected from C or N; X 8 is, each occurrence, independently selected from C or N; X 9 is, each occurrence, independently selected from C or N; X 10 is, each occurrence, independently selected from C or N; R 8 , R 9 , R 10 , R 11 , R 12 Each time any one of the following is present, it must be selected from the group consisting of: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Whenever Z is present, CR 13 ' or N, R 13', whenever present, means: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 14 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups.

[0016] In a seventh aspect of the first embodiment, W is [ka] and where: R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, X 8 is, each occurrence, independently selected from C or N; R 8 , R 9 , R 11 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups.

[0017] Preferably, W is [ka] is.

[0018] In an eighth aspect of the first embodiment, W is [ka] and B 1 is, at each occurrence, independently selected from C, CH, CD or N; B 2 is, at each occurrence, independently selected from C, CH, CD or N; or B 1 -B 2represents -(C=C)-, -(N=C)-, -(C=N)-, or -N=N-; X 2 Whenever present, CR 2 ' or N, R 2 ', whenever present, means: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 1is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 5 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 6 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 5 and R 6 together with the atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; X 11is, each occurrence, independently selected from C or N; X 12 is, each occurrence, independently selected from C or N; X 13 is, each occurrence, independently selected from C or N; X 14 is, each occurrence, independently selected from C or N; X 15 is, each occurrence, independently selected from C or N; R 15 , R 16 , R 17 , R 18 , R 19 Each time any one of the following is present, it must be selected from the group consisting of: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups.

[0019] In a ninth aspect of the first embodiment, W is [ka] and R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 5 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; and X 13 is, each occurrence, independently selected from C or N; R 15 , R 16 and R 18 Each time any one of the following is present, it must be selected from the group consisting of: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups.

[0020] In a tenth aspect of the first embodiment, W is [ka] and where: R 1is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 4 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; and X 16 Whenever present, CH, CD, CR 21 or N, X 17 Whenever present, CH, CD, CR 22 or N, X 18 Whenever present, CH, CD, CR 23 or N, X 19 Whenever present, CH, CD, CR 24 or N, X 20 Whenever present, CH, CD, CR 25 or N, R 21 , R 22 , R 23 , R 24 , R 25 Each time any one of the following is present, it must be selected from the group consisting of: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups.

[0021] In an eleventh aspect of the first embodiment, W is [ka] and R 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; R 2is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; or R 1 and R 2 together with the ring atoms to which they are attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and which ring system is optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups; R 1 , R 2 , R 1 and R 2 together, or R 1 and R 2 any one of the ring systems formed by these is bonded to the L group, R 4is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, allyl, propenyl, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; R 21 , R 22 Each time any one of the following is present, it must be selected from the group consisting of: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, allyl, propenyl, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH or a C1-C6 alkyl group substituted by a substituent optionally selected from a C1-C4 alkyl group, a cyclopropyl group, a halogen, a hydroxyl, a carbonyl, a nitro group; or R 21 , R 22 together with the ring atoms to which it is attached form a 5- or 6-membered ring having 0, 1 or 2 heteroatoms selected from N, O or S, said 5- or 6-membered ring being optionally substituted with substituents selected from a C1-C4 alkyl group, a cyclopropyl group, a halogen, a hydroxyl group, a carbonyl group, and a nitro group.

[0022] In a twelfth aspect of the first embodiment, W is [ka] and where: X 2 is CH or N, R 1 is hydrogen, fluorine, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L group; R 4 is an allyl group, a propargyl group, a methylenecyclopropyl group, an ethyl group, a trifluoroethyl group, a difluoroethyl group, an isopropyl group, a cyclopropyl group, a methylene C6-C 12 Aryl group, methylenephenyl group, C 1-4 Alkyl groups, optionally substituted C 2-4 Alkenyl groups, optionally substituted C 2-4 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups and optionally substituted C 3-6 Cycloalkyl(C 1-4 alkyl), wherein said C 1-4 Alkyl group, C2-4 Alkenyl groups and C 2-4 The alkynyl group is substituted with halogen, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy group, cyano group, amino group, mono-C 1-4 Alkylamines and Di-C 1-4 alkylamines, and 3-6 Cycloalkyl groups and the C 3-6 Cycloalkyl(C 1-4 One or more rings of the alkyl group may contain halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy group, cyano group, amino group, mono-C 1-4 Alkylamines and Di-C 1-4 optionally substituted independently by one or more substituents selected from alkylamines; R 3 teeth, [ka] , optionally substituted C6-C 12 Aryl group or optionally substituted C5-C 10 heteroaryl groups, wherein when said aryl group or said heteroaryl group is substituted, said C6-C 12 Aryl groups and the C5-C 10 The heteroaryl groups are independently substituted with one or more substituents, which are preferably fluorine, chlorine, methyl, ethyl, methoxy, hydroxymethyl, and halogenated alkyl groups.

[0023] Preferably, W is [ka] is.

[0024] In a thirteenth aspect of the first embodiment, W is [ka] and where: X 2 is CH or N, R 1 is hydrogen, fluorine, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L group; R 31 is hydrogen, a hydroxyl group, a fluorine group, an amino group, or a cyano group, R 32 is hydrogen, fluorine, a methyl group, an ethyl group, a fluoroethyl group, a trifluoromethyl group, a difluoromethyl group, or a cyclopropyl group, R 31 and R 32 together with the atom to which it is bonded, [ka] Forming X 3 are CH, O, N, and NR 39 where R 39 is C 1-3 is an alkyl group or a cycloalkyl group, n is 1 or 2, Y 35 is CH2 or O.

[0025] Preferably, W is [ka] is.

[0026] In a fourteenth aspect of the first embodiment, W is [ka] and where: X 2 is C or N, R1 is hydrogen, fluorine, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L group; Ar is a phenyl group optionally substituted with a substituent selected from halogen, methyl, or methoxy; a C5-C 10 is a heteroaryl group, [ka] is a nitrogen-containing heteroaromatic ring selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group.

[0027] In a fifteenth aspect of the first embodiment, W is [ka] and where: Ar is a C-C alkyl group optionally substituted with a substituent selected from halogen, methyl, or methoxy. 12 C5-C optionally substituted with a substituent selected from an aryl group, a halogen, a methyl group, or a methoxy group 10 is a heteroaryl group, R 1 is hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, hydroxymethyl, or a linking L substituent; X 3 ' is C, CH, CD, O or N, R 33 is absent, hydrogen, a methyl group, fluorine, or chlorine; R 34 is absent, hydrogen, deuterium, hydroxyl group, R 35 is absent, hydrogen, deuterium, a hydroxyl group, or R 34 and R 35 together form =O.

[0028] Preferably, W is [ka] is.

[0029] In a sixteenth aspect of the first embodiment, W is [ka] and where: X 2 is CH or N, X 4 is CH or N, R 1 is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L substituent; R 36 is selected from hydrogen, fluorine, a cyano group, and a methyl group; R 37 is hydrogen, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-OC 1-6 Alkyl group, -C 1-6 alkylene -NRaRb, -C(=O)NRcRd, -N=S(=O)(Re)(Rf), -P(=O)(Rg)(Rh), -NH-P(=O)(Ri)(Rj), a pyridone group, or [ka] wherein each occurrence of Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj is independently selected from C 1-6 Alkyl group, C 3-5 cycloalkyl groups, R 38 is hydrogen, C 1-6 Alkyl group, C 3-8 Cycloalkyl group, aryl group, -C 1-6 Alkylene -OH or -C 1-6 Alkylene-OC 1-6 The alkyl group is selected from the group consisting of:

[0030] In a seventeenth aspect of the first embodiment, W is [ka] and where: X 4 is CH or N.

[0031] In an eighteenth aspect of the first embodiment, W is [ka] and where: X 2 is CH or N, R 1 is selected from hydrogen, fluorine, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L substituent; R 41 is selected from hydrogen, fluorine, or a methyl group; R 42 is selected from hydrogen, fluorine, or a methyl group; R 43 is selected from a methyl group or an ethyl group, Preferably, W is [ka] is.

[0032] In a nineteenth aspect of the first embodiment, D is [ka] and Y 1 Whenever exists, CT 1 or N, T 1is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; Y 41 Whenever exists, C, CT 41 T 41 ', NT 41 ", C=O, or O; Y 42 Whenever exists, C, CT 42 T 42 ', NT 42 ", C=O, or O; Y 43 Whenever exists, C, CT 43 T 43 ', NT 43 ', C=O, or O; or Y 41 -Y 42 -T 41 (C=C)T 42 -, -(N=C)T 42 -, -T 41 (C=N)- or -(N=N)-, or Y42 -Y 43 -T 42 (C=C)T 43 -, -(N=C)T 43 -, -T 42 (C=N)- or -(N=N)-; T 41 , T 41 ', T 41 '', T 42 , T 42 ', T 42 '', T 43 , T 43 ', T 43 Each of "," each time present, represents the following: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Y 5 Whenever exists, CT 5 or N, Y 6 Whenever exists, CT 6 or N, Y 7 Whenever exists, CT7 or N, Y 8 Whenever exists, CT 8 or N, T 5 , T 6 , T 7 , T 8 each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Y 5 , Y 6 , Y 7 and Y 8 One or more of are linked to the L group.

[0033] In a twentieth aspect of the first embodiment, D is [ka] where: Y 1 Whenever exists, CT 1or N, T 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; Y 41 Whenever exists, CT 41 or N, Y 42 Whenever exists, CT 42 T 42 ', NT 42 ", C=O, or O; Y 43 Whenever exists, CT 43 T 43 ', NT 43 ', C=O, or O; or Y 41 -Y 42 is -(C=C)T 42 -, -(C=N)-, or Y 42 -Y 43 -T 42 (C=C)T 43-, -(N=C)T 43 -, -T 42 (C=N)- or -(N=N)-; T 41 , T 42 , T 42 ', T 42 '', T 43 , T 43 ', T 43 Each of "," each time present, represents the following: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Y 5 Whenever exists, CT 5 or N, Y 6 Whenever exists, CT 6 or N, Y 7 Whenever exists, CT 7 or N, Y 8 Whenever exists, CT 8 or N, T 5 , T 6 , T 7 , T 8 each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Y 5 , Y 6 , Y 7 and Y 8 One or more of are linked to the L group.

[0034] In a twenty-first aspect of the first embodiment, D is [ka] and where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 42 is, at each occurrence, independently selected from CH or N; Y 43each occurrence is independently selected from CH, —NH, O, or N—CH; Y 5 Whenever there is a 5 are independently selected from, where T 5 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y 6 Whenever there is a 6 are independently selected from, where T 6 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y 7 Whenever there is a 7 are independently selected from, where T 7 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y 8 Whenever there is a 8 are independently selected from, where T 8 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y 5 , Y 6 , Y 7 and Y 8 One or more of are linked to the L group. Preferably, D is [ka] [ka] [ka] is.

[0035] In a twenty-second aspect of the first embodiment, D is [ka] and where: Y 1 Whenever exists, CT 1 or N, T 1 is, whenever present, the following: absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C1-C6 alkyl groups; Y 4 Whenever exists, CT 4 T 4 ' or NT 4 '' are selected independently from T 4 , T 4 ', T 4Each of "," each time present, represents the following: absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Y 5 Whenever exists, CT 5 or N, Y 6 Whenever exists, CT 6 or N, Y 7 Whenever exists, CT 7 or N, Y 8 Whenever exists, CT 8 or N, T 5 , T 6 , T 7 , T 8each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; Y 5 , Y 6 , Y 7 and Y 8 One or more of are linked to the L group.

[0036] In a twenty-third aspect of the first embodiment, D is [ka] and where Y 1 is, at each occurrence, independently selected from CH, CD, or N; J 1 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 2 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J3 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 4 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 1 , J 2 , J 3 and J 4 One or more of are linked to the L group. Preferably, D is [ka] is.

[0037] In a twenty-fourth aspect of the first embodiment, D is [ka] and where Y 1 is, at each occurrence, independently selected from CH, CD, or N; J 1 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 2 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 3 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 4 is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J 1 , J 2 , J 3 and J 4 One or more of are linked to the L group.

[0038] Preferably, D is [ka] is selected from.

[0039] In a twenty-fifth aspect of the first embodiment, D is [ka] and Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 21 is, at each occurrence, independently selected from NH, N—CH or O; [ka] is an aromatic or heteroaromatic ring, Y 10 Whenever present, non-existent, O, S, N, NH, CT 10 are independently selected from, where T 10 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 10 ', where T 10 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 11 Whenever present, non-existent, O, S, N, NH, CT 11 are independently selected from, where T 11 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 11 ', where T 11 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 12 Whenever present, non-existent, O, S, N, NH, CT 12 are independently selected from, where T12 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 12 ', where T 12 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 13 Whenever present, non-existent, O, S, N, NH, CT 13 are independently selected from, where T 13 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 13 ', where T 13 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 14 Whenever present, non-existent, O, S, N, NH, CT 14 are independently selected from, where T 14 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 14 ', where T 14 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 10 , Y 11 , Y 12 , Y 13 and Y 14 one or more of which are linked to an L group, or Y 10 , Y 11 , Y 12 , Y 13 and Y 14any two adjacent groups together with the atoms to which they are attached form an optionally substituted aryl group or an optionally substituted heteroaryl group, and the optionally substituted aryl group or the optionally substituted heteroaryl group is linked to the L group via one or more bonds, and preferably the aryl group or the heteroaryl group is selected from a phenyl group, a naphthyl group, an anthracenyl group, an indenyl group, an indanyl group, a 1,2-dihydronaphthyl group, a 1,2,3,4-tetrahydronaphthyl group, a pyridyl group, a pyrimidinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a triazinyl group, and the substituents thereon are selected from absence, fluorine, chlorine, methyl group, CHF, CHF, CF, CHCl, CHCl, and methoxy group.

[0040] Preferably, D is selected from the following groups: [ka] [ka] [ka]

[0041] In a twenty-sixth aspect of the first embodiment, D is [ka] and where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; V is hydrogen or a methyl group; [ka] is an aromatic or heteroaromatic ring, Y 15Whenever present, non-existent, O, S, N, NH, CT 15 are independently selected from, where T 15 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 15 ', where T 15 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 16 Whenever present, non-existent, O, S, N, NH, CT 16 are independently selected from, where T 16 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 16 ', where T 16 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 17 Whenever present, non-existent, O, S, N, NH, CT 17 are independently selected from, where T 17 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 17 ', where T 17 ', each occurrence, is independently selected from absent, hydrogen, fluorine, chlorine, a methyl group, haloCH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, a methoxy group; Y 18 Whenever present, non-existent, O, S, N, NH, CT 18 are independently selected from, where T 18 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 18', where T 18 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 19 Whenever present, non-existent, O, S, N, NH, CT 19 are independently selected from, where T 19 is present whenever absent, hydrogen, fluorine, chlorine, methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, methoxy group, NT 19 ', where T 19 ', each occurrence, is independently selected from absence, hydrogen, fluorine, chlorine, a methyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, and a methoxy group; Y 15 , Y 16 , Y 17 , Y 18 and Y 19 one or more of which are linked to an L group, or Y 15 , Y 16 , Y 17 , Y 18 and Y 19 any two adjacent groups together with the atoms to which they are attached form an optionally substituted aryl group or an optionally substituted heteroaryl group, and the optionally substituted aryl group or the optionally substituted heteroaryl group is linked to the L group via one or more bonds, and preferably the aryl group or the heteroaryl group is selected from a phenyl group, a naphthyl group, an anthracenyl group, an indenyl group, an indanyl group, a 1,2-dihydronaphthyl group, a 1,2,3,4-tetrahydronaphthyl group, a pyridyl group, a pyrimidinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a triazinyl group, and the substituents thereon are selected from absence, fluorine, chlorine, methyl group, CHF, CHF, CF, CHCl, CHCl, and methoxy group.

[0042] Preferably, D is [ka] is.

[0043] In a twenty-seventh aspect of the first embodiment, D is [ka] and where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 41 Whenever exists, CT 41 or N, T 41 is, each occurrence, independently selected from absence, hydrogen, deuterium, and a methyl group; Y 42 Each occurrence of is CH2, CD2, CHD, C=O, C-CH3, or [ka] are independently selected from Y 43 Each occurrence of is CH2, CD2, CHD, C=O, C-CH3, or [ka] are independently selected from, or Y 42 -Y 43 is -CH=CH-, -CH=N- or -N=CH-, Y 5 Whenever there is a 5 are independently selected from, where T 5 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 6Whenever there is a 6 are independently selected from, where T 6 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 7 Whenever there is a 7 are independently selected from, where T 7 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 8 Whenever there is a 8 are independently selected from, where T 8 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 5 , Y 6 , Y 7 , and Y 8 One or more of are linked to the L group.

[0044] In a twenty-eighth aspect of the first embodiment, D is [ka] and where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 6 Whenever exists, CT 6 or N, Y 8 Whenever exists, CT 8 or N, T 6 , T 8each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; E 1 , E 2 and E 4 each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; E 1 , E 2 , Y 6 and Y 8 One or more of are linked to the L group.

[0045] Preferably, D is [ka] [ka] is.

[0046] In a twenty-ninth aspect of the first embodiment, D is [ka] and where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 6 Whenever exists, CT 6 or N, Y 8 Whenever exists, CT 8 or N, T 6 , T 8each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; E 5 , E 6 and E 8 each of which, whenever present, may be selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 alkylthio, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, —C0-C4 alkyl(C3-C7 cycloalkyl), —O—C0-C4 alkyl(C3-C7 cycloalkyl), C3-C 12 Heterocyclyl groups, C6-C 12Aryl groups and C5-C 10 heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, or C1-C6 alkyl groups; E 6 , E 8 , Y 6 and Y 8 One or more of are linked to the L group.

[0047] In a thirtieth aspect of the first embodiment, D is [ka] and where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 2 is, at each occurrence, independently selected from CH, CD, N, or oxygen; E 5 is, each occurrence, independently selected from absence, hydrogen, deuterium, or a methyl group; E 6 , E 7 , E 8 and E 9 each occurrence is independently selected from absence, hydrogen, deuterium, fluorine, chlorine, a methyl group, CHF, CHF, CF, a methoxy group, or a cyclopropyl group; E 6 , E 7 , E 8 and E 9 One or more of are linked to the L group.

[0048] Preferably, D is [ka] is.

[0049] In a thirty-first aspect of the first embodiment, D is [ka] and Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 10 Whenever there is a 10 are independently selected from, where T 10 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 11 Whenever there is a 11 are independently selected from, where T 11 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 12 Whenever there is a 12 are independently selected from, where T 12 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 13 Whenever there is a 13 are independently selected from, where T 13 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 14 Whenever there is a 14 are independently selected from, where T 14 is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, a methyl group, CHF, CHF, CF, CHCl, CHCl, CCl, and a methoxy group; Y 10 , Y 11 , Y 12, Y 13 and Y 14 One or more of are linked to the L group.

[0050] Preferably, D is selected from the following structures: [ka]

[0051] In a thirty-second aspect of the first embodiment, L is [ka] [ka] is selected from.

[0052] In a second embodiment, the present invention relates to formula (II): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0053] In a third embodiment, the present invention relates to formula (III): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0054] In a fourth embodiment, the present invention relates to formula (IV): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0055] In a fifth embodiment, the present invention relates to formula (V): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0056] In a sixth embodiment, the present invention relates to formula (VI): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0057] In a seventh embodiment, the present invention relates to formula (VIII): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0058] Preferably, X 15 -R 15 is CH, C or C-Cl, and X 14 -R 19 is CH, C or C-Cl, and X 13 -R 18 is CH, C or C-Cl, and X 12 -R 17 is CH, C or C—Cl, and / or X 11 -R 16 is CH, C, or C—Cl. More preferably, B 1 -R 6 is CH2, and / or B 2 -R 5 is NH, CH2 or N-CH3.

[0059] More preferably, Y 1 is CH or N. More preferably, Y 5 is CH or C, and Y 6 is CH or C, and Y 7 is CH or C, and / or Y 8 is CH or C. More preferably, Y41 is CH or N, and Y 42 is CH2 or ═O, and / or Y 43 is NH, CH2 or N-CH3.

[0060] In an eighth embodiment, the present invention relates to formula (IX): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0061] Preferably, X 15 -R 15 is CH, C or C-Cl, and X 14 -R 19 is CH, C or C-Cl, and X 13 -R 18 is CH, C or C-Cl, and X 12 -R 17 is CH, C or C—Cl, and / or X 11 -R 16 is CH, C, or C—Cl. More preferably, B 1 -R 6 is CH2, and / or B 2 -R 5 is NH, CH2 or N-CH3.

[0062] More preferably, Y 1 is CH or N. More preferably, Y 5 is CH or C, and Y 6 is CH or C, and Y 7 is CH or C, and / or Y 8 is CH or C. More preferably, Y 4 is CH2 or =O.

[0063] In a ninth embodiment, the present invention relates to formula (XIV): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0064] In a tenth embodiment, the present invention relates to formula (XV): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0065] In an eleventh embodiment, the present invention relates to formula (XVII): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0066] Preferably, X 8 -R 11 is CH and R 8 is Cl, and / or R 9 is Cl. More preferably, E 6 is H or absent, and / or E 8 is H or absent. More preferably, E 5 is H or -CH3. More preferably, Y 1 is CH. More preferably, Y 6 is CH or C, and Y 8 is CH or C.

[0067] In a twelfth embodiment, the present invention relates to formula (XVIII): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0068] Preferably, X 8 -R 11 is CH and R 8 is Cl, and / or R 9 is Cl. More preferably, E 1 is H, F or absent, and / or E 2 is H, F or absent. More preferably, E 4 is H or -CH3. More preferably, Y 1 is CH, CD or N. More preferably, Y 6 is CH or C, and / or Y 8 is CH, N or C.

[0069] In a thirteenth embodiment, the present invention relates to formula (XIX): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0070] Preferably, X 8 -R 11 is CH and R 8 is Cl, and / or R 9 is Cl. More preferably, J 1 is H or absent, and J 2 is H or absent, and J 3 is H or absent, and / or J 4 is H or absent. More preferably, Y 1 is CH. More preferably, Y 4 is CH2 or N-CH3.

[0071] In a fourteenth embodiment, the present invention relates to formula (XXIII): [ka]

[0072] In a fifteenth embodiment, the present invention relates to formula (XXIV): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0073] Preferably, R 4 is an allyl group, H or CH3. More preferably, R 21 is CH, C—CH3 or C—Cl, and / or R 22 is CH, C—CH3 or C—Cl.

[0074] More preferably, [ka] teeth, [ka] is selected from.

[0075] More preferably, E 1 is H, F or absent, and / or E 2 is H, F or absent. More preferably, E 4 is H or -CH3. More preferably, Y 1 is CH, CD or N. More preferably, Y 6 is CH or C, and / or Y 8 is CH, N or C. More preferably, R 2 is absent, H, F, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L group. More preferably, R 1is absent, H, F, chlorine, a methyl group, an ethyl group, a methoxy group, a hydroxymethyl group, or a linking L group.

[0076] In a sixteenth embodiment, the present invention relates to formula (XXV): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0077] In a seventeenth embodiment, the present invention relates to formula (XXVI): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0078] Preferably, X 8 -R 11 is CH and R 8 is Cl and R 9 is Cl. More preferably, Y 21 is NH, O or absent. More preferably, Y 10 is CH or C, and Y 12 is CH or C, and / or Y 13 is CH or C.

[0079] In an eighteenth embodiment, the present invention relates to formula (XXVII): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0080] Preferably, Y 21 is NH, O or absent. More preferably, Y 10 is CH or C, and Y 12 is CH or C, and / or Y13 is CH or C. More preferably, Y 1 is CH or N. More preferably, Y 10 is CH or C, and Y 12 is CH or C, and / or Y 13 is CH or C. More preferably, X 8 -R 11 is CH and R 8 is Cl and R 9 is Cl.

[0081] In a nineteenth embodiment, the present invention relates to formula (XXVIII): [ka] The remaining substituents are as defined in the first embodiment and any aspect thereof.

[0082] Preferably, R 4 is an allyl group, H or CH3. More preferably, Y 21 is NH, O or absent. More preferably, Y 10 is CH or C, and Y 12 is CH or C, and / or Y 13 is CH or C. More preferably, R 21 is CH, C—CH3 or C—Cl, and / or R 22 is CH, C—CH3 or C—Cl.

[0083] More preferably, [ka] teeth, [ka] is selected from.

[0084] In a twentieth embodiment, the present invention relates to formula (XXIX): [ka] where: [ka] represents =0 or absence, The group L is as defined in the first embodiment and any aspect thereof.

[0085] Preferably, [ka] teeth, [ka] is.

[0086] In a twenty-first embodiment, the present invention relates to formula (XXX): [ka] where: [ka] represents =0 or absence, The group L is as defined in the first embodiment and any aspect thereof.

[0087] Preferably, [ka] teeth, [ka] is.

[0088] In a twenty-second embodiment, the present invention relates to formula (XXXI): [ka] where: R 51 each occurrence is independently selected from F, Cl, or CF; The group L is as defined in the first embodiment and any aspect thereof.

[0089] In a twenty-third embodiment, the present invention relates to formula (XXXII): [ka] where: R 51 each occurrence is independently selected from F, Cl, or CF; The group L is as defined in the first embodiment and any aspect thereof.

[0090] In a twenty-fourth embodiment, the present invention relates to formula (XXXIII): [ka] where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; The group L is as defined in the first embodiment and any aspect thereof.

[0091] Preferably, [ka] teeth, [ka] is selected from.

[0092] In a 25th embodiment, the present invention relates to formula (XXXIV): [ka] where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; The group L is as defined in the first embodiment and any aspect thereof.

[0093] Preferably, [ka] teeth, [ka] is selected from.

[0094] In a twenty-sixth embodiment, the present invention relates to formula (XXXV): [ka] Preferably, [ka] teeth, [ka] is selected from.

[0095] In a 27th embodiment, the present invention relates to formula (XXXVI): [ka] The group L is as defined in the first embodiment and any aspect thereof.

[0096] Preferably, [ka] teeth, [ka] is selected from.

[0097] In a twenty-eighth embodiment, the present invention relates to a compound of formula (XXXXI), or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof, XXXXI: [ka] where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 21 each occurrence is independently selected from C, N, NH, N-CH3, N-C2H5, N-C3H7, and N-C4H9; Y 10 , Y 11 , Y 12 , Y 13 , Y 14 Each of N, CT, 101 are independently selected from, where T 101 each occurrence is independently selected from absence, hydrogen, fluorine, chlorine, methyl, CHF, CHF, CF, CHCl, CHCl, CCl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y 10 , Y 11 , Y 12 , Y 13 and Y 14 one of which is linked to the L group, Y 50 , Y 51 , Y 52 , Y 52 , Y 54 Each of N, CT, 102 are independently selected from, where T 102is, each occurrence, independently selected from: absence, hydrogen, fluorine, chlorine, methyl, CF3, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y 50 , Y 51 , Y 52 , Y 53 and Y 54 one of which is linked to the L group, R 4 Each occurrence of represents an allyl group, a propargyl group, a methylenecyclopropyl group, an ethyl group, a trifluoroethyl group, a difluoroethyl group, an isopropyl group, a cyclopropyl group, a methyleneC6-C 12 Aryl groups, methylenephenyl groups, optionally substituted C 1-4 Alkyl groups, optionally substituted C 2-4 Alkenyl groups, optionally substituted C 2-4 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups and optionally substituted C 3-6 Cycloalkyl(C 1-4 alkyl), wherein said C-C 12 Aryl group, C 1-4 Alkyl group, C 2-4 Alkenyl groups and C 2-4 The alkynyl group is substituted with halogen, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy group, cyano group, amino group, mono-C 1-4 Alkylamines and Di-C 1-4 alkylamines, and 3-6 Cycloalkyl groups and the C 3-6 Cycloalkyl(C 1-4 One or more rings of the alkyl group may contain halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4Halogenated alkoxy group, cyano group, amino group, mono-C 1-4 Alkylamines and Di-C 1-4 optionally substituted independently by one or more substituents selected from alkylamines; [ka] is non-existent, -(NR 81 )-N=, -(NR 82 )-(NR 83 )-, -(NR 84 )-(C=O)- or -(C=O)-(NR 85 )-, where R 81 , R 82 , R 83 , R 84 and R 85 each occurrence is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy; R 21 , R 22 each occurrence is independently selected from absent, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, wherein said alkyl, alkoxy groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, cyano, or amino groups, and preferably R 21 , R 22 each occurrence is independently selected from hydrogen, a 2-hydroxyisopropyl group, or R 21 , R 22 are joined together -(CR 91 R 92 )-(CR 93 R 94 )-(CR 95 R 96 )-, where R 91 , R 92 , R 93 , R94 , R 95 and R 96 Each occurrence of R is independently selected from hydrogen, hydroxyl, methyl, ethyl, and propyl, and more preferably, R 21 , R 22 are joined together -(CR 91 R 92 )-(CH2)-(CH2)- or -(CH2)-(CH2)-(CR 95 R 96 )-, where R 91 , R 92 , R 95 and R 96 each occurrence is independently selected from a hydroxyl group, a methyl group, an ethyl group, and a propyl group; L is a linker having the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] where: [ka] represents a bonding site, and the L group is optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C1-C6 alkyl groups.

[0098] In a second aspect of the twenty-eighth embodiment, said formula (XXXXI) is formula (XXXXII): XXXXII: [ka] where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 21 each occurrence is independently selected from NH, N-CH3, N-C2H5, N-C3H7, and N-C4H9; Y 10 , Y 11 , Y 12 , Y 13 , Y 14 Each of N, CT, 101 are independently selected from, where T 101 each occurrence is independently selected from absence, hydrogen, fluorine, chlorine, methyl, CHF, CHF, CF, CHCl, CHCl, CCl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y 10 , Y 11 , Y 12 , Y 13 and Y 14 one of which is linked to the L group, Y 50 , Y 51 , Y 52 , Y 52 , Y 54 Each of N, CT, 102 are independently selected from, where T 102each occurrence is independently selected from absence, hydrogen, fluorine, chlorine, methyl, CHF, CHF, CF, CHCl, CHCl, CCl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y 50 , Y 51 , Y 52 , Y 53 and Y 54 one or more of which are linked to the L group; R 4 each occurrence is independently selected from allyl, propargyl, methylenecyclopropyl, ethyl, trifluoroethyl, difluoroethyl, isopropyl, and cyclopropyl; R 21 , R 22 each occurrence is independently selected from hydrogen or a 2-hydroxyisopropyl group; or 21 , R 22 are joined together -(CR 91 R 92 )-(CH2)-(CH2)- or -(CH2)-(CH2)-(CR 95 R 96 )-, where R 91 , R 92 , R 95 and R 96 each occurrence is independently selected from hydrogen, hydroxyl, methyl, ethyl, and propyl; L is a linker having the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] where: [ka] represents a bonding site, and the L group is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, hydroxyl, nitro, cyano, amino, mercapto, —COOH, or a C1-C6 alkyl group.

[0099] In a third aspect of the twenty-eighth embodiment, formula (XXXXII) is formula (XXXXIII). XXXXIII: [ka]

[0100] In a fourth aspect of the twenty-eighth embodiment, said formula (XXXXI) is formula (XXXXIV): XXXXIV: [ka] where: Y 1 is, at each occurrence, independently selected from CH, CD, or N; Y 21 each occurrence is independently selected from C, CH, CD, and N; Y 10 , Y 11 , Y 12 , Y 13 , Y 14 Each of N, CT, 101 are independently selected from, where T 101each occurrence is independently selected from absence, hydrogen, fluorine, chlorine, methyl, CHF, CHF, CF, CHCl, CHCl, CCl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y 10 , Y 11 , Y 12 , Y 13 and Y 14 one of which is linked to the L group, Y 50 , Y 51 , Y 52 , Y 52 , Y 54 Each of N, CT, 102 are independently selected from, where T 102 each occurrence is independently selected from absence, hydrogen, fluorine, chlorine, methyl, CHF, CHF, CF, CHCl, CHCl, CCl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y 50 , Y 51 , Y 52 , Y 53 and Y 54 one or more of which are linked to the L group; Y 62 each occurrence is independently selected from N, NH, —(C═O)—, or —CH—; R 70 each occurrence is independently selected from hydrogen, methyl, ethyl, or propyl; [ka] represents a single bond or a double bond, R 4each occurrence is independently selected from allyl, propargyl, methylenecyclopropyl, ethyl, trifluoroethyl, difluoroethyl, isopropyl, and cyclopropyl; R 21 , R 22 each occurrence is independently selected from hydrogen or a 2-hydroxyisopropyl group; or 21 , R 22 are joined together -(CR 91 R 92 )-(CH2)-(CH2)- or -(CH2)-(CH2)-(CR 95 R 976 )-, where R 91 , R 92 , R 95 and R 96 each occurrence is independently selected from hydrogen, hydroxyl, methyl, ethyl, and propyl; L is a linker having the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] where: [ka] represents a bonding site, and the L group is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, hydroxyl, nitro, cyano, amino, mercapto, —COOH, or a C1-C6 alkyl group.

[0101] In a fifth aspect of the twenty-eighth embodiment, said formula (XXXXIV) is formula (XXXXV) or formula (XXXXVI). [ka] or [ka]

[0102] In a twenty-ninth embodiment, the present invention relates to a compound represented by structural formula (XXXXVII), or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof, [ka] where: Y 10 , Y 11 , Y 12 , Y 13 , Y 14 Each of N, CT, 101 are independently selected from, where T 101 each occurrence is independently selected from absent, hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a hydroxyl group, and a cyano group; Y 10 , Y 11 , Y 12 , Y 13 and Y 14 one of which is linked to the L group, Y 50 , Y 51 , Y 52 , Y 52 , Y 54 Each of N, CT, 102are independently selected from, where T 102 each occurrence is independently selected from absent, hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a hydroxyl group, and a cyano group; Y 50 , Y 51 , Y 52 , Y 53 and Y 54 one or more of which are linked to the L group; R 4 Each occurrence of represents an allyl group, a propargyl group, a methylenecyclopropyl group, an ethyl group, a trifluoroethyl group, a difluoroethyl group, an isopropyl group, a cyclopropyl group, a methyleneC6-C 12 Aryl groups, methylenephenyl groups, optionally substituted C 1-4 Alkyl groups, optionally substituted C 2-4 Alkenyl groups, optionally substituted C 2-4 Alkynyl group, optionally substituted C 3-6 Cycloalkyl groups and optionally substituted C 3-6 Cycloalkyl(C 1-4 alkyl), wherein said C-C 12 Aryl group, C 1-4 Alkyl group, C 2-4 Alkenyl groups and C 2-4 The alkynyl group is substituted with halogen, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy group, cyano group, amino group, mono-C 1-4 Alkylamines and Di-C 1-4 alkylamines, and 3-6 Cycloalkyl groups and the C 3-6 Cycloalkyl(C 1-4 One or more rings of the alkyl group may contain halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4Halogenated alkoxy group, cyano group, amino group, mono-C 1-4 Alkylamines and Di-C 1-4 optionally substituted independently by one or more substituents selected from alkylamines; Y 61 each occurrence is independently selected from CH, NH, and N(C-C alkyl); R 21 , R 22 each occurrence is independently selected from absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, and a C1-C6 alkoxy group, wherein said alkyl, alkenyl, alkynyl, and alkoxy groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, or -COOH; or R 21 , R 22 are joined together -(CR 91 R 92 )-(CR 93 R 94 )-(CR 95 R 96 )-, where R 91 , R 92 , R 93 , R 94 , R 95 and R 96 each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, -COOH, a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, and a C1-C6 alkoxy group, wherein said alkyl, alkenyl, alkynyl, and alkoxy groups are optionally substituted with 1, 2, 3, or 4 halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, or -COOH; L is a linker having the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] where: [ka] represents a bonding site, and the L group is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, hydroxyl, nitro, cyano, amino, mercapto, —COOH, or a C1-C6 alkyl group.

[0103] The structure "-L-" does not imply that L must be connected to W and / or D through a single bond. In each aspect of each embodiment of the present application, the connection of L to W and / or D can be achieved through one or more bonds.

[0104] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glycolate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. Pharmaceutically acceptable salts may contain another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt may have multiple charged atoms in its structure. Examples in which multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0105] If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, or the like; or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl acids such as glucuronic acid or galacturonic acid, α-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, or sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid.

[0106] If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonium, primary, secondary, and tertiary amines, cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0107] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0108] The compounds of the present application can exist in various stereoisomeric forms. The term "stereoisomers" refers to compounds that have the same chemical structure and bonding but differ in the orientation of their atoms in space and are not interconvertible by rotation about a single bond. "Stereoisomers" can include "diastereomers" and "enantiomers." "Diastereomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another. "R" and "S" refer to the substituent configurations surrounding one or more chiral atoms. The compounds of the present application can be prepared as individual isomers by chiral synthesis or resolution from a mixture of isomers. The disclosed compounds can have one or more stereocenters, and each stereocenter can independently exist in the R or S configuration. If the absolute stereochemistry of a stereocenter has not been determined, the stereochemical configuration can be assigned as (*) at the designated center. In one embodiment, the compounds described herein exist in optically active or racemic form. It is understood that the compounds described herein include racemic, optically active, regioisomeric and stereoisomeric forms or combinations thereof that have the therapeutically useful properties described herein. The chiral atoms described herein can be chiral carbon atoms, chiral nitrogen atoms or chiral phosphorus atoms.

[0109] Specifically, the compounds disclosed herein may have one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. If the absolute stereochemistry of a stereocenter cannot be determined, the stereochemical configuration may be marked with an "*" at that center, but the compound itself may be isolated as a single stereoisomer and be enantiomerically pure (diastereomerically). In other words, in some embodiments, the asterisk "*" indicates that the chiral atom is essentially in a single configuration, and its absolute stereochemistry is not specified (even if the bond is depicted in the stereochemical form). The actual absolute configuration of the atom marked with an "*" may be the same or a different configuration from the depicted stereochemical form. In other words, the atom marked with an "*" may be in either the absolute R or S configuration. The term "essentially" refers to variations that deviate from the standard by 5%, 2%, 1%, or even 0.1%. The term "single configuration" may be in either a single R or S configuration.

[0110] In some other embodiments, a stereocenter is designated "*R" or "*S". When a stereocenter is designated "*R" or "*S", this means that the absolute stereochemical nature of the stereocenter is uncertain, despite essentially having a single configuration (even though the bonds are drawn in the stereochemical form). The actual absolute configuration of an atom designated "*R" can be the same or a different configuration as the stereochemical form depicted, and the actual absolute configuration of an atom designated "*S" can be the same or a different configuration as the stereochemical form depicted. In other words, "*R" can be the absolute R configuration or the absolute S configuration. Similarly, "*S" can be the absolute R configuration or the absolute S configuration. "*R" or "*S" can be randomly assigned to the molecule. A stereocenter designated "*R" can have the same or a different single configuration as another stereocenter designated "*S". A stereocenter designated "*R" can have the same or a different single configuration as another stereocenter designated "*R". A stereocenter marked "*S" can have a single configuration that is the same as or different from another stereocenter marked "*S".

[0111] Similarly, a stereocenter designated "*R" can have a single configuration that is the same as or different from another stereocenter designated "X". A stereocenter designated "*S" can have a single configuration that is the same as or different from another stereocenter designated "X".

[0112] For example, the absolute configuration of compound 152-A is one of the following: [ka]

[0113] In one embodiment, the compounds described herein contain one or more chiral centers. These compounds can be prepared by any method, including stereoselective synthesis, enantiomerically selective synthesis, or separation of a mixture of enantiomers or diastereomers. Resolution of the compounds and their isomers can be achieved by any method, including, but not limited to, chemical processes, enzymatic processes, stepwise crystallization, distillation, and chromatography. DETAILED DESCRIPTION OF THE INVENTION

[0114] definition The term "substituted" refers to the replacement of any one or more hydrogens on the specified atom or group with a member selected from the specified group, provided that the normal valence of the specified atom is not exceeded.

[0115] An "alkyl group" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one embodiment, an alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl group is C1-C2, C1-C3, or C1-C6. As used herein, a specified range means that each member of the range functions as an independent type of alkyl group. For example, as used herein, the term C1-C6 alkyl group refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be an independent species. For example, as used herein, the term C1-C4 alkyl group refers to a straight or branched chain alkyl group having 1, 2, 3, or 4 carbon atoms, each of which is intended to be an independent species. C0-C n When an alkyl group is bonded to another group herein, for example, a (C3-C7 cycloalkyl)C0-C4 alkyl group or —C0-C4 alkyl(C3-C7 cycloalkyl group), it is either bonded directly to the specified group—the cycloalkyl group in this case, or through a single covalent bond (C0 alkyl group)—or through an alkyl group chain (in this case, 1, 2, 3, or 4 carbon atoms). The alkyl group may also be bonded through other groups, such as a heteroatom, for example, —O—C0-C4 alkyl(C3-C7 cycloalkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In one embodiment, the alkyl group is optionally substituted as described above.

[0116] An "alkenyl group" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which can occur at any stable point along the chain. Non-limiting examples include C2-C8 alkenyl groups, C2-C6 alkenyl groups, and C2-C4 alkenyl groups. As used herein, a specified range refers to a range as described above for the alkyl group moiety, with each member of the range being an independent type of alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl and propenyl groups. In one embodiment, an alkenyl group is optionally substituted as described above.

[0117] An "alkynyl group" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which can occur at any stable point along the chain, e.g., a C2-C8 alkynyl group or a C2-C6 alkynyl group. As used herein, a specified range refers to a range, as described above for the alkyl group moiety, with each member of the range representing an independent type of alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentyl, 2-pentyl, 3-pentyl, 4-pentyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl groups. In one embodiment, an alkynyl group is optionally substituted as described above.

[0118] An "alkoxy group" is an alkyl group as defined above covalently bonded through an oxygen bridge (-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentoxy. Similarly, an "alkylthio group" or "thioalkyl group" is an alkyl group as defined above with the specified number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, an alkoxy group is optionally substituted as defined above.

[0119] An "alkenyloxy group" is an alkenyl group as defined above covalently attached to its substituent via an oxygen bridge (-O-).

[0120] An "alkanoyl group" is an alkyl group as described above covalently bonded through a carbonyl (C=O) bridge. The carbonyl carbon is included in the carbon number; i.e., a C2 alkanoyl group is CH3(C=O)-yl. In one embodiment, the alkanoyl group is optionally substituted as described above.

[0121] An "alkyl ester" is an alkyl group, as described herein, covalently attached via an ester bond. The ester bond can be in any orientation, such as a group of the formula -O(C=O)alkyl or a group of the formula -(C=O)Oalkyl.

[0122] A "carbocyclic group," "carbocyclic ring," or "cycloalkyl group" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. A carbocyclic group typically contains one ring containing 3 to 7 carbon atoms or two fused rings containing 3 to 7 carbon atoms. The cycloalkyl group substituent may be a self-substituted nitrogen or carbon atom pendant group, or two optionally substituted carbon atoms may have a cycloalkyl group attached as a spirocyclic group. Examples of carbocyclic rings include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbocyclic ring is optionally substituted as described above. In one embodiment, a cycloalkyl group is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms.

[0123] A "carbocyclic-oxy ​​group" is a monocyclic carbocyclic or mono- or di-cyclic carbocyclic group as defined above attached to its substituent through an oxygen-O-linking group.

[0124] "Halogenated alkyl group" refers to branched and straight chain alkyl groups substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl groups. "Halogenated alkoxy group" refers to an oxygen bridge (an acid of an alcohol atom group)

[0125] refers to a halogenated alkyl group, as described herein, attached by a halogen atom. A "hydroxyalkyl group" is an alkyl group as defined above that is substituted with at least one hydroxy substituent.

[0126] An "aminoalkyl group" is an alkyl group as defined above that is substituted with at least one amino substituent. "Halogen" refers independently to any of fluorine, chlorine, bromine and iodine.

[0127] An "aryl group" refers to an aromatic ring or an aromatic group containing only carbon atoms in the ring. In one embodiment, an aryl group contains 1 to 3 single or fused rings, has 6 to 18 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) ring atoms, and has no heteroatoms as ring members. Where indicated, such aryl groups can be substituted with carbon or non-carbon atoms or groups. Such substitutions include fused to a 5- to 7-membered saturated ring group containing one or two heteroatoms independently selected from N, O, and S, forming, for example, 3,4-methylenedioxyphenyl. Aryl groups include phenyl and naphthyl groups, including 1-naphthyl and 2-naphthyl groups. In one embodiment, the aryl group is a side group. An example of a side ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above. Aryl groups include bicyclic groups containing a saturated, partially unsaturated ring or an aromatic ring fused to an aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Preferably, the aryl group is a phenyl group.

[0128] As used herein, the term "heterocycle" refers to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds without directionality within the ring) carbocyclic group having 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) ring atoms, where at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are C, and where one or more ring atoms are optionally independently substituted with one or more of the substituents described above. A heterocycle can be monocyclic having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or bicyclic having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), e.g., a bicyclic [4,5], [5,5], [5,6], or [6,6] system. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Heterocycles are described in Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to date), especially Chapters 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82:5566.Examples of heterocycles include pyrrolidine group, dihydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, dihydropyranyl group, tetrahydrothiuranyl group, piperidinyl group, piperidinone group, morpholinyl group, thiomorpholinyl group, thioxanyl group, piperazinyl group, higher piperazinyl group, azoheterocyclobutyl group, oxetanyl group, thioheterocyclobutyl group, higher piperidinyl group, oxepanyl group, thiepanyl group, oxazepinyl group, diazepinyl group, thiazepinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, dihydroindolyl group, 2H-pyranyl group, 4H-pyranyl group, dioxoheterocyclohexyl group, 1,3-dioxoheterocyclo Pentyl group, pyrazolinyl group, dithioalkyl group, dithiopentane ring group, dihydropyranyl group, dihydrothienyl group, dihydrofuryl group, dihydroisoquinolyl group, tetrahydroisoquinolyl group, pyrazolyleneimidazoline group, imidazolidinyl group, 2-oxo-5-azabicyclo[2.2.2]octane, 3-oxo-8-azabicyclo[3.2.1]octane, 8-oxo-3-azabicyclo[3. Examples of heterocyclyl groups include, but are not limited to, 2.1]octane, 6-oxo-3-azabicyclo[3.1.1]heptane, 2-oxo-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexaalkyl, 3-azabicyclo[4.1.0]heptaalkyl, azabicyclo[2.2.2]hexaalkyl, 3H-indolyl, quinoazinyl, N-pyridinyl urea, and pyropyridine. Spiro moieties are also included within the scope of this definition. Here, examples of heterocyclyl groups in which one or two ring carbon atoms are replaced by an oxo (=O) moiety include pyrimidine ketone and 1,1-dioxo-thiomorpholinyl. Heterocyclyl groups herein are optionally substituted independently with one or more substituents described herein. The term "heterocyclyl group" encompasses "heterocyclic alkyl groups." "Heterocyclic alkyl groups" are saturated ring groups. They can have, for example, 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, with the remaining ring atoms being carbon.In a typical embodiment, nitrogen is the heteroatom. Monocyclic heterocyclic alkyl groups typically have 3 to about 8 ring atoms, or 4 to 6 ring atoms. Examples of heterocyclic alkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl groups. A "heterocyclyl group" can contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.

[0129] "Heterocyclicoxy" is a monocyclic or bicyclic heterocyclic group, as defined above, attached to its substituent through an oxygen-O-linking group.

[0130] The term "heteroaryl group" refers to a stable monocyclic aromatic ring containing one to three, or in some embodiments one to two, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, or at least one stable bicyclic or tricyclic ring system containing a 5- to 10-membered (5, 6, 7, 8, 9, 10-membered) aromatic ring containing one to three, or in some embodiments one to two, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have five to eight ring atoms (5, 6, 7, 8). In some embodiments, dicycloheteroaryl groups are 9- to 10-membered heteroaryl groups, i.e., groups containing nine or ten ring atoms, in which one 5- to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In one embodiment, the total number of S and O atoms in the heteroaryl group does not exceed 1. In another embodiment, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyridyl groups (e.g., 2-hydroxypyridyl groups), furyl groups, imidazolyl groups, imidazopyridinyl groups, pyrimidinyl groups (including, e.g., 4-hydroxypyrimidinyl groups), pyrazolyl groups, triazolyl groups, pyrazinyl groups, tetrazolyl groups, furyl groups, thienyl groups, isoxazolyl groups, thiazolyl groups, oxadiazolyl groups, oxazolyl groups, isothiazolyl groups, pyrrolyl groups, quinolyl groups, isoquinolyl groups, tetrahydroisoquinolyl groups, indolyl groups, and benzoyl groups. These include, but are not limited to, midazolyl, benzofuryl, quinolyl, imidazolyl, indazinyl, phthalazine, pyridazine, triazinyl, isoindolyl, pyridyl, purine, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furanyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxazolyl, naphthalidinyl, tetrahydrofuryl, and furylpyridyl groups.Heteroaryl groups are optionally substituted independently with one or more substituents described herein. A "heterocyclooxy" is a heteroaryl group as defined above substituted with an oxygen-O-linked group. A "heteroaryl group" can contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.

[0131] In this specification, [ka] can represent binding sites through a selection from undefined connection methods.

[0132] This application includes bicyclic, tricyclic, tetracyclic, pentacyclic, etc. polycyclic ring systems formed where chemical bonds are permitted from one or more monocyclic rings selected from "cycloalkyl groups," "aryl groups," and "heteroaryl groups." A cyano group refers to -CN; The term CD refers to deuterated carbon.

[0133] The compounds described herein or pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes, or prodrugs thereof can be used to treat proliferative diseases. The present application further provides the use of the compounds described herein or pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes, or prodrugs thereof in a medicament for treating a proliferative disease. The present invention further provides the above compounds or pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes, or prodrugs thereof for use in treating a proliferative disease. The present application further provides a method for treating a proliferative disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof.

[0134] The term "proliferative disorder" or "cell proliferative disorder" refers to a disorder associated with some degree of abnormal cell proliferation, whether malignant or benign. In some embodiments, the proliferative disorder is cancer. In some aspects, the cancer is a solid tumor. In some aspects, the cancer is a hematological malignancy. The terms "proliferative disorder," "cell proliferative disorder," "cancer," "cancerous," and "tumor" are not mutually exclusive when referred to in this application.

[0135] The term "cancer" includes cancer cells and / or benign or pre-cancerous cells. Exemplary cancers include breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neurocytoma, cancers of the lymphoid organs, and myeloid malignancies including leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL)). HCL), T-cell prolymphocytic leukemia (T-PLL), giant lymphocytic leukemia, adult T-cell leukemia), lymphomas (small lymphocytic lymphoma (SLL), Hodgkin's lymphoma (nodular sclerosis, mixed cytology, lymphocyte-rich, lymphopenic or non-reduced and nodular lymphocyte-predominant Hodgkin's lymphoma), non-Hodgkin's lymphoma (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic leukemia (e.g., Waldenstrom's macroglobulinemia) , splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition disease, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), nodal marginal zone B-cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell giant lymphocytic leukemia, malignant Cancers include, but are not limited to, primary NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous NK-cell lymphoma, mycosis fungoides / Sézary syndrome, primary intracutaneous CD30-positive T-cell lymphoproliferative disorder, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (nonspecific), anaplastic large cell lymphoma, and multiple myeloma (plasma cell myeloma or Kahler's disease). The term "cancer" further includes leukemia, carcinoma, and sarcoma.Exemplary cancers include brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, and adult neurocytoma. Other examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, essential microplateletemia, primary macroglobulinemia, primary brain tumors, carcinoma, malignant pancreatic islet tumors, malignant carcinoid tumors, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine and exocrine tumors, and prostate cancer. The term cancer further includes leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal carcinoma, pharyngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, etc.

[0136] As used herein, a "linking L group" refers to a group where the L group is linked to the moiety represented by the corresponding variable (e.g., a moiety on a ring, e.g., R 1 or R 2 Benzene ring atom bonded to Y 5 , Y 6 , or Y 8 itself, etc., or R 1 and / or R 2 itself), in which case the corresponding variable may or may not be present.

[0137] In a preferred embodiment, the present application relates to the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), malignant melanoma, gastric cancer, gliomas, ovarian carcinoma, uterine serous carcinoma (USC), colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, glioblastoma, non-small-cell lung cancer, and the like. This information relates to diseases such as non-small-cell lung cancer (NSCLC), small-cell lung cancer (NSCLC), neuroblastoma, breast cancer, triple negative breast cancer (TNBC), neuroblastoma, and head and neck squamous cell carcinoma (HNSCC).

[0138] The present application further provides a pharmaceutical composition comprising a compound described herein, or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition described herein can be in the form of a tablet, capsule, granule, syrup, suspension, solution, dispersion, sustained release formulation for oral or parenteral administration, intravenous injection formulation, subcutaneous injection formulation, inhalation formulation, transdermal administration formulation, rectal or vaginal suppository.

[0139] The pharmaceutically acceptable carriers referred to in this application refer to pharmaceutically acceptable carriers well known to those skilled in the art, and include, but are not limited to, fillers, wetting agents, adhesives, disintegrants, lubricants, binders, glidants, masking agents, surfactants, preservatives, etc. Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, etc. Wetting agents and adhesives include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, etc. Disintegrants include, but are not limited to, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, etc. Lubricants include, but are not limited to, magnesium stearate, finely divided silica gel, talc powder, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl alcohol sulfate, etc. Binders include, but are not limited to, gum arabic, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, glucose binder, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, maltose dextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, sorbitol, starch, syrup, and xanthan gum. Glidants include, but are not limited to, colloidal silica, powdered cellulose, magnesium trisilicate, silica, and talc powder. Masking agents include, but are not limited to, aspartame, stearic acid, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, and glycyrrhetin. Surfactants include, but are not limited to, Twain-80 and poloxamer. Preservatives include, but are not limited to, nipoxyl esters, sodium benzoate, potassium sorbate, and the like.

[0140] Methods for preparing various pharmaceutical compositions containing various ratios of active ingredients are known or will be apparent to one skilled in the art in light of the disclosures herein. For example, they are described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995). Methods for preparing the pharmaceutical compositions include incorporating appropriate pharmaceutical excipients, carriers, diluents, etc. The pharmaceutical compositions described herein are prepared by known methods, including conventional mixing, dissolving, or lyophilizing methods.

[0141] In the pharmaceutical compositions described herein, the percentage of the active ingredient may vary and may comprise from about 0.01% to about 99% of the weight of a given unit dosage form. In the formulation of such therapeutically useful pharmaceutical compositions, the amount of the active ingredient is such that an effective dosage level can be obtained.

[0142] The tablets, capsules, etc. described in this application may contain adhesives such as xanthan gum, gum arabic, corn starch, or gelatin; excipients such as dicalcium hydrogen phosphate; disintegrating agents such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, fructose, lactose, or aspartame; and flavorings such as mint, wintergreen oil, or cherry flavor. When the unit dosage form is a capsule, in addition to the above-mentioned types of materials, a liquid carrier such as vegetable oil or polyethylene glycol may be included. Various other materials may be present as coatings or to modify the physical form of the solid unit dosage form. For example, tablets or capsules may be coated with gelatin, wax, shellac, or sugar. Syrups may contain sucrose or fructose as a sweetener, methylparaben or propylparaben as a preservative, and dyes and flavorings (e.g., cherry flavor or orange flavor). Of course, any material for preparing any unit dosage form should be pharmaceutically acceptable and non-toxic in the amounts applied. Moreover, the active ingredient can be incorporated into sustained-release preparations and devices.

[0143] The active ingredient can also be administered intravenously or intraperitoneally by infusion or injection.Aqueous solutions of the active ingredient or its salts can be prepared, optionally mixed with a non-toxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, glycerol triacetate and mixtures thereof, and oils.Under normal storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0144] Pharmaceutical compositions suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation as sterile injectable or injectable solutions or dispersions. In all cases, the final dosage form must be sterile, fluid, and stable under the conditions of production and storage. Liquid carriers can be solvents or liquid dispersion media containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersions, or by the use of surfactants. Prevention of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, it is preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using absorption delaying agents in the compositions (e.g., aluminum monostearate and gelatin).

[0145] Sterile injectable solutions can be prepared by combining the required amount of the active ingredient in an appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional required ingredients present in sterile-filtered solution.

[0146] Useful solid carriers include pulverized solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.). Useful liquid carriers include water, ethanol, or ethylene glycol, or a mixture of water-ethanol / ethylene glycol, in which the pharmaceutical compositions of the present application can be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant. Adjuvants (e.g., flavorings) and additional antimicrobial agents may be added to optimize the properties for a particular use.

[0147] Thickening agents (e.g., synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) may also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, etc., for application directly to the user's skin.

[0148] The therapeutically effective amount of active ingredient will ultimately depend on the attending physician or clinician's decision, depending on the particular salt selected, as well as the method of administration, the nature of the disease being treated, and the age and condition of the patient.

[0149] The above-mentioned preparations can be in unit dosage form, which is a physically discrete unit containing a unit dose suitable for administration to humans and other mammalian subjects. The unit dosage form can be a capsule or tablet. Depending on the specific treatment involved, the amount of active ingredient per unit dose can be varied or adjusted from about 0.01 to about 1000 mg or more.

[0150] The term "treatment," as used herein, generally refers to obtaining a desired pharmacological and / or physiological effect. The effect may be preventative, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that a disease and / or its side effects are partially or completely stabilized or cured. As used herein, "treatment" includes any treatment of a patient's illness, including (a) preventing a disease or condition in a patient who is susceptible to the disease or condition but has not yet been diagnosed with the disease, (b) inhibiting the symptoms of the disease, i.e., preventing its onset, or (c) alleviating the symptoms of the disease, i.e., causing the disease or condition to regress.

[0151] The compounds described herein or their pharmaceutically acceptable salts, isomers, solvates, hydrates, adducts, complexes, or prodrugs may also be administered in combination with one or more additional therapeutic agents used to treat cancer, including, but not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, cisplatin, and the like.

[0152] Unless otherwise stated, all percentages, ratios, proportions or parts used in this application are by weight or volume. The amounts used in this application are by weight or volume and can be readily determined by one of ordinary skill in the art.

[0153] In another aspect of this application, this application further includes compounds obtained by combining any of the groups defined in any variable group of this application, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof.

[0154] The present application further includes the following exemplary compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0155] Hereinafter, the present application will explain the beneficial effects of the present application through examples. Those skilled in the art will recognize that these examples are illustrative and not limiting. These examples do not limit the scope of the present application in any way. The experimental methods described in the following examples are conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

[0156] The following synthetic routes illustrate the preparation of compounds of the general formula of the present invention, and all final compounds of the present invention are prepared by methods described in these routes or analogous methods, which are well known to those skilled in the art of organic chemistry. All variables applied in these routes are as defined in the claims.

[0157] Route 1-1: [ka] As illustrated in the above pathway, intermediate amine A1-1 and intermediate aldehyde A2-1 are reacted by reductive amination to give the example compound, where the reductive amination conditions are common reductive amination conditions, including but not limited to, conditions such as sodium cyanoborohydride, acetic acid, and dichloromethane. X represents a carbon atom or a nitrogen atom, and the wavy line represents the connection of the reactive functional group to other fragments of the compound.

[0158] Route 1-2: [ka] As illustrated in the above pathway, intermediate amine A1-1 and intermediate ketone A2-2 are reacted by reductive amination to give the embodiment compound, where the reductive amination conditions are common reductive amination conditions including, but not limited to, conditions such as sodium cyanoborohydride, sodium triacetylborohydride, sodium borohydride, etc. X represents a carbon atom or a nitrogen atom, and the wavy line represents the connection of the reactive functional group to other fragments of the compound.

[0159] Route 1-3: [ka] As illustrated in the above pathway, intermediate aldehyde A1-3 and intermediate amine A2-3 are reacted by reductive amination to give the embodiment compound, where the reductive amination conditions are common reductive amination conditions including, but not limited to, conditions such as sodium cyanoborohydride, sodium triacetylborohydride, sodium borohydride, etc. X represents a carbon atom or a nitrogen atom, and the wavy line represents the connection of the reactive functional group to other fragments of the compound.

[0160] Routes 1-4: [ka] As illustrated in the above pathway, intermediate ketone A1-4 and intermediate amine A2-4 are reacted by reductive amination to give the example compounds, and the reductive amination conditions are common reductive amination conditions, including but not limited to conditions such as sodium cyanoborohydride, sodium triacetylborohydride, sodium borohydride, etc. X represents a carbon atom or a nitrogen atom, and the wavy line represents the connection of the reactive functional group to other fragments of the compound.

[0161] Route 2-1: [ka] As illustrated in the above pathway, intermediate amine B1-1 reacts with bromide B2-1 by nucleophilic substitution in the presence of an organic base such as diisopropylethylamine, triethylamine, or other inorganic bases such as potassium carbonate, cesium carbonate, etc., and an organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, etc., to give the compound of interest. The wavy line represents the connection of the reactive functional group to another fragment of the compound.

[0162] Route 2-2: [ka] As illustrated in the above pathway, intermediate amine B1-2 is reacted with fluoride B2-2 via SNAr substitution in the presence of an organic base such as diisopropylethylamine or triethylamine, or other inorganic bases such as potassium carbonate or cesium carbonate, and an organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or tetrahydrofuran to give the compound of interest. The wavy line represents the connection of the reactive functional group to another fragment of the compound.

[0163] Route 3-1: [ka] As illustrated in the above pathway, intermediate C1-1 reacts with intermediate amine C2-1 by nucleophilic substitution in the presence of an organic base such as diisopropylethylamine, triethylamine, or other inorganic bases such as potassium carbonate, cesium carbonate, etc., and an organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, etc., to give the compound of interest. The wavy line represents the connection of the reactive functional group to other fragments of the compound.

[0164] Route 3-2: [ka] As illustrated in the above pathway, intermediate A1-1 reacts with intermediate amine C2-2 by nucleophilic substitution in the presence of an organic base such as diisopropylethylamine, triethylamine, or other inorganic bases such as potassium carbonate, cesium carbonate, etc., and an organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, etc., to give the example compound. The wavy line represents the connection of the reactive functional group to another fragment of the compound.

[0165] Route 4-1: [ka] As illustrated in the above pathway, intermediates D1-1 and D2-1 are first oxidized via p-methylperoxybenzoic acid to form a leaving group methanesulfonyl group, followed by nucleophilic substitution in the presence of an organic base such as diisopropylethylamine or triethylamine, or other inorganic bases such as potassium carbonate or cesium carbonate, and an organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, or toluene to obtain the compound. The wavy line represents the connection between the reactive functional group and other fragments of the compound. The linker represents a linker.

[0166] Working Example: The compounds of the present application can be synthesized by the general synthetic methods exemplified below or by similar methods. Where chemical valence permits, the various intermediate compounds can bear various substituents as described in this application. List of Abbreviations [Table 1-1] [Table 1-2] [Table 1-3]

[0167] Intermediates B1 and B2 Synthesis of: [ka]

[0168] Step 1: Synthesis of Compound Intermediate B1-3 To a solution of intermediate B1-1 (8.85 g, 41.49 mmol) in N,N-dimethylformamide (80 mL) was added 60% sodium bicarbonate (2.83 g, 70.79 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and then a solution of intermediate B1-2 (7.8 g, 41.49 mmol) in N,N-dimethylformamide (20 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into ice water (50 mL) and extracted with two 60 mL portions of methyl tert-ether. The aqueous phase was adjusted to pH 4-5 with 1N hydrochloric acid and extracted with two 100 mL portions of ethyl acetate. The organic phase was washed with two 60 mL portions of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product is added with methanol (10 mL), stirred for 15 minutes, and filtered to give a white solid intermediate B1-3 (9.8 g, yield: 66.50%). 1 H NMR(400MHz,DMSO-d6)δ 12.91(s,1H),8.98(s,1H),7.67(d,J=8.0Hz,2H),7.55-7.50(m,1H),2.57(s,3H)

[0169] Step 2: Synthesis of intermediate B1-4 Intermediate B1-3 (14.6 g, 41.10 mmol), phosphorus oxychloride (82.50 g, 538.05 mmol, 50 mL), and N,N-diisopropylethylamine (55 mL) were stirred at 90 °C for 3 hours. The solvent was removed from the reaction by evaporation under reduced pressure. The residue was treated with saturated sodium bicarbonate solution (500 mL) and extracted with three 300 mL portions of ethyl acetate. The combined organic solvents were washed with three 300 mL portions of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give a yellow solid, Intermediate B1-4 (15.3 g, crude product), which was used directly in the next step.

[0170] Step 3: Synthesis of Compound Intermediate B1-6 A solution of intermediate B1-4 (15.3 g, 40.95 mmol) and intermediate B1-5 (8.61 g, 81.90 mmol, 8.92 mL) in acetonitrile (150 mL) was purged with nitrogen gas three times and stirred at 80 °C for 1 hour under nitrogen gas protection. The reaction solution was spin-dried to obtain a crude product. Petroleum ether / ethyl acetate / dichloromethane (3 / 1 / 0.2, 50 mL) was added to the crude product and stirred for 1 hour. The filter cake was filtered to obtain white solid intermediate B1-6 (8.2 g, yield: 32.60%). The filtrate was separated and purified by chromatography column (petroleum ether / ethyl acetate = 1 / 1) to obtain pale yellow solid intermediate B1-6 (3.2 g, yield: 17.67%). MS(ESI+): m / z 441.95[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.92(s,1H),7.80-7.75(m,2H),7.71-7.64(m,2H),4.58(t,J=5.4Hz,1H),3.47-3.41(m,2H),3.33-3.27(m,6H),2.58(s,3H).

[0171] Step 4: Synthesis of Compound Intermediate B1 Intermediate B1-6 (700 mg, 1.58 mmol) and concentrated hydrochloric acid (12 M, 132 μL) were added to a microwave tube, and acetonitrile (6 mL) was added. The reaction was heated to 160° C. in a microwave and stirred for 15 minutes. Ethyl acetate (15 mL) was added to the reaction, stirred for 15 minutes, and filtered to give the crude product. The mother liquor was washed with two 10 mL portions of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and spun to give brown solid Intermediate B1 (580 mg, crude product), which was used directly in the next step.

[0172] Step 5: Synthesis of intermediate B2-1, Metachloroperbenzoic acid (268 mg, 1.32 mmol, 85% purity) and Intermediate B1 (200 mg, 529 μmol) are added to dichloromethane (5 mL). The reaction is stirred at 25 °C for 2 hours. It is then quenched with 20 mL of sodium thiosulfate, extracted three times with 20 mL of dichloromethane, and the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to give yellow solid Intermediate B2-1 (200 mg, 57.6% yield). MS(ESI+):m / z 393.9[M+H] + .

[0173] Step 6: Synthesis of intermediate B2-2 Intermediate B2-1 (200 mg, 507 μmol) and Intermediate B2-3 (151 mg, 609 μmol) were added to dimethyl sulfoxide (3 mL). The reaction mixture was stirred at 120 °C for 8 hours. The reaction mixture was spin-dried to obtain a crude product. 20 mL of ethyl acetate and 10 mL of water were added to the crude product, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) yielded brown solid Intermediate B2-2 (100 mg, yield: 34.1%).

[0174] Step 7: Synthesis of intermediate B2 Dioxane hydrochloride (4 M, 3 mL) was added to a mixture of intermediate B2-2 (100 mg, 173 μmol) and dioxane (1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then spin-dried to obtain the crude product. The crude product was separated and purified using a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 × 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 30% B to 60% B) to obtain brown solid intermediate B2 (45.0 mg, yield: 51.0%). MS(ESI+): m / z 477.9[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.84(s,1H),9.16(s,1H),7.81-7.73(m,3H),7.69-7.53(m,3H),7.18-7.08(m,2H),3.93(s,2H),3.08-3.01(m,2H),2.81(s,2H).

[0175] The following intermediates are synthesized using methods similar to the routes above. [Table 2-1] [Table 2-2]

[0176] Synthesis of intermediates B6 and B7-B: [ka]

[0177] Step 1: Synthesis of intermediate B6-3 Dissolve intermediate B6-1 (6.76 g, 29.0 mmol), intermediate B6-2 (5.00 g, 29.0 mmol), and diisopropylethylamine (9.38 g, 72.6 mmol) in tetrahydrofuran (50 mL) and react the mixture at 70 °C under a nitrogen atmosphere for 16 hours. The reaction mixture is spin-dried to obtain the crude product compound. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) yields colorless oily intermediate B6-3 (8.50 g, yield: 73.9%). MS(ESI+):m / z 369.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.73(s,1H),8.66(s,1H),5.96-5.80(m,1H),5.26-5.03(m,2H),4.30(q,J=7.2Hz,2H),4.16-4.06(m,2H),2.46(s,3H),1.44-1.20(m,12H).

[0178] Step 2: Synthesis of intermediate B6-4 Intermediate B6-3 (8.5 g, 23.07 mmol) is dissolved in dichloromethane (20 mL), hydrochloric acid / dioxane (4 M, 58 mL) is added, and the mixture is stirred for 1 hour at 25° C. The reaction is spun to dryness to give white solid intermediate B6-4 (7.00 g, crude product, hydrochloride salt). MS(ESI+): m / z 268.7[M+H] + .

[0179] Step 3: Synthesis of intermediate B6-5 Intermediate B6-4 (5.00 g, 16.4 mmol, HCl) was placed in ethanol (30 mL), and then 6 M aqueous NaOH (21 mL) was added. The mixture was reacted at 25 °C under a nitrogen atmosphere for 3 h. The reaction mixture was acidified using 6 N aqueous hydrochloric acid, and then the ethanol was removed by spin evaporation. The mixture was extracted three times with 100 mL of dichloromethane, separated, and the combined organic phases were washed with 150 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and spin-dried to give yellow solid intermediate B6-5 (3.30 g, crude product). MS(ESI+): m / z 223.06[M+H] + .

[0180] Step 4: Synthesis of intermediate B6 Intermediate B6-5 (1.10 g, 4.95 mmol), Intermediate B6-6 (1.18 g, 5.44 mmol), cuprous iodide (943 mg, 4.95 mmol), potassium carbonate (1.03 g, 7.42 mmol), and N,N-dimethylethylenediamine (873 mg, 9.90 mmol) were added to dioxane (10 mL). The mixture was heated at 100 °C under microwave irradiation for 1 h. The reaction was carried out in three batches in parallel. The reaction mixture was poured into 20 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was collected, washed with 20 mL of water, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain white solid Intermediate B6 (2.85 g, yield: 53.7%). MS(ESI+): m / z 358.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.01(s,1H),8.03(t,J=8.0Hz,1H),7.79-7.73(m,1H),7.69-7.60(m,1H),5.75-5.59(m,1H ),5.39(s,1H),4.98(dd,J=1.2,10.4Hz,1H),4.84-4.72(m,3H),2.55(s,3H),1.45(s,6H).

[0181] Step 5: Synthesis of intermediate B7 Intermediate B6 (2.00 g, 5.60 mmol) was dissolved in toluene (10 mL), followed by the addition of metachloroperbenzoic acid (1.36 g, 6.71 mmol, 85% purity). The reaction mixture was allowed to react at 25 °C for 1 hour. t-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.86 g, 6.71 mmol) and diisopropylethylamine (2.89 g, 22.4 mmol, 3.90 mL) were then added to the reaction mixture. The mixture was allowed to react at 25 °C for 12 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate solution, extracted twice with 20 mL of ethyl acetate, and the combined organic phases were washed twice with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1:0 to 3:5) to obtain a yellow solid intermediate B7 (2.79 g, yield: 85%). 1 H NMR(400MHz,DMSO-d6)δ 10.28-10.11(m,1H),8.83(s,1H),8.13-7.97(m,1H),7.81-7.71(m,1 H),7.64-7.55(m,3H),6.95(d,J=8.8Hz,2H),5.79-5.56(m,1H),5.37( s,1H),4.99(dd,J=1.2,10.3Hz,1H),4.84-4.78(m,1H),4.72-4.64(m,2H),3.36-3.34(m,4H),3.07-3.02(m,4H),1.45(s,6H),1.42(s,9H).

[0182] Step 6: Synthesis of intermediate B7-B Dissolve intermediate B7 (100 mg, 170 μmol) in dichloromethane (1 mL), add hydrochloric acid / dioxane (4 M, 2 mL), and stir at 25 °C for 1 hour. Spin dry the reaction mixture to give intermediate B7-B (90.0 mg, crude product, hydrochloride salt), a yellow solid. MS (ESI+): m / z 487 [M+H] + .

[0183] The following intermediates are purified in a similar manner to the above route or deprotected with hydrochloric acid or trifluoroacetic acid to give the corresponding amines. [Table 3-1] [Table 3-2]

[0184] Synthesis of intermediate B11: [ka]

[0185] Step 1: Synthesis of intermediate B11-3 Intermediate B11-1 (2 g, 12.3 mmol) and pyridine (1.22 g, 15.4 mmol, 1.3 mL) were dissolved in dichloromethane (20 mL). Intermediate B11-2 (2.75 g, 12.3 mmol) was added under ice-water conditions, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (100 mL). The organic phase was washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was slurried with acetonitrile (30 mL) to give Intermediate B11-3 (1 g, 23.24% yield). 1 H NMR (400MHz, DMSO-d6) δ10.71 (s, 1H), 8.82 (s, 1H), 7.62 (d, J = 8.0Hz, 2H), 7.46-7.40 (m, 1H), 2.60 (s, 3H).

[0186] Step 2: Synthesis of intermediate B11-4 Intermediate B11-3 (500 mg, 1.43 mmol) and methylamine hydrochloride (290 mg, 4.30 mmol) were dissolved in tetrahydrofuran (10 mL). Triethylamine (435 mg, 4.30 mmol, 600 μL) was added to the reaction mixture and stirred at room temperature for 48 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain intermediate B11-4 (320 mg, yield: 49.41%). MS (ESI+): m / z 343.0 [M+H] + .

[0187] Step 3: Synthesis of intermediate B11 Intermediate B11-4 (100 mg, 291 μmol), dibromomethane (152 mg, 874 μmol, 61 μL), and cesium carbonate (380 mg, 1.17 mmol) were dissolved in acetonitrile (5 mL) and the reaction mixture was reacted at 80° C. for 16 hours. The reaction mixture was diluted with 25 mL of water and extracted with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate B11 (60 mg, yield: 53.59%). MS (ESI+): m / z 355.2 [M+H] + .

[0188] Synthesis of intermediate B12-B: [ka]

[0189] Step 1: Synthesis of intermediate B12-2 Intermediate B12-1 (2 g, 10.8 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid zonacol ester (3.32 g, 10.8 mmol) were dissolved in acetonitrile (20 mL) and water (4 mL). Potassium carbonate (4.46 g, 32.3 mmol) and 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (787 mg, 1.07 mmol) were added and the mixture was stirred at 95 °C under nitrogen gas protection for 6 h. The reaction mixture was spin-dried to give the crude product, which was then separated by forward column chromatography (petroleum ether:ethyl acetate = 1 / 0 to 5 / 1) to give intermediate B12-2 (1.02 g, 32.8% yield) as a yellow oil. MS (ESI+): m / z 388.8 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 7.56(q,J=8.4Hz,2H),4.42-4.32(m,2H),2.80(s,3H),1.58(s,12H),1.43-1.36(m,3H).

[0190] Step 2: Synthesis of intermediate B12-3 Intermediate B12-2 (500 mg, 1.73 mmol) was dissolved in tetrahydrofuran (10 mL), 10% palladium on carbon (500 mg) was added, and the mixture was stirred and purged with hydrogen gas three times. The mixture was stirred under hydrogen gas at 20° C. for 16 hours. The reaction mixture was filtered and spin-dried to obtain the crude product, white solid intermediate B12-3 (241 mg, yield: 83.7%). 1 H NMR(400MHz,CDCl3)δ 6.96(d,J=7.9Hz,1H),6.59-6.47(m,2H),4.38-4.04(m,2H),3.53(br s, 2H), 2.84-2.69 (m, 3H), 2.27 (s, 3H), 1.76-1.67 (m, 2H), 1.54-1.51 (m, 2H), 1.49 (s, 9H).

[0191] Step 3: Synthesis of intermediate B12-4 Intermediate B11 (100 mg, 282 μmol) was added to dichloromethane (5 mL), and 85% perchloromethane (143 mg, 704 μmol) was added at 0°C. The mixture was stirred at 20°C for 16 hours. Sodium thiosulfate (10 mL) and sodium bicarbonate (10 mL) were added to the reaction mixture at 0°C. Water (20 mL) was then added, and the mixture was extracted twice with dichloromethane (20 mL). The combined organic layer was washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. White solid intermediate B12-4 (246 mg, yield: 60.2%) was obtained.

[0192] Step 4: Synthesis of intermediate B12 Intermediate B12-4 (60 mg, 155 μmol) and intermediate B12-3 (45 mg, 155 μmol) were added to dimethyl sulfoxide (1 mL), and the mixture was then purged with nitrogen gas three times and stirred under a nitrogen atmosphere at 120° C. for 16 hours. The reaction mixture was purified by preparative high-performance liquid chromatography, and the residue was purified to give white solid intermediate B12 (19 mg, yield: 20.3%). 1 H NMR(400MHz,DMSO-d6)δ 11.02(br s,1H),9.54-9.41(m,1H),8.13(br s,1H),8.04(d,J=8.0Hz,1H),7.86-7.78(m,1H),7.42-7.32(m,8H),7.28(d,J=6.4Hz,2H),6.51-6.37(m,1H),5.18-5.11(m,1 H),4.57-4.48(m,1H),4.44-4.36(m,1H),2.96-2.87(m,1H),2.60(d,J=16.4Hz,1H),2.45-2.34(m,1H),2.03(d,J=5.6Hz,1H).

[0193] Step 5: Synthesis of intermediate B12-B Intermediate B12 (19 mg, 31.8 μmol) was added to dichloromethane (5 mL), and hydrochloric acid in dioxane (4 M, 5 mL) was added. The mixture was purged with nitrogen gas three times and stirred under a nitrogen atmosphere at 20° C. for 2 hours. The reaction mixture was filtered, and the filter cake was concentrated to give the crude product, the hydrochloride salt of intermediate B12-B (10 mg, yield: 42.0%) as a white solid. Intermediate B12-B was used directly in the next step reaction without further purification.

[0194] The following intermediates are synthesized in a similar manner to the above route: [Table 4]

[0195] Synthesis of intermediate B30: [ka] Step 1: Synthesis of intermediate B30-1 Intermediate B6 (246 mg, 689 μmol) was dissolved in toluene (5 mL), metachloroperbenzoic acid (326 mg, 758 μmol) was added, and the mixture was stirred at 20 °C for 0.5 h. N,N-Diisopropylethylamine (267 mg, 2.07 mmol) and Intermediate B12-3 (200 mg, 689 μmol) were added, and the mixture was stirred at 20 °C for 16 h. Sodium thiosulfate (10 mL) and sodium bicarbonate (10 mL) were added to the reaction mixture at 0 °C. Water (20 mL) was then added, and the mixture was extracted twice with dichloromethane (20 mL). The combined organic layers were washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification by column chromatography (dichloromethane / methanol = 1:0 to 10:1) gave yellow solid Intermediate B30-1 (287 mg, 69.5%). LCMS(ESI+):m / z 544.4[M+H] + .

[0196] Step 2: Synthesis of intermediate B30 Intermediate B30-1 (274 mg, 457 μmol) was added to dichloromethane (5 mL), and hydrochloric acid in dioxane (4 M, 5 mL) was added. The mixture was purged with nitrogen gas three times and stirred under a nitrogen atmosphere at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. A yellow solid, intermediate B30 (274 mg, crude hydrochloride salt), was obtained, and the crude product was used directly in the next step of the reaction.

[0197] The following intermediates are synthesized using methods similar to the routes above via different intermediates. [Table 5]

[0198] Synthesis of intermediates B15-A and B15-B: [ka]

[0199] Step 1: Synthetic compound intermediate B15-2 To a toluene solution (40 mL) of intermediate B15-1 (4 g, 26.0 mmol), phosphorus oxybromide (14.9 g, 52.1 mmol) was added. The reaction mixture was stirred at 130 °C for 72 hours. The reaction mixture was diluted with 200 mL of water and slowly added to 200 mL of saturated aqueous sodium bicarbonate. The resulting mixture (pH > 7) was stirred at room temperature for 10 minutes and filtered. The filtrate was extracted three times with 200 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain white solid intermediate B15-2 (3.0 g, yield: 52.4%). MS (ESI+): m / z 199.92 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.56(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),2.92-2.80(m,4H),2.11-2.00(m,2H).

[0200] Step 2: Synthesis of intermediate B15-3 To a solution of intermediate B15-2 (3.44 g, 17.4 mmol) in dichloromethane (40 mL) was added 3-chloroperoxybenzoic acid (14.9 g, 52.1 mmol, 85% purity). The reaction mixture was stirred at 25 °C for 5 h. 50 mL of saturated aqueous sodium bicarbonate and 50 mL of saturated sodium thiosulfate were added to the reaction mixture. The mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain white solid intermediate B15-3 (3.50 g, yield: 94.1%). 1 H NMR(400MHz, CDCl3)δ 7.46(d,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),3.26-3.18(m,2H),3.04-2.97(m,2H),2.26-2.17(m,2H).

[0201] Step 3: Synthesis of intermediate B15-4 Intermediate B15-3 (3.5 g, 16.4 mmol) was dissolved in acetic anhydride (33 mL, 349 mmol) and the reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was evaporated to dryness, redissolved in 100 mL of ethyl acetate, and washed twice with 15 mL of saturated sodium bicarbonate solution and then with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:1) gave intermediate B15-4 (4 g, yield: 82.62%) as a yellow oil. MS (ESI+): m / z 257.89 [M+H] + .

[0202] Step 4: Synthesis of intermediate B15-5 Intermediate B15-4 (6.20 g, 24.2 mmol) was dissolved in tetrahydrofuran (65 mL) and water (65 mL), and lithium hydroxide (2.32 g, 96.8 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into 100 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) gave yellow solid intermediate B15-5 (4.5 g, yield: 78.15%). 1 H NMR(400MHz,CDCl3)δ 7.45(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),5.19(t,J=6.8Hz,1H),3.0 7-2.94(m,1H),2.85-2.73(m,2H),2.63-2.50(m,1H),2.13-2.00(m,1H).

[0203] Step 5: Synthesis of intermediate B15-6 Dissolve intermediate B15-5 (4.80 g, 22.4 mmol) in dichloromethane (100 mL) and add Dess-Martin reagent (19.0 g, 44.9 mmol) at 0 °C. Stir the reaction mixture at 25 °C for 2 hours. Filter the reaction mixture and spin-dry the filtrate to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) yields white solid intermediate B15-6 (4 g, yield: 75.71%). 1 H NMR (400MHz, CDCl3) δ 7.76(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),3.16-3.10(m,2H),2.82-2.77(m,2H).

[0204] Step 6: Synthesis of intermediate B15-7 Intermediate B15-6 (4 g, 18.86 mmol) was dissolved in tetrahydrofuran (80 mL) and 3 M ethylmagnesium bromide solution (19.0 g, 44.9 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was cooled to 0 °C and slowly added dropwise to 100 mL of saturated aqueous ammonium chloride solution, followed by extraction with 50 mL of ethyl acetate twice. The combined organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to obtain brown solid intermediate B15-7 (2.20 g, yield: 43.4%). 1 H NMR(400MHz,CDCl3)δ 7.34(d,J=8.0Hz,1H),7.25(d,J=8.0Hz,1H),2.94-2.80(m,1H),2.76-2.61(m,1H),2.40-2 .18(m,2H),2.17-2.07(m,1H),1.97-1.84(m,1H),1.81-1.68(m,1H),0.88(t,J=7.2Hz,3H).

[0205] Step 7: Synthesis of intermediate B15 Add intermediate B15-7 (1.1 g, 4.54 mmol), intermediate B15-8 (1.51 g, 6.82 mmol), cuprous iodide (865 mg, 4.54 mmol), potassium carbonate (1.26 g, 9.09 mmol), and N,N-dimethylethylenediamine (801 mg, 9.09 mmol) to dioxane (10 mL) and react the mixture at 100 °C under microwave irradiation for 2 h. Filter the reaction mixture and spin-dry the filtrate to obtain the crude product. Separate the crude product by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain white solid intermediate B15 (0.6 g, yield: 32.89%). 1H NMR(400MHz,CDCl3)δ 8.94(s,1H),7.79-7.73(m,1H),7.71-7.66(m,1H),5.76-5.64(m,1H),5.07-5.01(m,1H),4.96-4.85(m,2H),4.79-4.67(m,1H),3.11-3.0 0(m,1H),2.93-2.81(m,1H),2.57(s,3H),2.45-2.34(m,1H),2.29-2.19(m,2H),2.04-1.94(m,1H),1.91-1.79(m,1H),1.01-0.97(m,3H).

[0206] Step 8: Synthesis of Intermediates B15-A and B15-B Intermediate B15 (1.2 g, 3.13 mmol) was separated by chiral separation chromatography column (Phenomenex-Cellulose-2 (250 mm × 50 mm, 10 μm), mobile phase: [0.1% aqueous ammonia / ethanol]:carbon dioxide:45% to give peak 1 yellow solid intermediate B15-A (460 mg, yield: 38.33%) and peak 2 yellow solid intermediate B15-B (460 mg, yield: 38.3%).

[0207] Specific rotation value of intermediate B15-A: −46.64 (C=0.1, chloroform). Chiral analysis: Analytical column: Cellulose 2 100 × 4.6 mm ID, 3 μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), elution gradient: 40% B, flow rate: 2.8 mL / min, column temperature: 35 °C, detection wavelength: 220 nM, Rt = 1.76 min. 1H NMR(400MHz,DMSO)δ 9.03(s,1H),7.91(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),5.81-5.59(m,1 H),5.10(s,1H),5.03-4.96(m,1H),4.90-4.79(m,2H),4.70-4.59(m,1H),3 .07-2.92(m,1H),2.87-2.73(m,1H),2.54(s,3H),2.28-2.16(m,1H),2.10 -1.97(m,1H),1.93-1.82(m,1H),1.77-1.65(m,1H),0.87(t,J=7.6Hz,3H).

[0208] Specific rotation value of intermediate B15-B: +48.265 (C = 0.1, chloroform). Chiral analysis: Analytical column: Cellulose 2 100 × 4.6 mm ID, 3 μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), elution gradient: 40% B, flow rate: 2.8 mL / min, column temperature: 35 °C, detection wavelength: 220 nM, Rt = 2.41 min. 1 H NMR(400MHz,DMSO)δ 9.03(s,1H),7.91(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),5.81-5.59(m,1 H),5.10(s,1H),5.03-4.96(m,1H),4.90-4.79(m,2H),4.70-4.59(m,1H),3 .07-2.92(m,1H),2.87-2.73(m,1H),2.54(s,3H),2.28-2.16(m,1H),2.10 -1.97(m,1H),1.93-1.82(m,1H),1.77-1.65(m,1H),0.87(t,J=7.6Hz,3H).

[0209] Synthesis of Intermediate B26, Intermediate B26-A, and Intermediate B26-B [ka] Intermediate B26 is synthesized by using the method for synthesizing intermediate B15, but replacing the ethyl Grignard reagent with a methyl Grignard reagent and carrying out the addition reaction.

[0210] Intermediate B26 (1.10 g, 2.98 mmol) was separated using a chiral separation chromatography column (Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm), mobile phase: [neutral-ETOH], carbon dioxide %: 45%-45%, 45 mL / min) to give peak 1 of yellow solid compound B 2 6-A (500 mg, yield: 45%) and peak 2 yellow solid compound B 2 6-B (550 mg, yield: 50%) was obtained.

[0211] Intermediate B26-A: Chiral analysis: Analytical column: Cellulose 2 100 × 4.6 mm ID, 3 μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), elution gradient: 40% B, flow rate: 2.8 mL / min, column temperature: 35 °C, detection wavelength: 220 nM, Rt = 2.16 min.

[0212] Intermediate B26-B: Chiral analysis: Analytical column: Cellulose 2 100 × 4.6 mm ID, 3 μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), elution gradient: 40% B, flow rate: 2.8 mL / min, column temperature: 35 °C, detection wavelength: 220 nM, Rt = 2.68 min.

[0213] Intermediate B49 is synthesized in a similar manner to B15 using 6,7-dihydro-5H-8-quinolinone. [ka] Intermediate B49 (212 mg, 533 μmol) was separated by chiral separation chromatography column DAICEL CHIRALPAK IE (250 mm × 30 mm, 10 μm), mobile phase: [Neu-ETOH], B%: 60%-60%, 45 mL / min) to obtain the first peak 1 (Rt = 4.63 min) of intermediate B49-A (110 mg, crude product), which was used directly in the next step, and the second peak 2 (Rt = 6.59 min) of intermediate B49-B (100 mg, yield: 47.2%).

[0214] Intermediate B50 is synthesized by a similar method to B15 using 6,7-dihydro-5H-8-quinolinone. [ka] Intermediate B50 (240 mg, 627 μmol) was separated by chiral separation chromatography column DAICEL CHIRALPAK IE (250 mm × 30 mm, 10 μm), mobile phase: [Neu-ETOH], B%: 30%-30%, 45 mL / min) to obtain the first peak 1 (Rt = 3.76 min) white solid intermediate B50-A (120 mg, yield: 50.0%) and the second peak 2 (Rt = 3.97 min) B50-B (120 mg, yield: 50.0%).

[0215] The following intermediates can be synthesized using the synthetic route of intermediate B7-B, and intermediate B15-B or B 2 It is synthesized via 6-B. [Table 6]

[0216] The following intermediate compounds are synthesized using methods described in the literature or methods expected to be similar. B 1 7. B 1 8, B 1 9 and B 2 8 is based on the literature (US2019 / 192668A 1 ) is synthesized using the method described in 2 0 and B2 1 is described in the literature (WO2018 / 102725A 1 ) is synthesized by the method described in [Table 7-1] [Table 7-2] [Table 7-3]

[0217] Synthesis of intermediate B25: [ka]

[0218] Step 1: Synthesis of intermediate B25-2 Compound intermediate B25-1 (25.0 g, 125 mmol) and hydrazine methyl sulfate (36.0 g, 250 mmol) were dissolved in ethanol (150 mL), sodium carbonate (39.7 g, 375 mmol) was added, and the mixture was purged with nitrogen gas three times. The mixture was then stirred at 120 °C for 16 h under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, and after removing the ethanol, 200 mL of water was added. The mixture was extracted twice with 300 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain yellow solid compound intermediate B25-2 (14.0 g, yield: 45.6%). LCMS (ESI+): m / z 228.9 [M+H] + .

[0219] Step 2: Synthesis of compound intermediate B25-3 1,8-Diazabicyclo[5.4.0]undecane-7-ene (9.16 g, 60.2 mmol, 9.07 mL) and L-lactic acid (9.26 g, 60.16 mmol) were mixed at 0°C and stirred for 16 hours. Then, compound intermediate B25-2 (17.0 g, 75.0 mmol) was added and dissolved with stirring at 80°C. Ethyl acrylate (11.3 g, 113 mmol, 12.3 mL) was added and stirred for 24 hours. After that, ethyl acrylate (11.3 g, 113 mmol, 12.3 mL) was added again and stirred for another 24 hours. The reaction mixture was diluted with 200 mL of 30% sodium hypochlorite solution, diluted with 200 mL of water, and extracted twice with 500 mL of ethyl acetate. The combined organic phase was washed twice with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain intermediate B25-3 (8.00 g, yield: 30.3%) as a yellow oil. LCMS (ESI+): m / z 328.7 [M+H] + .

[0220] Step 3: Synthesis of compound intermediate B25-4 Compound intermediate B25-3 (8.00 g, 24.5 mmol) was dissolved in ethanol (100 mL), sodium acetate (4.02 g, 49.1 mmol) and cyanogen bromide (8.45 g, 79.8 mmol) were added, and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was evaporated to dryness, and after removing the ethanol, 100 mL of water was added. The mixture was extracted twice with 200 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to obtain yellow solid compound intermediate B25-4 (5.80 g, yield: 67.3%). LCMS (ESI+): m / z 352.5 [M+H] + .

[0221] Step 4: Synthesis of compound intermediate B25-5 Compound intermediate B25-4 (5.80 g, 16.5 mmol) was dissolved in dichloromethane (50 mL), acetaldoxime (2.93 g, 49.5 mmol, 2.99 mL) and indium trichloride (365 mg, 1.65 mmol) were added, and the mixture was stirred at 110 °C for 1 hour. The reaction mixture was evaporated to dryness, and after removing the toluene, 50 mL of water was added. The mixture was extracted twice with 80 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain yellow solid compound intermediate B25-5 (5.60 g, yield: 81.7%). LCMS (ESI+): m / z 371.8 [M+H] + .

[0222] Step 4: Synthesis of intermediate B25 Compound intermediate B25-5 (5.60 g, 15.2 mmol) was dissolved in acetonitrile (150 mL), and benzyltrimethylammonium hydroxide methanol solution (9.51 g, 22.8 mmol, 10.3 mL, 40%) was added and stirred at 20 °C for 0.5 h. The reaction mixture was evaporated to dryness, and 50 mL of water was added. The mixture was stirred at 20 °C for 5 min and filtered to give pale yellow solid intermediate B25 (3.55 g, 72.4% yield). LCMS (ESI+): m / z 324.5 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.95-7.76(m,1H),7.66-7.52(m,2H),7.05-6.94(m,1H),4.41-4.33(m,3H),4.11-4.04(m,2H),2.94-2.85(m,2H).

[0223] Intermediate B23 and intermediate B51 are synthesized using the synthetic route of intermediate B25 but with different starting materials. [Table 8]

[0224] Synthesis of intermediate B46: [ka]

[0225] Step 1: Synthetic intermediate B46-3 Intermediate B23 (250 mg, 774 μmol), B46-2 (287 mg, 928 μmol), cesium carbonate (756 mg, 2.32 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (131 mg, 155 μmol) were placed in 1,4-dioxane (1.5 mL) and water (0.06 mL), purged with nitrogen three times, and stirred under nitrogen at 60 °C for 3 h. The reaction mixture was dried over anhydrous sodium sulfate, filtered, washed with dichloromethane, and the combined organic phase was spin-dried to give the crude product. The crude product was separated by column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) to obtain intermediate B46-3 (285 mg, yield: 83.1%). LCMS (ESI+): m / z 427.2 [M+H] + .

[0226] Step 2: Synthesis of intermediate B46-4 Intermediate B46-3 (285 mg, 670 μmol) was dissolved in tetrahydrofuran (10 mL), platinum dioxide (250 mg, 1.10 mmol) was added, and the mixture was purged with hydrogen gas three times. The mixture was stirred under a hydrogen atmosphere at 25°C for 16 hours. Saturated ammonium chloride solution (1 mL) and reduced iron powder (1.17 g, 21.0 mmol) were added and stirred at 80°C for 1 hour. The reaction mixture was filtered, washed with dichloromethane, and the combined organic phase was spin-dried to give crude intermediate B46-4 (240 mg, crude). LCMS (ESI+): m / z 372.3 [M+H-56] + .

[0227] Step 3: Synthesis of intermediate B46 Dissolve intermediate B46-4 (240 mg, 561 μmol) in dichloromethane (2 mL), add hydrochloric acid / 1,4-dioxane solution (4 M, 2 mL), and stir for 0.5 hours at 25° C. Spin-dry the reaction mixture to give crude intermediate B46 (265 mg, crude).

[0228] Synthesis of intermediate B47: [ka]

[0229] Step 1: Synthesis of intermediate B47-3 Intermediate B47-1 (300 mg, 560 μmol) and intermediate B47-2 (222 mg, 719 μmol) were dissolved in dioxane (5 mL) and water (0.1 mL). Potassium carbonate (249 mg, 1.80 mmol) and 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (26.3 mg, 36.0 μmol) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. Anhydrous sodium sulfate was added to the reaction mixture, and the mixture was filtered. The filter cake was rinsed with dichloromethane (100 mL). The filtrate was spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain colorless oily intermediate B47-3 (314 mg, yield: 69.5%).

[0230] 1 H NMR(400MHz,CDCl3)δ 7.91(d,J=8Hz,1H),7.67(d,J=8.8Hz,1H),7.48-7.43(m,2H),7.42-7.33( m,5H),7.30-7.27(m,4H),7.15-7.07(m,1H),6.53(d,J=8Hz,1H),6.14(br s,1H),5.48(s,2H),5.44-5.35(m,2H),4.14(br s,2H),4.12-4.10(m,3H),3.69(t,J=5.2Hz,2H),2.63(br s,2H),1.52(s,9H).

[0231] Step 2: Synthesis of intermediate B47-4 Intermediate B47-3 (314 mg, 521 μmol) was dissolved in tetrahydrofuran (10 mL) and platinum dioxide (200 mg, 881 μmol) was added to the reaction mixture under a nitrogen atmosphere. The suspension was purged with hydrogen gas three times. The reaction mixture was reacted at 20 °C under a hydrogen gas (15 Psi) atmosphere for 48 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was rinsed with dichloromethane (80 mL), and the filtrate was concentrated and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain a colorless oil B 4 Obtain 7-4 (65 mg, yield: 25.1%). LCMS (ESI+): m / z 449.3 [M+23] + .

[0232] Step 3: Synthesis of intermediate B47 Intermediate B47-4 (65 mg, 152 μmol) was dissolved in dichloromethane (1 mL), and the reaction mixture was added with hydrochloric acid / dioxane (4 M, 1.5 mL) and stirred at 25° C. for 5 hours. The reaction mixture was concentrated and spun to dryness to give intermediate B47 (60 mg, crude product, hydrochloride salt), a brown solid, which was used directly in the next step of the reaction. LCMS (ESI+): m / z 327.2 [M+H] + .

[0233] Example 1: Compound 1 [ka]

[0234] Step 1: Synthesis of Intermediate 1-2 N,N-Diisopropylethylamine (702 mg, 5.43 mmol) was added to a mixture containing intermediate 1-1 (500 mg, 1.81 mmol), 4-hydroxymethylpiperidine (417 mg, 3.62 mmol), and N-methylpyrrolidone (8 mL). The reaction mixture was stirred at 140 °C under microwave conditions for 2 h. The mixture was then quenched with 20 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product compound. Separation by column chromatography (dichloromethane:methanol = 1:0 to 10:1) afforded a yellow solid intermediate 1-2 (500 mg, yield: 66.9%). MS(ESI+):m / z 371.8[M+H] + .

[0235] Step 2: Synthesis of intermediates 1-3 Dess-Martin reagent (857 mg, 2.02 mmol) was added to a mixture containing intermediate 1-2 (500 mg, 1.35 mmol) and dichloromethane (20 mL), and the reaction was stirred at 25 °C for 2 h. The mixture was then quenched with 20 mL of sodium thiosulfate solution and 20 mL of sodium bicarbonate solution, extracted, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product compound. Separation by column chromatography (dichloromethane:methanol = 1:0 to 10:1) gave yellow solid intermediate 1-3 (400 mg, yield: 79.6%). MS (ESI+): m / z 370.0 [M+H] + .

[0236] Step 3: Synthesis of Compound 1 [ka] Intermediate 1-3 (46.3 mg, 125 μmol), Intermediate B-2 (30.0 mg, 62.7 μmol), and triethylamine (6.35 mg, 62.7 μmol) were dissolved in dichloromethane (5 mL) and stirred at 25° C. for 10 minutes. Acetic acid (3.77 mg, 62.72 μmol) was then added and stirred at 25° C. for 50 minutes. Sodium cyanoborohydride (7.88 mg, 125.44 μmol) was then added and stirred for 1 hour. The reaction mixture was spin-dried to obtain the crude product. The crude product was purified by thin-layer chromatography (dichloromethane:methanol=20:1) to obtain a yellow solid product, Compound 1 (3.96 mg, yield: 7.44%). MS (ESI+): m / z 831.1 [M+H] + .

[0237] 1 H NMR(400MHz,DMSO-d6)δ 11.10(br s,1H),10.80(br s,1H),9.15(s,1H),8.35-8.29(m,2H),7.85-7.73(m,3H),7.68-7.62(m,2H),7.61-7.55(m,1H), 7.36-7.30(m,1H),7.28-7.20(m,1H),7.11(d,J=1.6Hz,1H),5.06(dd,J=5.2,13.2Hz,1H),4.06( d,J=13.2Hz,2H),3.62-3.57(m,2H),3.00(t,J=12.0Hz,2H),2.93-2.82(m,3H),2.63-2.52(m,3H ),2.37-2.34(m,1H),2.04-1.94(m,2H),1.87-1.81(m,1H),1.27-1.10(m,3H),1.00-0.92(m,2H).

[0238] Compounds 2-25 were synthesized using a similar method to compound 1 but with different intermediates. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10]

[0239] Example 26: [ka]

[0240] Step 1: Synthesis of intermediate 26-1 Intermediate B16 (0.65 g, 2.46 mmol), 4-hydroxymethylpiperidine (340 mg, 2.95 mmol), and triethylamine (747 mg, 7.38 mmol) were dissolved in dichloromethane (40 mL), followed by the slow dropwise addition of tri-n-propyl cyclic phosphoric anhydride (1.88 g, 2.95 mmol). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was spin-dried to obtain the crude product. The crude product was separated by column chromatography (dichloromethane:methanol = 1:0 to 9:1) to obtain white solid intermediate 26-1 (0.700 g, yield: 78.0%). MS (ESI+): m / z 362.0 [M+H] + .

[0241] Step 2: Synthesis of intermediate 26-2 Intermediate 26-1 (0.700 g, 1.94 mmol) was dissolved in dichloromethane (10 mL) and Dess-Martin reagent (1.23 g, 2.91 mmol) was added to the above reaction solution. The reaction solution was stirred at 25 °C for 1.5 h. The reaction solution was diluted with 30 mL of dichloromethane, washed twice with 10 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (dichloromethane:methanol = 1:0 to 10:1) to obtain the crude white solid intermediate 26-2 (0.350 g, crude), which was used directly in the next step of the reaction. MS(ESI+): m / z 360.0[M+H] + .

[0242] Step 3: Synthesis of compound 26 [ka] Intermediate B4 (75.0 mg, 138 μmol) was dissolved in dichloromethane (5 mL) and triethylamine (76.9 μL, 553 μmol) was added to adjust the pH of the reaction solution to 7-8. Then, acetic acid (31.6 μL, 553 μmol) was added to adjust the pH of the reaction solution to 5-6. Intermediate 26-2 (75.0 mg, 138 μmol) was then added to the above solution and reacted at 25 °C for 2 hours. Finally, sodium cyanoborohydride (17.4 mg, 276 μmol) was added to the above solution and reacted at 25 °C for 1 hour. The reaction mixture was diluted with 30 mL of dichloromethane, washed twice with 10 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-performance liquid chromatography (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 10% B to 50% B) to obtain white solid compound 26 (29.05 mg, yield: 23%). MS (ESI+): m / z 849.2 [M+H]+.

[0243] 1H NMR(400MHz,DMSO-d6)δ 10.96-10.69(m,1H),10.36(s,1H),9.15(s,1H),7.90-7.60(m,6H),7.41-7.08(m,6H),3.84(s,3H),3.54-3.52(m,2H),3.07-2 .87(m,4H),2.73-2.64(m,2H),2.49-2.42(m,4H),2.23-2.11(m,2H),2.03-1.93(m,2H),1.80-1.57(m,6H),1.16-0.99(m,2H).

[0244] Examples 27-30 are synthesized using a similar method to compound 26, but with different intermediates. [Table 10-1] [Table 10-2]

[0245] Example 31: Compound 31 [ka]

[0246] Step 1: Synthesis of intermediate 31-2 Intermediate 31-1 (2.00 g, 12.9 mmol), 4-hydroxymethylpiperidine (1.63 g, 14.2 mmol), and diisopropylethylamine (5.00 g, 38.7 mmol) were dissolved in N-methylpyrrolidone (5 mL) and the mixture was reacted at 140 °C for 2 hours under microwave irradiation. The reaction mixture was poured into 50 mL of water. The mixture was extracted three times with 100 mL of ethyl acetate, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain a yellow solid intermediate 31-2 (2.70 g, yield: 74.5%). MS (ESI+): m / z 251.12 [M+H] + .

[0247] 1 H NMR(400MHz,DMSO-d6)δ 8.06-7.94(m,2H),7.11(d,J=8.4Hz,1H),4.54(t,J=5.2Hz,1H),3.34-3.29(m,4H),2.32(s,3H) ,2.21-2.14(m,1H),1.95-1.86(m,1H),1.82-1.73(m,2H),1.60-1.48(m,1H),1.36-1.25(m,2H).

[0248] Step 2: Synthesis of intermediate 31-3 Intermediate 31-2 (1.20 g, 4.79 mmol), reduced iron powder (1.34 g, 24.0 mmol), and ammonium chloride (1.28 g, 24.0 mol) were dissolved in ethanol (30 mL) and water (4 mL). The mixture was heated to 80 °C and reacted for 2 h. The reaction mixture was filtered through diatomaceous earth and extracted twice with 30 mL of ethyl acetate. The organic phase was collected, washed with 20 mL of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and spin-dried to give black liquid intermediate 31-3 (0.830 g, 70.7% yield). MS (ESI+): m / z 221.13 [M+H] + .

[0249] Step 3: Synthesis of compound 31-4 Intermediate 31-3 (305 mg, 1.38 mmol) and intermediate B12-4 (428 mg, 1.15 mmol) were dissolved in dimethyl sulfoxide (3 mL), and the mixture was heated to 120 °C for 16 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed twice with 50 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 1:0 to 10:1) to obtain a yellow solid intermediate 31-4 (260 mg, yield: 33.4%).

[0250] Step 4: Synthesis of intermediate 31-5 Intermediate 31-4 (260 mg, 493 μmol) was dissolved in dichloromethane (20 mL), and then Dess-Martin (314 mg, 740 μmol) was slowly added to the solution and allowed to react for 1 h at 25 °C. The reaction mixture was diluted with 30 mL of dichloromethane, washed twice with 10 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was separated by column chromatography (dichloromethane:methanol = 1:0 to 10:1) to give white solid intermediate 31-5 (120 mg, yield: 43.6%). MS(ESI+): m / z 525.07[M+H] + .

[0251] Step 5: Synthesis of Compound 31 [ka] Intermediate B20 (34.6 mg, 91.4 μmol, hydrochloride salt) was dissolved in dichloromethane (5 mL) and triethylamine (30 mg, 304 μmol) was added to measure the pH at approximately 7-8. Intermediate 31-5 (40.0 mg, 76.1 μmol) and acetic acid (4.57 mg, 76.1 μmol) were then added to measure the pH at approximately 5-6. The reaction mixture was stirred at 25°C for 3.5 hours. Sodium cyanoborohydride (9.57 mg, 152 μmol) was added to the reaction mixture, and the mixture was allowed to react for 1.5 hours. The reaction mixture was spin-dried and separated using a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% trifluoroacetic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 10% B to 50% B) to obtain compound 31 (30.5 mg, yield: 46.6%) as a yellow solid. MS (ESI+): m / z 851.2 [M+H] + .

[0252] 1H NMR(400MHz,DMSO-d6)δ 11.13(s,1H),10.00-9.79(m,1H),8.47(s,1H),7.81-7.74(m,1H),7.69-7.54(m,4H),7. 53-7.38(m,3H),7.17-6.95(m,1H),5.17-5.06(m,1H),4.99(s,2H),3.90-3.87(m,2H),3 .74-3.60(m,2H),3.41-3.20(m,6H),3.12(s,5H),2.95-2.83(m,1H),2.78-2.55(m,3H), 2.45-2.38(m,1H),2.26(s,3H),2.09-1.95(m,2H),1.93-1.80(m,2H),1.51-1.37(m,2H).

[0253] Compounds 32-33 are synthesized using a similar method to compound 31 but with different intermediates. [Table 11]

[0254] Example 34: Compound 34 [ka]

[0255] Step 1: Synthetic compound 34 [ka] Intermediate B21 (70.0 mg, 192 μmol, HCl) and triethylamine (92.4 mg, 913 μmol) were dissolved in dichloromethane (5 mL) and the pH was measured to be about 7 to 8. Intermediate 31-5 (120 mg, 228 μmol) and acetic acid (13.7 mg, 228 μmol) were then added to the reaction mixture and the pH was measured to be about 5 to 6. The mixture was stirred at 25°C for 2 hours, and then sodium cyanoborohydride (21.5 mg, 342 μmol) was added and the mixture was stirred at 25°C for 12 hours. The reaction mixture was spin-dried and separated using a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 10% B to 45%) to obtain white solid compound 34 (8.50 mg, yield: 4.35%). MS (ESI+): m / z 837.2 [M+H] + .

[0256] 1 H NMR(400MHz,DMSO-d6)δ 10.96(br s,1H),9.73(s,1H),8.45(s,1H),7.67-7.61(m,2H),7.59-7.43(m,4H),7.11-7.03(m,2H), 7.00-6.93(m,1H),5.10-5.00(m,1H),4.96(s,2H),4.39-4.14(m,2H),3.35-3.30(m,4H),3 .10(s,3H),3.04-2.97(m,2H),2.94-2.84(m,1H),2.64-2.51(m,7H),2.39-2.31(m,1H),2. 28-2.19(m,5H),2.02-1.90(m,1H),1.87-1.76(m,2H),1.73-1.58(m,1H),1.33-1.23(m,2H)

[0257] Compounds 56-57 were synthesized using a similar method to compound 34, but with different intermediates. [Table 12]

[0258] Example 35: Compound 35 [ka]

[0259] Step 1: Synthesis of intermediate 35-3 Diisopropylethylamine (6.67 g, 51.57 mmol) was added to a mixture containing 4-hydroxymethylpiperidine (1.47 g, 9.67 mmol), intermediate 35-1 (1 g, 6.45 mmol), and DMF (10 mL). The reaction mixture was stirred at 100 °C for 12 h. The mixture was then quenched with 50 mL of saturated sodium chloride, extracted three times with 50 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:2) afforded white solid 35-3 (1.30 g, yield: 80.5%). MS (ESI+): m / z 250.8 [M+H] + .

[0260] Step 2: Synthesis of intermediate 35-4 Lithium hydroxide monohydrate (327 mg, 7.79 mmol) was added to a mixture containing intermediate 35-3 (1.30 g, 5.19 mmol), water (5 mL), and tetrahydrofuran (5 mL), and the reaction was stirred at 25 °C for 2 h. The pH was then adjusted to 3 with hydrochloric acid (2 M) and spin-dried to give white solid intermediate 35-4 (1.20 g, 96.8% yield). MS (ESI+): m / z 237.12 [M+H] + .

[0261] Step 3: Synthesis of intermediate 35-6 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (609 mg, 3.17 mmol) was added to a mixture containing intermediate 35-4 (500 mg, 2.12 mmol), intermediate 35-5 (418 mg, 2.54 mmol), diisopropylethylamine (1.37 g, 10.58 mmol), 1-hydroxybenzotriazole (572 mg, 4.23 mmol), and DMF (10 mL). The reaction was stirred at 25 °C for 2 h. The reaction mixture was spin-dried to obtain a crude product. The crude product was separated and purified by high-performance liquid chromatography (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 25% B to 55%) to obtain white solid intermediate 35-6 (150 mg, yield: 19.9%). MS (ESI+): m / z 347.08 [M+H] + .

[0262] Step 4: Synthesis of intermediate 35-7 Dess-Martin oxidant (122 mg, 289 μmol) was added to a solution containing intermediate 35-6 (50.0 mg, 144 μmol) and dichloromethane (5 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then spin-dried to obtain the crude product. Separation by column chromatography (dichloromethane:methanol = 1:0 to 10:1) gave intermediate 35-7 (50.0 mg, yield: 74.4%) as a yellow oil. MS (ESI+): m / z 345.08 [M+H] + .

[0263] Step 5: Synthesis of Compound 35 [ka] Acetic acid (8.72 mg, 145 μmol) was added to a solution containing Intermediate 35-7 (50.0 mg, 145 μmol), Intermediate B8 (70.50 mg, 145 μmol), and dichloromethane (5 mL). After stirring for 1 h, sodium cyanoborohydride (18.3 mg, 290 μmol) was added. The reaction was stirred at 25 °C for 1 h. It was then quenched with 10 mL of water, extracted three times with 10 mL of dichloromethane, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and spun to give the crude product. The crude product was separated and purified by high-performance liquid chromatography (chromatography column: Kromasil 100-5-C18 30 × 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 10% B to 45%) to obtain white solid compound 35 (8.24 mg, yield: 6.94%). MS (ESI+): m / z 814.6 [M+H] + .

[0264] 1 H NMR(400MHz,DMSO-d6)δ 10.86(s,1H),10.26(s,1H),8.88(s,1H),8.77-8.66(m,1H),8.35-8.29(m,1H),8.15-8.00(m,1H),7.90-7.82 (m,1H),7.79-7.73(m,1H),7.72-7.57(m,3H),7.47-7.32(m,1H),7.27-7.13(m,2H),5.76-5.58(m,1H),5.00(d ,J=10.0Hz,1H),4.88-4.79(m,1H),4.79-4.72(m,1H),4.72-4.63(m,2H),4.04-3.87(m,2H),3.26-3.19(m,1H) ),3.12-2.70(m,6H),2.26-2.11(m,3H),2.05-1.95(m,3H),1.87-1.62(m,7H),1.47(s,6H),1.26-1.14(m,2H).

[0265] Example 36: Compound 36 [ka]

[0266] Step 1: Synthesis of intermediate 36-2 Intermediate 061-1 (2.00 g, 9.94 mmol) and triethylamine (3.02 g, 29.8 mmol) were dissolved in dichloromethane (10 mL), and then p-toluenesulfonyl chloride (2.84 g, 14.9 mmol) was added in batches and stirred at 25 °C for 2 hours. The reaction mixture was spin-dried. Purification by column chromatography (petroleum ether: ethyl acetate = 1:0 to 1:1) gave white solid intermediate 36-2 (2.78 g, yield: 73.2%). MS (ESI+): m / z 378.1 [M+Na] + .

[0267] Step 2: Synthesis of intermediate 36-3 Intermediate B8 (140 mg, 268 μmol, hydrochloride salt), Intermediate 36-2 (143 mg, 402 μmol), and triethylamine (81.4 mg, 805 μmol) were dissolved in acetonitrile (2 mL), potassium iodide (134 mg, 805 μmol) was added, and the mixture was then heated at 100 °C for 2 hours under microwave irradiation. The reaction mixture was concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to give white solid Intermediate 36-3 (150 mg, yield: 64.4%). MS (ESI+): m / z 669.5 [M+H] + .

[0268] Step 3: Synthesis of intermediate 36-4 Dissolve intermediate 36-3 (150 mg, 224 μmol) in dichloromethane (2 mL), add hydrochloric acid / dioxane (4 M, 4 mL), and stir at 25 °C for 1 hour. Spin-dry the reaction mixture to give intermediate 36-4 (130 mg, crude product, hydrochloride salt), a yellow solid. MS (ESI+): m / z 569.24 [M+H] + .

[0269] Step 4: Synthesis of compound 36 [ka] Intermediate 36-4 (65.0 mg, 107 μmol, hydrochloride), intermediate 1-1 (32.6 mg, 118 μmol), and N,N-diisopropylethylamine (41.7 mg, 322 μmol) were dissolved in DMSO (1 mL) and reacted at 110 °C for 1 h under microwave irradiation. The reaction mixture was concentrated to give the crude product. Separation was performed using a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 × 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 15% B to 55% B) to give yellow solid compound 36 (10.0 mg, yield: 11.1%). MS (ESI+): m / z 825.4 [M+H] + .

[0270] 1 H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),10.25(s,1H),8.87(s,1H),8.10-8.00(m,1H),7.83-7.71(m,1H),7.69-7.56(m,4H),7.25-7.18(m,2H),6.9 2-6.89(m,1H),6.86-6.78(m,1H),5.72-5.61(m,1H),5.34(s,1H),5.09-5.02(m,1H),5.01-4.96(m,1H),4.85-4.78(m,1H) ),4.71-4.64(m,2H),3.61-3.55(m,1H),3.53-3.47(m,1H),3.19-3.12(m,1H),3.08-2.97(m,2H),2.92-2.83(m,1H),2.65 -2.58(m,2H),2.55-2.54(m,1H),2.46-2.35(m,4H),2.21-2.10(m,1H),2.06-1.95(m,3H),1.82-1.60(m,5H),1.46(s,6H).

[0271] Example 37: Compound 37 [ka]

[0272] Step 1: Synthesis of compound 37-2 Intermediate 37-1 (2 g, 9.94 mmol), 4-methylbenzenesulfonyl chloride (2.8 g, 14.9 mmol), 4-dimethylaminopyridine (364 mg, 2.98 mmol), and triethylamine (2 g, 19.87 mmol, 2.8 mL) were reacted in dichloromethane (20 mL) at 20 °C for 16 hours. The reaction mixture was spin-dried and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1). The resulting product was white intermediate 37-2 (4.2 g, crude product). MS (ESI+): m / z 355.7 [M+H] + .

[0273] Step 2: Synthesis of compound 37-4 Intermediate 37-2 (2 g, 5.63 mmol), intermediate 37-3 (387 mg, 1.88 mmol), triethylamine (1.9 g, 18.76 mmol, 2.6 mL), and potassium iodide (934 mg, 5.63 mmol) were dissolved in 1-methyl-2-pyrrolidone (1 mL) and heated in a microwave oven at 110 °C for 2 h. The mixture was extracted twice with water (80 mL) and dichloromethane (500 mL). The organic phase was separated, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) and spin-dried to give yellow solid intermediate 37-4 (400 mg, yield: 42.5%). MS (ESI+): m / z 390.4 [M+H] + .

[0274] Step 3: Synthesis of intermediate 37-5 Intermediate 37-4 (200 mg, 513.50 μmol) was dissolved in dichloromethane (5 mL), and then hydrochloric acid in dioxane (4 M, 5 mL) was added and reacted at 20° C. for 1 hour. The reaction solution was spin-dried. After spin-drying, the resulting product was a yellow solid, intermediate 37-5 (300 mg, crude product), which was used directly in the next step. MS (ESI+): m / z 290.1 ​​[M+H] + .

[0275] Step 4: Synthesis of intermediate 37-6 Intermediate 37-5 (200 mg, 691 μmol), Intermediate 1-1 (210 mg, 760 μmol), and diisopropylethylamine (268 mg, 2.07 mmol, 361 μL) were dissolved in dimethyl sulfoxide (1 mL) and reacted at 20 °C for 2 hours. Water (30 mL) and ethyl acetate (150 mL) were added and extracted three times. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The product was separated and purified by column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) and spin-dried to give yellow solid intermediate 37-6 (100 mg, yield: 26.0%). MS (ESI+): m / z 546.2 [M+H] + .

[0276] Step 5: Synthesis of intermediate 37-7 Intermediate 37-6 (100 mg, 183 μmol) and palladium carbon (300 mg, 10%) were dissolved in tetrahydrofuran (3 mL) and reacted under hydrogen gas at 20°C for 2 hours. The mixture was filtered and the filtrate was spin-dried. The product was separated and purified by column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) and spin-dried to give yellow solid intermediate 37-7 (30 mg, yield: 31.7%). MS (ESI+): m / z 516.2 [M+H] + .

[0277] Step 6: Synthesis of compound 37 [ka] To a solution of intermediate B6 (20 mg, 55.96 μmol) in toluene (3 mL) was added metachloroperbenzoic acid (18.8 mg, 87.3 μmol, 80%) and the reaction was allowed to react for 30 min at 20 °C. Intermediate 37-7 (30 mg, 58.2 μmol) and N,N-diisopropylethylamine (22.6 mg, 175 μmol, 30 μL) were then added. The reaction was allowed to react for 16 h at 20 °C. The reaction was quenched with 10 mL of sodium thiosulfate and 10 mL of saturated sodium bicarbonate and then extracted with two 60 mL portions of ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product. The crude product is purified by high performance liquid chromatography (acetonitrile / water (0.1% trifluoroacetic acid)) to give the crude product, which is further purified by thick preparative chromatography plate (dichloromethane:methanol=10:1) to give yellow solid compound 37 (4 mg, yield: 8.15%).

[0278] MS(ESI+):m / z 825.6[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),10.26(br s,1H),8.88(s,1H),8.16-7.97(m,1H),7.76(d,J=8.0Hz,1H),7.71-7.59(m,4H),7.23(d,J=12.0Hz, 2H),6.91(s,1H),6.83(d,J=8.0Hz,1H),5.75-5.60(m,1H),5.35(s,1H),5.11-4.96(m,2H),4.82(d,J =16.0Hz,1H),4.72-4.62(m,2H),3.61-3.54(m,1H),3.44-3.38(m,2H),3.20-3.12(m,1H),3.10-2.95 (m,2H),2.94-2.82(m,1H),2.58(d,J=20.0Hz,2H),2.38(d,J=8.0Hz,2H),2.16(d,J=8.0Hz,2H),2.09 1.90 (m, 4H), 1.83-1.62 (m, 5H), 1.47-1.43 (s, 6H).

[0279] Compound 38 is synthesized using a similar method to compound 37, but with different intermediates. [Table 13]

[0280] Example 39: Compound 39 [ka]

[0281] Step 1: Synthesis of compound 39-2 Intermediate B8 (80.0 mg, 153 μmol, HCl) and triethylamine (62.0 mg, 613 μmol) were dissolved in methanol (2 mL) and the pH was measured to be about 7-8. Intermediate 39-1 (114 mg, 613 μmol) and acetic acid (9.20 mg, 153 μmol) were then added to the reaction mixture, and the pH was measured to be about 5-6. The mixture was stirred at 25°C for 2 hours, followed by the addition of sodium cyanoborohydride (14.4 mg, 230 μmol) and stirring at 25°C for 12 hours. The reaction mixture was quenched with 10 mL of ammonium chloride solution and extracted twice with 20 mL of dichloromethane. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain a yellow solid intermediate 39-2 (100 mg, yield: 97.7%). MS (ESI+): m / z 655.0 [M+H] + .

[0282] Step 2: Synthesis of intermediate 39-3 Dissolve intermediate 39-2 (100 mg, 153 μmol) in dichloromethane (1 mL), add hydrochloric acid / dioxane (4 M, 2 mL), and stir at 25 °C for 1 h. Spin-dry the reaction mixture to give intermediate 39-3 (85.0 mg, crude product, hydrochloride salt), a yellow solid. MS (ESI+): m / z 555.21 [M+H] + .

[0283] Step 3: Synthesis of compound 39 [ka] Intermediate 39-3 (85.0 mg, 144 μmol, hydrochloride salt), Intermediate 1-1 (43.7 mg, 158 μmol), and triethylamine (43.7 mg, 431 μmol) were dissolved in N-methylpyrrolidone (2 mL) and reacted at 110 °C for 1 h under microwave irradiation. The reaction mixture was concentrated to give the crude product. Separation was performed using a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 × 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 10% B to 50%) to give compound 39 (10.0 mg, yield: 8.25%) as a white solid. MS (ESI+): m / z 811.5 [M+H] + .

[0284] 1 H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),10.27(s,1H),8.87(s,1H),8.10-7.99(m,1H),7.79-7.72(m,1H),7.71-7.59(m,4H),7.27-7.19(m,2H),6.99-6.9 6(m,1H),6.89-6.81(m,1H),5.73-5.61(m,1H),5.38-5.31(m,1H),5.19-5.04(m,1H),5.02-4.96(m,1H),4.86-4.78(m,1H),4.73 -4.64(m,2H),3.77-3.69(m,1H),3.62-3.55(m,1H),3.14-3.04(m,2H),3.03-2.96(m,1H),2.93-2.84(m,1H),2.60-2.56(m,1H) ,2.45-2.41(m,2H),2.32-2.24(m,2H),2.18-2.04(m,3H),2.03-1.98(m,1H),1.92-1.84(m,1H),1.79-1.64(m,4H),1.46(s,6H).

[0285] Compounds 40-44 were synthesized using a similar method to compound 39 but with different intermediates. [Table 14-1] [Table 14-2] [Table 14-3]

[0286] Example 45: Compound 45 [ka]

[0287] Step 1: Synthesis of intermediate 45-2 Intermediate 45-1 (1.00 g, 2.97 mmol), t-butyldimethyl(2-propynyloxy)silane (1.01 g, 5.93 mmol), triethylamine (300 mg, 2.97 mmol), and cuprous iodide (113 mg, 593 μmol) were dissolved in dimethyl sulfoxide (20 mL), stirred, and vented three times. Tetrakis(triphenylphosphine)palladium (343 mg, 297 μmol) was then added and stirred at 85 °C under nitrogen gas protection for 1 hour. The reaction mixture was diluted with 30 mL of ethyl acetate, 40 mL of water was added, and the mixture was extracted twice with 30 mL of ethyl acetate. The combined organic layer was washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purify by column chromatography (petroleum ether: ethyl acetate = 1:0 to 3:1) to obtain brown solid intermediate 45-2 (1.18 g, yield: 92.3%).

[0288] 1 H NMR(400MHz,DMSO-d6)δ 11.14(s,1H),8.17-7.65(m,3H),5.16(dd,J=5.2,12.8Hz,1H),4.75-4.38(m,2H), 3.02-2.77(m,1H),2.64-2.55(m,2H),2.14-2.02(m,1H),0.90(s,9H),0.15(s,6H).

[0289] Step 2: Synthesis of intermediate 45-3 Intermediate 45-2 (500 mg, 1.17 mmol) was dissolved in tetrahydrofuran (10 mL). Wet palladium on carbon (200 mg, 606.28 μmol, 10%) and palladium hydroxide on carbon (200 mg, 142 μmol) were added to the reaction mixture, and the mixture was stirred for 12 hours under hydrogen gas at 25° C. The reaction mixture was filtered, spin-dried, and filtered again to give intermediate 45-3 (380 mg, 75.3% yield) as a yellow oil.

[0290] 1 H NMR(400MHz,DMSO-d6)δ 11.12(s,1H),7.83(d,J=7.8Hz,1H),7.76(s,1H),7.70(d,J=7.8Hz,1H),5.13(s,1H),3.67-3.52(m,2H),2 .97-2.77(m,3H),2.65-2.52(m,2H),2.10-2.01(m,1H),1.87-1.70(m,2H),0.92-0.82(m,9H),0.03(s,6H).

[0291] Step 3: Synthesis of intermediate 45-4 Dissolve intermediate 45-3 (200 mg, 465 μmol) in dichloromethane (8 mL), add HCl-dioxane (12 mL, 4 M) to the reaction mixture, and stir the mixture at 25 °C for 1 h. Spin-dry the reaction mixture to give intermediate 45-4 (120 mg, 81.7% yield), a yellow solid. MS(ESI+):m / z 317.03[M+H] + .

[0292] Step 4: Synthesis of intermediate 45-5 Intermediate 45-4 (120 mg, 379 μmol) was dissolved in dichloromethane (4 mL). Dess-Martin (241 mg, 569 μmol) was added to the reaction mixture and stirred at 25 °C under nitrogen for 1 h. 6 mL of sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with 8 mL of dichloromethane. The organic layers were combined, washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) afforded colorless oily intermediate 45-5 (102 mg, yield: 85.6%).

[0293] 1 H NMR(400MHz,DMSO-d6)δ 11.12(s,1H),9.71(s,1H),7.86-7.79(m,2H),7.77-7.70(m,1H),5.18-5.08( m, 1H), 3.12-3.01 (m, 2H), 2.94-2.78 (m, 3H), 2.59 (s, 2H), 2.11-2.00 (m, 1H).

[0294] Step 5: Synthesis of compound 45 [ka] Intermediate B7-B (136 mg, 260 μmol, hydrochloride) was dissolved in dichloromethane (6 mL), triethylamine (98.5 mg, 974 μmol) was added to the solution, and the pH of the reaction solution was adjusted to 8. Intermediate 45-5 (102 mg, 325 μmol) and acetic acid (39.0 mg, 649 μmol) were added to the mixed solution, and the pH of the reaction solution was adjusted to 5-6. The reaction solution was stirred at 25°C under a nitrogen gas atmosphere for 12 hours, and sodium cyanoborohydride was added to the reaction solution. Sodium (24.5 mg, 389 μmol) was added and the reaction mixture was stirred at 25 °C under nitrogen for 1 hour. The reaction mixture was diluted with 16 mL of dichloromethane, 20 mL of water was added, and the mixture was extracted twice with 30 mL of dichloromethane. The combined organic layers were washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid preparative chromatography (chromatography column: Kromasil 100-5-C18 30 × 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 40% B to 60%) to obtain compound 45 (36.0 mg, yield: 13.4%) as a white solid. MS (ESI+): m / z 785.5 [M+H] + .

[0295] 1 H NMR(400MHz,DMSO-d6)δ 11.15(s,1H),10.65-9.97(m,1H),8.85(s,1H),8.11-7.99(m,1H),7.94-7.88(m,2H),7.86 -7.42(m,5H),7.01(d,J=8.8Hz,2H),5.75-5.56(m,1H),5.16(dd,J=5.6,12.8Hz,1H),5.05- 4.95(m,1H),4.88-4.76(m,1H),4.73-4.60(m,2H),3.83-3.72(m,2H),3.66-3.52(m,2H),3. 19-3.00(m,6H),2.97-2.80(m,3H),2.65-2.53(m,2H),2.22-2.02(m,3H),1.52-1.40(m,6H)

[0296] Compounds 46-51 were synthesized using a similar method to compound 45 but with different intermediates. [Table 15-1] [Table 15-2] [Table 15-3]

[0297] Example 52: Compound 52 [ka]

[0298] Step 1: Synthesis of intermediate 52-2 Intermediate B6 (200 mg, 560 μmol) was dissolved in toluene (3 mL). Metachloroperbenzoic acid (136 mg, 671 μmol, 85% purity) was slowly added to the solution, and the mixture was allowed to react at 25 °C for 1 h. Diisopropylethylamine (289 mg, 2.24 mmol) and Intermediate 52-1 (139 mg, 671 μmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 3 h. The reaction mixture was quenched with 10 mL of 1 M sodium thiosulfate, extracted three times with 10 mL of ethyl acetate, and the organic phase was collected. The organic phase was washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to give yellow solid Intermediate 52-2 (230 mg, yield: 71.8%). MS(ESI+): m / z 516.19[M+H] + .

[0299] 1H NMR(400MHz,DMSO-d6)δ 10.15(s,1H),8.82(s,1H),8.15-7.97(m,1H),7.82-7.70(m,1H),7.63-7.47(m,3 H),7.09-6.83(m,2H),5.74-5.53(m,1H),5.36(s,1H),5.08-4.93(m,1H),4.88-4. 77(m,1H),4.74-4.59(m,2H),4.57-4.48(m,1H),3.73-3.56(m,2H),3.31-3.29(m ,2H),2.63-2.58(m,2H),1.80-1.70(m,2H),1.50-1.42(m,7H),1.29-1.21(m,2H).

[0300] Step 2: Synthesis of intermediate 52-3 Intermediate 52-2 (122 mg, 237 μmol) and triethylamine (71.8 mg, 710 μmol) were dissolved in dichloromethane (5 mL), methylsulfonyl chloride (190 mg, 1.66 mmol) was slowly added to the solution, and the mixture was reacted for 1 hour at 25 °C. The reaction mixture was poured into 20 mL of water, extracted twice with 30 mL of dichloromethane, and the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and spin-dried to give green solid intermediate 52-3 (130 mg, yield: 70.7%).

[0301] 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.82(s,1H),8.17-7.98(m,1H),7.81-7.70(m,1H),7.62-7.52(m,3 H),6.96-6.85(m,2H),5.73-5.59(m,1H),5.36(s,1H),5.05-4.94(m,1H),4.88-4 .79(m,1H),4.76-4.61(m,2H),4.16-4.04(m,2H),3.72-3.64(m,2H),3.19-3.17( m,3H),2.67-2.60(m,2H),1.81-1.75(m,2H),1.50-1.43(m,7H),1.42-1.33(m,2H)

[0302] Step 3: Synthesis of compound 52 [ka] Dissolve intermediate 52-3 (130 mg, 153 μmol), intermediate 52-4 (52.5 mg, 153 μmol), and diisopropylethylamine (59.4 mg, 460 μmol) in DMF (3 mL) and microwave the mixture at 100 °C for 1 h. Pour the reaction mixture into 20 mL of water. Extract twice with 30 mL of dichloromethane. Collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and spin-dry to obtain the crude product. Separation was performed on a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 20% B to 50%) to obtain yellow solid compound 52 (10.0 mg, yield: 15.5%).

[0303] MS(ESI+):m / z 840.6[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),10.05(s,1H),8.86-8.68(m,1H),8.08-7.95(m,1H),7.90-7.19(m,5H),7.16- 6.85(m,3H),6.54-6.47(m,1H),5.72-5.59(m,1H),5.33(dd,J=5.2,12.8Hz,1H),5.05-4.94( m,1H),4.88-4.76(m,1H),4.74-4.60(m,2H),3.32(s,3H),3.05-3.00(m,2H),2.93-2.82(m,3 H),2.67-2.61(m,2H),2.46-2.25(m,5H),2.18-1.94(m,5H),1.81-1.58(m,7H),1.45(s,6H).

[0304] Compounds 53-54 were synthesized using a similar method to compound 52, but with different intermediates. [Table 16]

[0305] Example 55: Compound 55 [ka]

[0306] Step 1: Synthesis of intermediate 55-2 Intermediate B17 (250 mg, 793 μmol) and intermediate 55-1 (297 mg, 961 μmol) were dissolved in 1,4-dioxane (5 mL) and water (0.2 mL). Cesium carbonate (723 mg, 2.22 mmol) and XPhos Pd G3 (125 mg, 148 μmol) were added, and the mixture was purged with nitrogen gas three times and stirred at 60 °C for 3 h under nitrogen gas protection. The reaction mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was separated by column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain white solid intermediate 55-2 (322 mg, 85.0% yield). MS (ESI+): m / z 384.8 [M+H-56] + .

[0307] Step 2: Synthesis of intermediate 55-3 Intermediate 55-2 (322 mg, 629 μmol) was dissolved in tetrahydrofuran (15 mL), platinum dioxide (500 mg, 2.20 mmol) was added, and the mixture was purged with hydrogen gas three times and stirred under a hydrogen gas atmosphere at 20° C. for 32 hours. The reaction mixture was filtered, and the filtrate was spin-dried to give white solid intermediate 55-3 (324 mg, crude product). MS (ESI+): m / z 387.0 [M+H-56] + .

[0308] Step 3: Synthesis of intermediate 55-4 Dissolve intermediate 55-3 (324 mg, 732 μmol) in dichloromethane (5 mL), add hydrochloric acid / dioxane solution (4 M, 4 mL), and stir the reaction for 1 h at 20° C. Spin dry the reaction to give white solid intermediate 55-4 (302 mg, crude).

[0309] Step 4: Synthesis of intermediate 55-7 Intermediate 55-5 (1.0 g, 7.09 mmol) and intermediate 55-6 (1.13 g, 7.09 mmol) were dissolved in dimethyl sulfoxide (5 mL), diisopropylethylamine (4.58 g, 35.4 mmol, 6.17 mL) was added, and the mixture was stirred at 90 °C for 1 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether / ethyl acetate = 3 / 1) gave yellow solid intermediate 55-7 (1.50 g, yield: 75.5%).

[0310] Step 5: Synthesis of intermediate 55-8 Intermediate 55-7 (1.5 g, 5.53 mmol) was dissolved in tetrahydrofuran (20 mL), palladium on carbon (1 g, 10%) was added, and the mixture was purged with hydrogen gas three times and stirred under hydrogen gas atmosphere for 1 h at 30° C. The reaction mixture was filtered and spin-dried to give brown solid intermediate 55-8 (1.35 g, crude product).

[0311] Step 6: Synthesis of intermediate 55-9 Intermediate B6 (100 mg, 280 μmol) was dissolved in toluene (3 mL), metachloroperbenzoic acid (62.5 mg, 308 μmol) was added, and the mixture was stirred at 30 °C for 0.5 h. Diisopropylethylamine (72.3 mg, 560 μmol, 98 μL) was added, followed by intermediate 55-8 (77.0 mg, 308 μmol), and the mixture was stirred at 30 °C for 10 h. Saturated sodium thiosulfate solution (30 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the layers were separated. The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether / ethyl acetate = 1 / 2) gave intermediate 55-9 (160 mg, 98.9% yield) as a yellow solid. MS (ESI+): m / z 560.0 [M+H] + .

[0312] Step 7: Synthesis of intermediate 55-10 Intermediate 55-9 (60 mg, 107 μmol) is dissolved in a solution of hydrochloric acid in dioxane (4 M, 2 mL) and stirred for 1 h at 30° C. The reaction is spun to dryness to give a yellow solid, intermediate 55-10 (65.0 mg, crude), which is used directly in the next step.

[0313] Step 8: Synthesis of Compound 55 [ka] Intermediate 55-10 (50 mg, 132 μmol) and intermediate 55-4 (65 mg, 118 μmol) were dissolved in N,N-dimethylformamide (1.5 mL) and dichloromethane (4 mL). Triethylamine (120 mg, 1.18 mmol, 164 μL) was added and the mixture was stirred at 30° C. for 0.5 h. Acetic acid (70.6 mg, 1.18 mmol, 67.6 μL) was then added and the mixture was stirred at 30° C. for 0.5 h. Sodium triacetoxyborohydride (150 mg, 709 μmol) was then added and the mixture was stirred at 30° C. for 16 h. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product. Separation by high-performance liquid chromatography (acetonitrile / water (2% formic acid)) gave yellow solid compound 55 (30.0 mg, yield: 28.9%). MS (ESI+): m / z 840.6 [M+H] + .

[0314] 1H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),10.12(br s,1H),8.82(s,1H),8.22(s,0.476 H),8.04(br s,1H),7.82-7.69(m,J=8.4Hz,1H),7.68-7.45(m,3H),7.10-6.85(m,5H),5.73-5.59(m,1H),5.43-5.2 4(m,2H),5.07-4.94(m,J=10.4Hz,1H),4.82(d,J=17.2Hz,1H),4.73-4.59(m,J=4.8Hz,2H),3.64(d,J= 12.0Hz,2H),3.58(s,3H),2.99(d,J=10.8Hz,2H),2.93-2.81(m,1H),2.76-2.57(m,4H),2.45-2.38(m, 1H), 2.28-2.17 (m, J=6.4Hz, 2H), 2.14-1.93 (m, 3H), 1.86-1.62 (m, 7H), 1.46 (s, 6H), 1.31-1.15 (m, 2H).

[0315] Compounds 95 and 96 are synthesized using a similar method to compound 55 by reductive amination of different intermediates. [Table 17]

[0316] Example 58: Compound 58 [ka]

[0317] Step 1: Synthesis of compound 58-1 Intermediate B16 (500 mg, 1.89 mmol) and 3-aminopiperidine-2,6-dione (492 mg, 2.99 mmol, hydrochloride salt) were dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (957 mg, 9.46 mmol, 1.3 mL) and 50% T3P in ethyl acetate (2.4 g, 3.78 mmol, 2.3 mL). The reaction was stirred at 20 °C for 6 h. The reaction was diluted with water (30 mL) and extracted with four 200 mL portions of 10:1 dichloromethane:methanol. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give yellow solid intermediate 58-1 (200 mg, 14.6% yield). MS (ESI+): m / z 362.1 [M+H] + .

[0318] Step 2: Synthesis of intermediate 58-2 Intermediate 58-1 (300 mg, 830.12 μmol) was dissolved in dichloromethane (5 mL), followed by the addition of DMP (704 mg, 1.66 mmol, 514 μL) and stirring the reaction at 20 °C for 1 h. The reaction was quenched by the addition of sodium thiosulfate:sodium bicarbonate = 1:1 (100 mL), extracted with dichloromethane (30 mL), and the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. A yellow liquid, intermediate 58-2 (280 mg, 91.7% yield), was obtained. MS (ESI+): m / z 360.1 [M+H] + .

[0319] Step 3: Synthesis of intermediate 58-3 Intermediate 58-2 (200 mg, 557 μmol) and piperazine-1-carboxylic acid t-butyl ester (103 mg, 557 μmol) were dissolved in dichloromethane (2 mL), acetic acid (67 mg, 1.11 mmol) was added, and the mixture was stirred for 1 hour. Sodium borohydride acetate (354 mg, 1.67 mmol) was added, and the mixture was stirred at 20 °C for 16 hours. Water (20 mL) and dichloromethane (50 mL) were added to the reaction mixture, and the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. Purification by column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) gave yellow solid intermediate 58-3 (150 mg, yield: 45.0%). MS (ESI+): m / z 529.9 [M+H] + .

[0320] Step 4: Synthesis of intermediate 58-4 Intermediate 58-3 (150 mg, 283.22 μmol) is dissolved in dichloromethane (3 mL), HCl in dioxane (4 M, 10 mL) is added, and the reaction is stirred at 20 °C for 1 h. The reaction is spun to dryness to give intermediate 58-4 (150 mg, yield: crude product), a gray solid, which is used directly in the next step. MS (ESI+): m / z 430.1 [M+H] + .

[0321] Step 5: Synthesis of intermediate 58-5 Intermediate B2-1 (1.6 g, 4.06 mmol) and 4-aminobenzyl alcohol (800 mg, 6.50 mmol) were reacted in dimethyl sulfoxide (8 mL) at 120 °C for 3 hours, and the reaction mixture was spin-dried to give brown solid intermediate 58-5 (330 mg, 12.6% yield). MS (ESI+): m / z 454.96 [M+H] + .

[0322] Step 6: Synthesis of intermediate 58-6 Intermediate 58-5 (30 mg, 66.2 μmol) and thionyl chloride (40 mg, 331 μmol, 24.0 μL) were added to dichloromethane (3 mL) and reacted for 1 hour at 20° C. The reaction solution was spun dry to give a yellow solid intermediate 58-6 (31 mg, yield: 99.29%).

[0323] Step 7: Synthesis of compound 58 [ka] A solution of intermediate 58-4 (30 mg, 63.60 μmol), intermediate 58-6 (30 mg, 59.71 μmol, hydrochloride salt), and potassium carbonate (41.26 mg, 299 μmol) in N,N-dimethylformamide (3 mL) was purged with nitrogen gas three times and stirred under nitrogen gas protection at 20 °C for 16 hours. The reaction mixture was filtered, spin-dried, and then separated using a high-performance liquid chromatography column (acetonitrile / water (0.1% trifluoroacetic acid)) to give compound 58 (2.43 mg, yield: 4.66%) as a white solid. MS (ESI+): m / z 864.2 [M+H] + .

[0324] 1 H NMR(400MHz,DMSO-d6)δ 11.22-10.81(m,1H),10.36(s,1H),9.20(s,1H),8.95(br s,1H),7.90(br s,2H),7.83-7.72(m,2H),7.70-7.59(m,1H),7.48(d,J=8.0Hz,1H),7.42-7.29(m,3H),7.24-7.08(m,2H),4.40(br s,1H),4.02(br s,2H),3.85(s,3H),3.88-3.82(m,1H),3.62 3.57(m,4H),3.27(br s,5H),2.74-2.60(m,5H),2.33(br s,1H),1.95(br s,1H),1.76(br s,2H),1.25-1.03(m,3H).

[0325] Examples 59-60 are synthesized using a similar method to compound 58, but with different intermediates. [Table 18]

[0326] Example 61: Compound 61 [ka]

[0327] Step 1: Synthesis of intermediate 61-2 Intermediate B19 (500 mg, 1.09 mmol), Intermediate 61-1 (304 mg, 1.42 mmol), and cesium carbonate (1.07 g, 3.27 mmol) were dissolved in toluene (5 mL) and dioxane (5 mL). Pd-PEPPSI-IPentCl (53.1 mg, 54.6 μmol) was added, and the mixture was purged with nitrogen three times and stirred at 100 °C for 16 h. The reaction mixture was diluted with dichloromethane, filtered, spin-dried, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give colorless oily intermediate 61-2 (330 mg, 39.4% yield). MS (ESI+): m / z 592.2 [M+H] + .

[0328] Step 2: Synthesis of intermediate 61-3 Intermediate 61-2 (390 mg, 659 μmol) was dissolved in toluene (0.94 mL), methylsulfonic acid (1.27 g, 13.2 mmol, 938 μL) was added, and the mixture was purged with nitrogen three times. The mixture was then stirred at 120 °C for 2 h. The mixture was stirred at 0 °C for 15 min, and triethylamine (2.67 g, 26.4 mmol, 3.67 mL) and di-t-butyl dicarbonate (1.44 g, 6.59 mmol) were added at 0 °C. The mixture was then stirred at 0 °C for 15 min. The reaction mixture was diluted with dichloromethane (30 mL), water (50 mL) was added, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product, which was purified by column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain colorless oily intermediate 61-3 (267 mg, yield: 53.3%). MS (ESI+): m / z 472.3 [M+H] + .

[0329] Step 3: Synthesis of intermediate 61-4 Intermediate 61-3 (267 mg, 566 μmol) was dissolved in dichloromethane (1 mL) and hydrochloric acid in dioxane (4 M, 2.33 mL) was added. The reaction was stirred at 30 °C for 1 h. The reaction was spun to dryness to give a yellow solid, intermediate 61-4 (239 mg, hydrochloride salt), which was used crude in the next step directly.

[0330] Step 4: Synthesis of compound 61 [ka] Intermediate 55-10 (30 mg, 58.4 μmol) and intermediate 61-4 (23.8 mg, 58.4 μmol, hydrochloride salt) were dissolved in dichloromethane (3 mL), triethylamine (17.7 mg, 175 μmol, 24 μL) was added, and the mixture was stirred at 25 °C for 30 min. Acetic acid (10.5 mg, 175 μmol, 10.0 μL) was added, and the mixture was stirred at 25 °C for 30 min. Finally, sodium borohydride acetate (37.1 mg, 175 μmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was spin-dried to obtain the crude product, which was then separated by high-performance liquid chromatography (acetonitrile / water (0.1% trifluoroacetic acid)). The crude product was separated by high-performance liquid chromatography (acetonitrile / water (2% formic acid)) to obtain compound 61 (3 mg, yield: 5.5%) as a yellow solid.

[0331] MS(ESI+):m / z 869.6[M+H] + 1 H NMR(400MHz,DMSO-d6)δ 11.25-10.93(m,1H),10.25-9.93(m,1H),8.81(s,1H),8.36(s,1.07H),8.04(t,J=8.0Hz,1H),7.75(d,J=6.8Hz,1H) ,7.63-7.40(m,3H),7.02-6.79(m,5H),5.76-5.60(m,1H),5.45-5.24(m,2H),4.99(d,J=10.0Hz,1H),4.88-4.80(m,1 H),4.75-4.60(m,2H),3.63(s,5H),3.16-3.12(m,2H),2.89-2.85(m,1H),2.74-2.70(m,3H),2.64-2.60(m,4H),2.36 -2.31(m,2H),2.25(s,3H),2.04-1.94(m,1H),1.88-1.74(m,4H),1.71-1.53(m,3H),1.46(s,6H),1.31-1.16(m,2H).

[0332] Compounds 90, 98 and Example 99 are synthesized using a similar method to compound 61, but with different intermediates. [Table 19-1] [Table 19-2]

[0333] Example 62: Compound 62 [ka]

[0334] Step 1: Synthesis of intermediate 62-3 Intermediate 62-1 (500 mg, 1.82 mmol) and 1,3-dibromopropane (1.84 g, 9.12 mmol) were dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (252 mg, 1.82 mmol) was added, and the reaction mixture was stirred at 50 °C for 16 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to obtain colorless oily intermediate 62-3 (480 mg, yield: 26.7%). MS (ESI+): m / z 395.20 [M+H] + .

[0335] Step 2: Synthesis of compound 62 [ka] Intermediate 62-3 (75.6 mg, 191 μmol) and intermediate B7-B (100 mg, 191 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), followed by the addition of potassium carbonate (252 mg, 1.82 mmol). The reaction mixture was stirred at 60 °C for 16 h. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance liquid chromatography (trifluoroacetic acid) and lyophilized to give a yellow solid. The yellow solid was diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate (3 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by column chromatography (dichloromethane:methanol = 10:1, silica gel column 4 g) to give yellow solid compound 62 (12 mg, 14.83 μmol, yield: 7.76%). MS(ESI+): m / z 800.82[M+H] + .

[0336] 1 H NMR(400MHz,DMSO-d6)δ 11.13(s,1H),10.16(s,1H),8.83(s,1H),8.05(s,1H),7.85(d,J=8.4Hz,1H),7.75(d,J=8.0Hz,1H),7.61(d,J=8.0 Hz,3H),7.46(d,J=2.0Hz,1H),7.38(d,J=8.4Hz,1H),6.93(d,J=8.0Hz,2H),5.73-5.61(m,1H),5.35(s,1H),5.13(d d,J=5.6,13.2Hz,1H),4.99(d,J=10.0Hz,1H),4.82(d,J=17.2Hz,1H),4.68(d,J=4.4Hz,2H),4.26(t,J=6.0Hz,2H), 3.39(s,1H),3.30-3.29(m,1H),3.12(s,4H),2.97-2.82(m,1H),2.64-2.54(m,5H),2.15-1.88(m,4H),1.46(s,6H).

[0337] Compound 63 is synthesized using a similar method to compound 62, but with different intermediates. [Table 20]

[0338] Example 64: Compound 64 [ka] Step 1: Synthesis of compound 64 Intermediate 64-1 (82.0 mg, 132.28 μmol) and intermediate B28 (38.0 mg, 132.28 μmol) were dissolved in dichloroethane (10 mL), triethylamine (53.5 mg, 529.12 μmol) was added, and the mixture was stirred at 25 °C for 30 minutes. After that, acetic acid (23.8 mg, 396.84 μmol) was added and the mixture was stirred at 25 °C for 30 minutes. Sodium borohydride acetate (84.1 mg, 397 μmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (formic acid conditions) and lyophilized to obtain compound 64 (3 mg, 3.51 μmol, 2.65% yield) as a yellow solid. MS(ESI+):m / z 877.6[M+Na] + .

[0339] 1H NMR(400MHz,DMSO-d6)δ 11.11(s,1H),10.38-9.93(m,1H),8.84(s,1H),8.13-7.99(m,1H),7.7 6(d,J=4.0Hz,1H),7.61(d,J=8.0Hz,3H),7.31-6.86(m,5H),5.78-5.59 (m,1H),5.46-5.28(m,2H),5.00(d,J=8.0Hz,1H),4.83(d,J=16.0Hz,1H),4.68(d,J=4.0Hz,2H),3.72-3.62(m,4H),3.31-3.29(m,3H),3.09(br s,4H),2.94-2.81(m,2H),2.76-2.69(m,1H),2.57-2.53(m,6H),2.45-2.36(m,2H),2.08-1.93(m,4H),1.71(br s,2H),1.47(s,6H).

[0340] Example 65: Compound 65 [ka]

[0341] Step 1: Synthesis of intermediate 65-3 Intermediate B19 (500 mg, 1.09 mmol), intermediate 65-2 (325 mg, 1.42 mmol), and cesium carbonate (1.07 g, 3.27 mmol) were dissolved in toluene (8 mL) and dioxane (8 mL). Pd-PEPPSI-IPentCl (53.1 mg, 54.6 μmol) was added, the mixture was purged with nitrogen three times, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with dichloromethane, filtered, spin-dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to give colorless oily intermediate 65-3 (95 mg, 12.9% yield).

[0342] 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.15(m,2H),6.95-6.88(m,2H),6.87-6.83(m,2H),6.81-6.70(m,1H), 5.58-5.42(m,1H),4.92-4.51(m,2H),3.72(s,3H),3.61(s,3H),3.55-3.43( m,2H),3.21-2.98(m,3H),2.88-2.63(m,4H),2.10-2.01(m,1H),1.86-1.70( m, 2H), 1.63-1.50 (m, 1H), 1.46-1.31 (m, 2H), 0.88 (s, 9H), 0.08-0.04 (m, 6H).

[0343] Step 2: Synthesis of intermediate 65-4 Intermediate 65-3 (110 mg, 181 μmol) was dissolved in toluene (2 mL), methylsulfonic acid (1.35 g, 14.1 mmol, 1 mL) was added, and the mixture was purged with nitrogen gas three times, followed by stirring at 120 °C for 1.5 hours. Triethylamine (3 mL) was added at 0 °C, and the mixture was separated by high-performance liquid chromatography (HPLC) under neutral conditions to obtain the crude product. Dichloromethane (10 mL) was added, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. Water (5 mL) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain colorless oily intermediate 65-4 (31 mg, 38.6% yield). MS (ESI+): m / z 373.2 [M+H] + .

[0344] Step 3: Synthesis of intermediate 65-5 Intermediate 65-4 (31 mg, 83.2 μmol) was dissolved in dichloromethane (2 mL) and dimethyl sulfoxide (0.1 mL). Dess-Martin reagent (70.6 mg, 166 μmol) was added to the reaction mixture and stirred at 25 °C for 30 min. The reaction mixture was diluted with dichloromethane, quenched with sodium thiosulfate (5 mL) and sodium bicarbonate (5 mL), and extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun to give colorless oily intermediate 65-5 (30 mg, crude), which was used directly in the next step.

[0345] Step 4: Synthesis of compound 65 [ka] Intermediate 65-5 (30 mg, 81.0 μmol) and intermediate B7-B (42.4 mg, 81.0 μmol, hydrochloride salt) were dissolved in dichloromethane (3 mL), triethylamine (24.6 mg, 243 μmol, 33.8 μL) was added, and the mixture was stirred at 25 °C for 30 min. Acetic acid (14.6 mg, 243 μmol) was added, and the mixture was stirred at 25 °C for 30 min. Finally, sodium borohydride acetate (51.5 mg, 243 μmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was spin-dried to obtain the crude product, which was then separated by a high-performance liquid chromatography column (acetonitrile / water (2% formic acid)). The crude product was obtained by slurrying with acetonitrile (3 mL) to obtain yellow solid compound 65 (16 mg, yield: 22.9%). MS (ESI+): m / z 841.6 [M+H] +

[0346] 1H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),10.29-10.06(m,1H),8.82(s,1H),8.15-7.98(m,1H),7.82-7.69(m,1H),7.68-7.44(m,3H),7.05-6.79(m, 5H),5.74-5.58(m,1H),5.40-5.27(m,2H),5.05-4.94(m,1H),4.89-4.78(m,1H),4.75-4.61(m,2H),3.63(s,3H),3.11(br s,5H),2.95-2.83(m,1H),2.76-2.62(m,4H),2.59(br s,1H),2.56-2.52(m,4H),2.31-2.19(m,2H),2.07-1.93(m,1H),1.90-1.79(m,2H),1.77-1.62(m,1H),1.46(s,6H),1.40-1.28(m,2H).

[0347] Compounds 66 and 97 are synthesized using a similar method to compound 65, but with different intermediates. [Table 21]

[0348] Example 67: Compound 67 [ka]

[0349] Step 1: Synthesis of intermediate 67-3 Intermediate 67-1 (3 g, 18.9 mmol) and intermediate 67-2 (5.27 g, 28.3 mmol) were dissolved in N-methylpyrrolidone (10 mL) and stirred at 60 °C for 3 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give white solid intermediate 67-3 (6.01 g, crude product). The crude product was used directly in the next step. MS (ESI+): m / z 269.8 [M+H-56] + .

[0350] Step 2: Synthesis of intermediate 67-4 Intermediate 67-3 (6.01 g, 18.5 mmol) was dissolved in tetrahydrofuran (60 mL), palladium on carbon (2 g, 10%) was added, and the mixture was purged with hydrogen gas three times and stirred under a hydrogen gas atmosphere at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was spin-dried to give white solid intermediate 67-4 (5.66 g, crude product), which was used directly in the next step. MS (ESI+): m / z 240.0 [M-56+H] + .

[0351] Step 3: Synthesis of intermediate 67-6 Intermediate 67-4 (1 g, 3.39 mmol) and intermediate 67-5 (1.25 g, 3.39 mmol) were dissolved in 1,4-dioxane (20 mL), and cesium carbonate (3.31 g, 102 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (141.6 mg, 169 μmol) were added and the mixture was stirred at 100° C. for 16 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the organic phase was washed with two 60 mL portions of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 20 / 1 to 3 / 1) to give a yellow oily compound. The reaction mixture was spin-dried to give white solid intermediate 67-6 (908 mg, yield: 94%). MS (ESI+): m / z 528.9 [M+H-56] + .

[0352] Step 4: Synthesis of intermediate 67-7 Intermediate 67-6 (908 mg, 1.55 mmol) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL), and palladium on carbon (800 mg, 10%) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain white solid intermediate 67-7 (324 mg, yield: 51.3%). m / z 350.9 [M-56] + .

[0353] Step 5: Synthesis of intermediate 67-8 Intermediate 67-7 (324 mg, 797 μmol) is dissolved in dichloromethane (5 mL), hydrochloric acid / 1,4-dioxane (4 M, 5 mL) is added, and the mixture is stirred for 1 h at 25° C. The reaction is spun to dryness to give white solid intermediate 67-8 (242 mg, crude). Step 6: Synthesis of intermediate 67-10 Intermediate 67-8 (50.0 mg, 146 μmol) and intermediate 67-9 (48.2 mg, 219 μmol) were dissolved in dichloromethane (2 mL), triethylamine (44.3 mg, 438 μmol, 60.91 μL) was added, and the mixture was stirred at 20 °C for 0.5 h. Acetic acid (26.3 mg, 438 μmol, 25.0 μL) was then added, and the mixture was stirred at 20 °C for 0.5 h. Sodium cyanoborohydride (18.33 mg, 292 μmol) was then added, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product. Separation by column chromatography (dichloromethane:methanol = 1:0 to 10:1) gave yellow solid intermediate 67-10 (56 mg, yield: 61.7%). MS (ESI+): m / z 510.5 [M].

[0354] Step 7: Synthesis of intermediate 67-11 Intermediate 67-10 (56 mg, 110 μmol) is dissolved in tetrahydrofuran (1 mL) and saturated ammonium chloride solution (0.3 mL), reduced iron powder (61 mg, 1.10 mmol) is added, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is filtered and spin-dried to give gray solid intermediate 67-11 (60.0 mg, crude product).

[0355] Step 8: Synthesis of compound 67 [ka] Intermediate B6 (60 mg, 125 μmol) was dissolved in toluene (2 mL), 3-chloroperoxybenzoic acid (27.9 mg, 137 μmol) was added, and the mixture was stirred at 25 °C for 0.5 h. N,N-diisopropylethylamine (32.3 mg, 250 μmol, 43.5 μL) and intermediate 67-11 (44.6 mg, 125 μmol) were then added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched at 20 °C using a saturated solution of sodium thiosulfate and sodium bicarbonate (1:1, 50 mL), diluted with ethyl acetate (50 mL), and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product. High-performance liquid chromatography (HPLC) separation (acetonitrile / water (2% formic acid)) afforded compound 67 (1.00 mg, 1.01% yield) as a yellow solid.

[0356] MS(ESI+): m / z 790.5[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.23-10.11(m,1H),8.83(s,1H),8.38(s,1.897H),8.06(br s,1H),7.75(d,J=8.4Hz,1H),7.68-7.49(m,3H),6.95(d,J=8.6Hz,2H),6.83(t,J= 9.6Hz,1H),6.52(d,J=16.0Hz,1H),6.43(d,J=8.4Hz,1H),5.82(d,J=7.6Hz,1H),5 .73-5.59(m,1H),5.37(s,1H),5.00(d,J=11.2Hz,1H),4.86-4.77(m,J=16.8Hz,1H ),4.73-4.61(m,J=5.2Hz,2H),4.29-4.21(m,1H),3.70(d,J=11.2Hz,2H),2.86(br s,4H),2.64(br s,4H),2.59(d,J=4.4Hz,2H),2.12-2.04(m,2H),1.94-1.83(m,4H),1.55(d,J=8.4Hz,2H),1.47(s,6H).

[0357] Compounds 68, 69, 70, 123, 154 and compound 155 are synthesized using a similar method to compound 67 but with different intermediates. [Table 22-1] [Table 22-2] [Table 22-3]

[0358] Example 71: Compound 71 [ka] Step 1: Synthesis of compound 71 Intermediate 67-8 (100 mg, 292 μmol) and intermediate 55-10 (160 mg, 292 μmol) were dissolved in dichloromethane (2 mL), triethylamine (88.6 mg, 875 μmol, 122 μL) was added, and the mixture was stirred at 25 °C for 0.5 h. Acetic acid (52.6 mg, 875 μmol, 50 μL) was then added, and the mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (124 mg, 583 μmol) was then added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. High-performance liquid chromatography (HPLC) column chromatography (acetonitrile / water (2% formic acid)) afforded compound 71 (8.98 mg, 3.64% yield) as a yellow solid.

[0359] MS(ESI+): m / z 804.5[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),10.13(br s,1H),8.81(s,1H),8.32(s,0.337 H),8.04(br s,1H),7.74(d,J=7.2Hz,1H),7.64-7.47(m,3H),6.97-6.89(m,2H),6.87- 6.77(m,1H),6.56-6.48(m,1H),6.46-6.38(m,1H),5.80(d,J=7.6Hz,1H), 5.73-5.58(m,1H),5.35(s,1H),4.99(d,J=10.0Hz,1H),4.82(d,J=18.0Hz ,1H),4.67(d,J=5.2Hz,2H),4.30-4.20(m,1H),3.66-3.61(m,2H),2.86(br s,4H),2.76-2.67(m,1H),2.65-2.57(m,2H),2.48-2.46(m,5H),2.21(d,J=6.8Hz,2H),2.12-2.00(m,1H),1.89-1.76(m,3H),1.66(br s, 1H), 1.46 (s, 6H), 1.30-1.24 (m, 2H).

[0360] Compounds 72, 91, 92, 94, 140 and compound 147 are synthesized using a similar method to compound 71 but with different intermediates. [Table 23-1] [Table 23-2] [Table 23-3]

[0361] Example 73: Compound 73 [ka]

[0362] Step 1: Synthesis of intermediate 73-3 Intermediate 73-1 (4.50 g, 28.26 mmol) and intermediate 73-2 (3 g, 18.84 mmol) were dissolved in dimethyl sulfoxide (10 mL) and stirred at 90 °C for 16 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was carried out by column chromatography (dichloromethane / methanol = 10:1) to obtain white solid intermediate 73-3 (6.93 g, crude product), which was used directly in the next step of the reaction. MS(ESI+): m / z 298.31[M+H] + .

[0363] Step 2: Synthesis of intermediate 73-4 Intermediate 73-3 (6.39 g, 21.4 mmol) is dissolved in tetrahydrofuran (30 mL), then 10% palladium on carbon (4 g) is added, and the reaction is stirred for 16 hours at 20° C. under a hydrogen gas atmosphere. Filtration and concentration under reduced pressure give red solid intermediate 73-4 (7.42 g, crude product), which is used directly in the next step of the reaction. MS (ESI+): m / z 268.33 [M+H] + .

[0364] Step 3: Synthesis of intermediate 73-6 Intermediate 73-4 (2.63 g, 9.80 mmol) and intermediate 73-5 (3.63 g, 9.80 mmol) were dissolved in 1,4-dioxane (30 mL), and cesium carbonate (9.58 g, 29.41 mmol) and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (410 mg, 490 μmol) were added. The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours, and ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purify by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain red solid intermediate 73-6 (3.4 g, yield: 62.2%). MS (ESI+): m / z 557.65 [M+H] + .

[0365] Step 4: Synthesis of intermediate 73-7 Intermediate 73-6 (3.39 g, 6.08 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of 10% palladium on carbon (2 g). The reaction mixture was purged with hydrogen gas three times and stirred at 20 °C for 16 h under a hydrogen atmosphere. The mixture was filtered under reduced pressure and the filtrate was concentrated to give the crude product. The crude product was purified by chromatography (petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give the pale green solid intermediate 73-7 (699 mg, yield: 30%). MS (ESI+): m / z 379.42 [M+H] + .

[0366] Step 5: Synthesis of intermediate 73-8 Intermediate 73-7 (293 mg, 772 μmol) is dissolved in dichloromethane (5 mL), then hydrochloric acid / 1,4-dioxane (5 mL) is added and the reaction is stirred at 20° C. for 3 hours. Filtration and concentration under reduced pressure give a yellow solid intermediate 73-8 (350 mg, crude product), which is used directly in the next step of the reaction. MS (ESI+): m / z 333.365 [M+H]+ .

[0367] Step 6: Synthesis of compound 73 [ka] Intermediate 73-8 (80.0 mg, 216 μmol, HCl) and intermediate B8 (113 mg, 216 μmol, hydrochloride salt) were dissolved in dichloromethane (2 mL), triethylamine (87.6 mg, 865 μmol) was added, and the mixture was stirred at 25 °C for 30 min. After that, acetic acid (39.0 mg, 649 μmol) was added to adjust the pH to 5-6, and the mixture was stirred at 25 °C for 30 min. Sodium borohydride acetate (138 mg, 649 μmol) was added, and the reaction mixture was stirred at 25 °C for 16 h. The mixture was then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance liquid chromatography (formic acid conditions) and lyophilized to give compound 73 (81 mg, 46.6% yield) as a white solid. MS (ESI+): m / z 803.6 [M+H] + .

[0368] 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),10.27(br s,1H),8.87(s,1H),8.20(s,1.07H),8.07(t,J=7.6Hz,1H),7.86-7.52(m,4H),7.21(d,J=8.4Hz,2H),6.83(t, J=9.6Hz,1H),6.50(d,J=14.8Hz,1H),6.41(d,J=8.4Hz,1H),5.79(d,J=7.6Hz,1H),5.73-5.64(m,1H),5.35(br s,1H),4.99(d,J=10.4Hz,1H),4.82(d,J=17.2Hz,1H),4.68(d,J=5.6Hz,2H),4.32-4. 17(m,1H),3.12(d,J=11.2Hz,2H),2.96(d,J=10.4Hz,2H),2.81-2.63(m,2H),2.54(br s,2H),2.46-2.41(m,1H),2.21(d,J=6.8Hz,2H),2.08(s,1H),1.98(t,J=10.8Hz,2H),1.9 0-1.81(m,1H),1.80-1.69(m,4H),1.62(d,J=9.2Hz,2H),1.46(s,6H),1.32-1.16(m,2H).

[0369] Compound 74, compounds 83 to 88, and compound 109, compound 122, compound 125, and compound 158, and compound 73 were synthesized by using the same method as the same method and the iso-なる intermediate によって.

Table 24-1

Table 24-2

Table 24-3

Table 24-4

Table 24-5

[0370] Example 75: Compound 75 [ka]

[0371] Step 1: Synthesis of intermediate 75-3 Intermediate 75-1 (300 mg, 1.45 mmol) and intermediate 75-2 (434.74 mg, 2.18 mmol) were dissolved in dichloromethane (5 mL), triethylamine (441.57 mg, 4.36 mmol) was added, and the mixture was stirred at 25 °C for 30 min. After that, acetic acid (349.41 mg, 5.82 mmol) was added and the mixture was stirred at 25 °C for 30 min. Sodium borohydride acetate (182.82 mg, 2.91 mmol) was added, and the mixture was stirred at 25 °C for 16 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give intermediate 75-3 (675 mg, crude product) as a yellow oil, which was used in the next step of the reaction. MS(ESI+):m / z 389.49[M+H] + .

[0372] Step 2: Synthesis of intermediate 75-4 Intermediate 75-3 (675 mg, 1.73 mmol) is dissolved in dichloromethane (5 mL), then hydrochloric acid / dioxane (5 ml) is added, and the reaction is stirred at 20° C. for 2 hours. Filtration and concentration under reduced pressure give white solid intermediate 75-4 (861 mg, crude product), which is used crude in the next step reaction. MS (ESI+): m / z 289.37 [M+H] + .

[0373] Step 3: Synthesis of intermediate 75-5 Intermediate 75-4 (861 mg, 2.98 mmol) was dissolved in ethyl trifluoroacetate (5 mL), triethylamine (903 mg, 8.93 mmol) was added, and the mixture was stirred at 80 °C for 16 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was carried out by column chromatography (dichloromethane / methanol = 20 / 1) to obtain yellow solid intermediate 75-5 (358 mg, crude product), which was used directly in the next step of the reaction. MS (ESI+): m / z 385.38 [M+H] + .

[0374] Step 4: Synthesis of intermediate 75-6 Intermediate 75-5 (358.3 mg, 929.73 μmol) is dissolved in tetrahydrofuran (10 mL), then palladium on carbon (300 mg, 5%) is added, and the reaction is stirred under hydrogen gas at 20° C. for 16 hours. Filtration under reduced pressure and concentration of the filtrate gives black oily intermediate 75-6 (121 mg, crude product), which is used directly in the next step of the reaction. MS (ESI+): m / z 355.40 [M+H] + .

[0375] Step 5: Synthesis of intermediate 75-8 Intermediate 75-6 (68.66 mg, 179.06 μmol) was dissolved in toluene (1 mL), followed by the addition of m-CPBA (123.60 mg, 286.49 μmol) and stirring at 20 °C for 30 min. Diisopropylethylamine (69.43 mg, 537.17 μmol) was added, followed by the addition of Intermediate B15-B (70 mg, 196.96 μmol) and stirring at 20 °C for 16 h. The reaction mixture was quenched with saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) at 0 °C. Ethyl acetate (30 mL) and water (30 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The mixture was purified by column chromatography (dichloromethane:methanol = 10:1). Filtration and concentration under reduced pressure gave a yellow solid intermediate 75-8 (149 mg, crude product), which was used directly in the next step of the reaction. MS (ESI+): m / z 690.76 [M+H] + .

[0376] Step 6: Synthesis of intermediate 75-9 Intermediate 75-8 (149 mg, 216 μmol) was dissolved in methanol (5 mL), and then potassium carbonate (89.44 mg, 647.12 μmol) was added. The mixture was stirred at 25° C. for 2 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The mixture was purified by column chromatography (dichloromethane:methanol=10:1). The mixture was filtered and concentrated under reduced pressure to obtain the yellow solid intermediate 75-9 (120 mg, crude product). The crude product was used directly in the next step of the reaction. MS (ESI+): m / z 594.75 [M+H] + .

[0377] Step 7: Synthesis of Compound 75 [ka] Intermediate 75-9 (120 mg, 202 μmol) and Intermediate 1-1 (83.6 mg, 303 μmol) were dissolved in 1-methyl-2-pyrrolidone (5 mL), and then N,N-diisopropylethylamine (78.2 mg, 605 μmol) was added. The reaction mixture was stirred at 100°C for 16 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (acetonitrile / water (0.1% trifluoroacetic acid)) and lyophilized to obtain a yellow solid. The yellow solid was diluted with dichloromethane (5 mL) and washed with sodium bicarbonate (3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (dichloromethane / methanol = 10 / 1, silica gel column 4 g) to give yellow solid compound 75 (19 mg, yield: 10.5%). MS (ESI+): m / z 851.6 [M+H] + .

[0378] 1 H NMR(400MHz,DMSO-d6)11.10(s,1H),10.43-10.10(m,1H),8.87(s,1H),7.94(d,J=7.6Hz,1H),7.75-7.60(m,4H),7.3 9-7.31(m,1H),7.27(d,J=7.2Hz,1H),7.20(d,J=8.4Hz,2H),5.81-5.56(m,1H),5.11-4.95(m,3H),4.85(d,J=18.4Hz) ,1H),4.76(d,J=12.8Hz,1H),4.63-4.50(m,1H),4.12(d,J=11.6Hz,2H),3.06-2.93(m,5H),2.90-2.72(m,3H),2.59( d,J=16.0Hz,2H),2.32-2.15(m,3H),2.08-1.97(m,2H),1.96-1.83(m,3H),1.83-1.44(m,8H),0.87(t,J=7.6Hz,3H).

[0379] Example 76: Compound 76 [ka]

[0380] Step 1: Synthesis of intermediate 76-3 Intermediate 76-1 (1 g, 2.97 mmol) and intermediate 76-2 (1.24 g, 2.97 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Sodium carbonate (944 mg, 8.90 mmol) and tetrakistriphenylphosphorus palladium (343 mg, 297 μmol) were added, and the mixture was purged with nitrogen gas three times and stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) gave yellow solid intermediate 76-3 (946 mg, 52.9% yield). MS (ESI+): m / z 502.0 [M+H] + .

[0381] Step 2: Synthesis of intermediate 76-4 Intermediate 76-3 (300 mg, 600 μmol) and 4-(dimethoxymethyl)piperidine (191 mg, 1.20 mmol) were dissolved in toluene (5 mL), cesium carbonate (586 mg, 1.80 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (50.1 mg, 60.0 μmol) were added, the mixture was purged with nitrogen gas three times, and the mixture was stirred under a nitrogen atmosphere at 100 °C for 16 hours. The reaction mixture was spin-dried, diluted with ethyl acetate (40 mL), and washed with 50 mL of water. The organic phase was dried over anhydrous sodium sulfate and spin-dried to give the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 5 / 1 to 1 / 1) to obtain white solid intermediate 76-4 (201 mg, yield: 55.0%). MS (ESI+): m / z 579.3 [M+H] + .

[0382] Step 3: Synthesis of intermediate 76-5 Intermediate 76-4 (201 mg, 347 μmol) was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL), palladium on carbon (200 mg, 10%) was added, and the mixture was purged with hydrogen gas three times and stirred under a hydrogen gas atmosphere at 20°C for 16 hours. The reaction mixture was filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 5 / 1 to 1 / 1) to obtain white solid intermediate 76-5 (82 mg, yield: 58.9%). MS (ESI+): m / z 401.3 [M+H] + .

[0383] Step 4: Synthesis of intermediate 76-6 Intermediate 76-5 (82 mg, 205 μmol) is dissolved in dichloromethane (1 mL), hydrochloric acid / dioxane solution (4 M, 2 mL) is added, and the reaction is stirred for 16 h at 25° C. The reaction is spun to dryness to give white solid intermediate 76-6 (113 mg, crude), which is used directly in the next step.

[0384] Step 5: Synthesis of Compound 76 [ka] Intermediate 76-6 (50 mg, 128 μmol) and intermediate B7-B (80.3 mg, 154 μmol) were dissolved in dichloromethane (2 mL), triethylamine (25.9 mg, 256 μmol, 36 μL) was added, and the mixture was stirred at 25 °C for 0.5 h. Acetic acid (15.4 mg, 256 μmol, 15 μL) was then added, and the mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (81.3 mg, 384 μmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was spin-dried to obtain the crude product. Separation by high-performance liquid chromatography (acetonitrile / water (2% formic acid)) gave compound 76 (45 mg, yield: 41.4%) as a yellow solid.

[0385] MS(ESI+):m / z 825.6[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.85(s,1H),10.26-10.00(m,1H),8.82(s,1H),8.27(s,0.336 H),8.04(br s,1H),7.75(d,J=8.4Hz,1H),7.60(d,J=7.6Hz,3H),7.47(d,J=8.8Hz,1H),6.99-6.87(m,3H),6.83(s,1H),5.72-5.58(m,1H),5.33( s,1H),4.99(d,J=10.4Hz,1H),4.82(d,J=18.4Hz,1H),4.72-4.63(m,2H),4.29-4.22(m,1H),3.88(s,3H),3.84-3.73(m,2H),3.11(br s,4H),2.81-2.69(m,2H),2.64-2.58(m,1H),2.55-2.52(m,4H),2.42(br s,1H),2.31-2.20(m,3H),2.19-2.11(m,1H),1.83(d,J=12.4Hz,3H),1.46(s,6H),1.34-1.20(m,2H).

[0386] Compounds 111, 117, and 144 were synthesized using a similar method to compound 76 but with different intermediates. [Table 25-1] [Table 25-2]

[0387] Example 77: Compound 77 [ka]

[0388] Step 1: Synthesis of intermediate 77-3 Intermediate 77-1 (500 mg, 2.27 mmol) and intermediate 77-2 (443 mg, 2.27 mmol) were dissolved in methanol (10 mL), acetic acid (130 μL, 2.27 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. Sodium cyanoborohydride (214 mg, 3.41 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. 20 mL of saturated sodium bicarbonate was added to the reaction mixture. The mixture was extracted three times with 40 mL of ethyl acetate, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 65:35) to obtain yellow solid intermediate 77-3 (280 mg, yield: 31.6%).

[0389] MS(ESI+):m / z 391.14[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.03(d,J=9.6Hz,2H),7.01(d,J=9.6Hz,2H),4.15-3.99(m,2H),3.30-3.24(m,4H),3.02- 2.90(m,2H),2.57-2.52(m,1H),2.45-2.38(m,4H),1.88-1.78(m,2H),1.49-1.35(m,11H).

[0390] Step 2: Synthesis of intermediate 77-4 Intermediate 77-3 (500 mg, 1.28 mmol) is dissolved in methanol (10 mL). Wet palladium on carbon (50 mg, 10% purity) is added and the mixture is stirred at 25 °C under 15 psi and hydrogen gas for 1 h. The reaction is filtered and spun dry to give a brown solid crude product, Intermediate 77-4 (480 mg, crude).

[0391] Step 3: Synthesis of intermediate 77-5 Intermediate B6 (262 mg, 733 μmol) was dissolved in toluene (10 mL), metachloroperbenzoic acid (298 mg, 1.47 mmol, 85% purity) was added, and the mixture was reacted at 25 °C for 1 h. Intermediate 77-4 (317 mg, 879 μmol) and N,N-diisopropylethylamine (379 mg, 2.93 mmol) were added to the reaction mixture. The mixture was reacted at 25 °C for 12 h. The reaction mixture was quenched with 5 mL of saturated aqueous sodium bicarbonate and 5 mL of saturated aqueous sodium thiosulfate, then extracted twice with 20 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (dichloromethane:methanol = 1:0 to 10:1) to obtain yellow solid intermediate 77-5 (480 mg, yield: 98%). MS(ESI+): m / z 669.9[M+H] + .

[0392] Step 4: Synthesis of intermediate 77-6 Intermediate 77-5 (480 mg, 717 μmol) was dissolved in dichloromethane (4 mL), and hydrochloric acid in dioxane (10 mL, 4 M) was added. The mixture was allowed to react for 2 h at 25° C. The reaction mixture was filtered, spun dry, filtered, and spun dry to give a white solid crude product, intermediate 77-6 (408 mg, 93.9% yield, hydrochloride salt). MS(ESI+): m / z 569.6[M+H] + .

[0393] Step 5: Synthesis of compound 77 [ka] Intermediate 77-6 (200 mg, 352 μmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of Intermediate 1-1 (97.0 mg, 351 μmol) and N,N-diisopropylethylamine (183 μL, 1.05 mmol). The mixture was incubated at 100 °C for 2 h under microwave irradiation. The reaction mixture was diluted with 20 mL of dichloromethane and washed with 28 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by high-performance liquid chromatography (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 30% B to 70%) to obtain yellow solid compound 77 (25.36 mg, yield: 8.66%). MS(ESI+):m / z 826.5[M+H] + .

[0394] 1 H NMR(400MHz,DMSO-d6)δ 11.10(s,1H),10.27-10.10(m,1H),8.83(s,1H),8.14-8.00(m,1H),7.80-7.74(m,1H),7.70-7.67(m,1H),7.64-7. 51(m,3H),7.35(s,1H),7.31-7.24(m,1H),7.01-6.90(m,2H),5.75-5.59(m,1H),5.35(s,1H),5.08(dd,J=5.2,12.8 Hz,1H),5.01-4.97(m,1H),4.88-4.77(m,1H),4.71-4.62(m,2H),3.77-3.67(m,2H),3.45-3.43(m,4H),2.95-2.82 (m,1H),2.70-2.55(m,8H),2.42-2.36(m,1H),2.06-1.96(m,1H),1.94-1.84(m,2H),1.62-1.52(m,2H),1.46(s,6H)

[0395] Compound 78 is synthesized using a similar method to compound 77, but with different intermediates. [Table 26]

[0396] Example 79: Compound 79 [ka]

[0397] Step 1: Synthesis of intermediate 79-2 Pd(dppf)Cl2 (216 mg, 296 μmol) was added to a mixture of intermediate B18 (1 g, 2.96 mmol), intermediate 79-1 (1.19 g, 8.87 mmol), and cesium carbonate (1.93 g, 5.91 mmol) in dioxane (5 mL) and water (1 mL). After purging with nitrogen gas for 5 minutes, the reaction mixture was incubated at 80 °C under microwave conditions for 1 hour. The crude product was spin-dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain intermediate 79-2 (750 mg, 72% yield) as a brown solid. MS (ESI+): m / z 286.07 [M+H] + .

[0398] Step 2: Synthesis of intermediate 79-3 Sodium periodate (2.25 g, 10.5 mmol) was dissolved in water (10 mL) and added to a solution of intermediate 79-2 (750 mg, 2.63 mmol) in tetrahydrofuran (50 mL) at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. Potassium osmate (48.4 mg, 131 μmol) was then added to the above solution, and the mixture was stirred at 25 °C for 50 minutes. The reaction mixture was quenched with 50 mL of saturated sodium sulfite and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:0 to 0:1) to obtain brown solid intermediate 79-3 (550 mg, yield: 30%). MS(ESI+):m / z 288.04[M+H] + .

[0399] Step 3: Synthesis of intermediate 79-5 Acetic acid (20.9 mg, 20.0 μL) was added to a mixture of intermediate 79-3 (100 mg, 348 μmol), 4-hydroxypiperidine (60.1 mg, 522 μmol) in N,N-dimethylformamide (1 mL) and tetrahydrofuran (2 mL). The reaction mixture was stirred at 80 °C for 0.5 h. Sodium cyanoborohydride (43.8 mg, 696 μmol) was then added at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 10 mL of saturated sodium chloride and extracted three times with 20 mL of dichloromethane. The aqueous phase was concentrated and spun to dryness to obtain the crude product. The crude product was separated by high-performance liquid chromatography (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 5% B to 35% B) to obtain white solid intermediate 79-5 (4.69 mg, yield: 16%). MS (ESI+): m / z 387.3 [M+H] + .

[0400] Step 4: Synthesis of intermediate 79-6 Intermediate 79-5 (10 mg, 25.9 μmol) was dissolved in dichloromethane (1 mL) and dimethyl sulfoxide (0.1 mL), and Dess-Martin reagent (22.0 mg, 51.8 μmol) was added to the solution at 0° C. The reaction was stirred at 20° C. for 2 hours. The reaction was quenched with 0.5 mL of saturated sodium bicarbonate, filtered, and spun dry to give crude intermediate 79-6 (10 mg, crude), which was used directly in the next step of the reaction. MS (ESI+): m / z 385.07 [M+H] + .

[0401] Step 5: Synthesis of Compound 79 Triethylamine (5.04 mg, 49.8 μmol) was added to a solution of intermediate B8 (13.0 mg, 24.9 μmol, HCl) and intermediate 79-6 (9.57 mg, 24.9 μmol) in N,N-dimethylformamide (5 mL) and stirred at 25 °C for 0.5 hours. Then, acetic acid (1.50 mg, 24.9 μmol, 1.42 μL) was added to the mixture and stirred for 0.5 hours. Finally, sodium cyanoborohydride (3.13 mg, 49.8 μmol) was added to the reaction mixture and reacted at 25 °C for 2 hours. The reaction mixture was quenched with 0.5 mL of saturated sodium bicarbonate, filtered, and spin-dried to obtain the crude product. The crude product is separated by a high-performance liquid chromatography column (chromatography column: Kromasil 100-5-C18 30 x 150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 20 mL / min, gradient 10% B to 50% B) to obtain a white solid compound 79 (4.69 mg, yield: 22%).

[0402] MS(ESI+): m / z 854.6[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 11.12(br s,1H),10.27(br s,1H),8.88(s,1H),8.12-7.94(m,1H),7.82-7.72(m,1H),7.70-7.56(m,3H),7.20(d,J=8.4Hz,2H),7.11(s,1H),7. 07-7.01(m,1H),6.99-6.88(m,1H),5.78-5.58(m,1H),5.55-5.16(m,2H),5.03-4.96(m,1H),4.88-4.78(m,1H),4.7 5-4.62(m,2H),3.48-3.47(m,2H),3.34(s,3H),2.98-2.80(m,6H),2.77-2.70(m,1H),2.65-2.59(m,1H),2.44-2.39 (m,1H),2.17-2.09(m,2H),2.05-1.90(m,5H),1.74-1.61(m,5H),1.53-1.49(m,1H),1.46(s,6H),1.18-1.05(m,2H).

[0403] Example 80: Compound 80 [ka]

[0404] Step 1: Synthesis of intermediate 80-3 Intermediate 80-1 (5.00 g, 20.8 mmol) and Intermediate 80-2 (7.73 g, 25 mmol) were dissolved in dioxane (30 mL) and water (6 mL). Cesium carbonate (20.36 g, 62.49 mmol) and 1,1-bis(diphenylphosphorus)ferrocene palladium chloride (1.52 g, 2.08 mmol) were added and the mixture was stirred at 90 °C for 8 hours under a nitrogen atmosphere. The reaction mixture was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:1 to 50:50) to obtain yellow solid Intermediate 80-3 (6.5 g, yield: 91.1%).

[0405] LCMS(ESI+):m / z 287.8[M-56] + . 1 H NMR(400MHz,DMSO-d6)δ 6.94(d,J=8.4Hz,1H),6.86-6.84(m,1H),6.75-6.71(m,1H),5.54-5.43(m,3H),3.88(br s.,2H),3.50-3.44(m,2H),2.23-2.16(m,2H),1.41(s,9H).

[0406] Step 2: Synthesis of intermediate 80-4 Intermediate 80-3 (2.00 g, 1.28 mmol) was dissolved in ethanol (30 mL), wet palladium on carbon (50 mg, 10%) was added, and the mixture was purged with hydrogen gas three times and stirred under hydrogen gas (15 psi) at 25° C. for 20 hours. The reaction mixture was filtered, and the filtrate was spin-dried to give a brown solid crude product, Intermediate 80-4 (1.8 g, crude), which was used directly in the next step.

[0407] 1H NMR(400MHz,DMSO-d6)δ 7.17(d,J=8.4Hz,1H),6.82(d,J=2.4Hz,1H),6.78-6.73(m,1H),5.34(s,2 H),2.82-2.65(m,4H),2.47-2.41(m,1H),1.61-1.45(m,4H),1.41(s,9H).

[0408] Step 3: Synthesis of intermediate 80-6 Intermediate 80-4 (1.00 g, 2.90 mmol) and intermediate 80-5 (1.12 g, 5.81 mmol) were dissolved in N,N-dimethylformamide (10 mL), sodium bicarbonate (731.89 mg, 8.71 mmol) was added, and the mixture was reacted at 80 °C for 8 h. The reaction mixture was diluted with water (20 mL) and then extracted twice with ethyl acetate (60 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 3:1 to 63:27) to obtain green oily intermediate 80-6 (400 mg, yield: 30.2%).

[0409] LCMS(ESI+):m / z 358.3[M-100+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),7.27(d,J=8.4Hz,1H),6.96-6.83(m,2H),6.24(d,J=8.0Hz,1H),4.45-4.36(m,1H),4.15-4.00(m,2H),2.97 -2.90(m,2H),2.84-2.77(m,2H),2.59-2.55(m,1H),2.13-2.03(m,1H),1.96-1.87(m,1H),1.61-1.48(m,4H),1.41(s,9H).

[0410] Step 4: Synthesis of intermediate 80-7 Intermediate 80-6 (400 mg, 878.21 μmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid in dioxane (10 mL, 4 M) was added. The mixture was allowed to react for 1 h at 25 °C. The reaction mixture was filtered, spun dry, filtered, and spun dry to give a white solid crude product, intermediate 80-7 (300 mg, 87.2% yield). LCMS(ESI+):m / z 356.4[M+H] + .

[0411] Step 5: Synthesis of Compound 80 Intermediate 80-7 (70 mg, 179 μmol) and intermediate 55-10 (91.8 mg, 179 μmol) were dissolved in dichloromethane (4 mL). Triethylamine (75 μL, 536 μmol) and acetic acid (10.2 μL, 179 μmol) were added and the mixture was reacted at 25 °C for 1 h. Sodium cyanoborohydride (16.8 mg, 268 μmol) was added and the mixture was reacted at 25 °C for 3 h. The mixture was then spin-dried. The crude product was purified by high-performance liquid chromatography (acetonitrile / water (2% formic acid)) and lyophilized to give a yellow solid compound. Separation and purification by preparative TLC plate (dichloromethane:methanol = 10:1) gave yellow solid compound 80 (12.93 mg, yield: 8.15%).

[0412] LCMS(ESI+):m / z 853.6[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.14(br s,1H),8.82(s,1H),8.09-8.00(m,1H),7.78-7.72(m,1H),7.63-7.52(m,3H),7.33-7.27(m,1H),6.95-6.87(m,4H), 6.26-6.18(m,1H),5.73-5.60(m,1H),5.33(s,1H),5.02-4.97(m,1H),4.86-4.79(m,1H),4.72-4.64(m,2H),4.45-4. 37(m,1H),3.69-3.60(m,2H),3.07-2.88(m,2H),2.79-2.69(m,1H),2.64-2.56(m,3H),2.45-2.35(m,1H),2.29-2.13 (m,2H),2.10-2.04(m,1H),1.96-1.87(m,2H),1.86-1.78(m,3H),1.76-1.58(m,5H),1.46(s,6H),1.27-1.22(m,2H).

[0413] Compounds 81, 82 and 145 are synthesized using a similar method to compound 80, but with different intermediates. [Table 27-1] [Table 27-2]

[0414] Example 89: Compound 89 [ka]

[0415] Step 1: Synthesis of intermediate 89-3 Intermediate B23 (100 mg, 309 μmol) and intermediate 89-2 (86.5 mg, 464 μmol) were dissolved in 1,4-dioxane (1 mL). Cesium carbonate (302 mg, 928 μmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (51.8 mg, 61.9 μmol) were added. The reaction mixture was stirred at 100 °C under nitrogen for 2 h. The reaction mixture was filtered and the filtrate was spin-dried to give the crude product. Purification by column chromatography (dichloromethane:methanol = 10:1) gave red solid intermediate 89-3 (91 mg, 54.9% yield). LCMS(ESI+):m / z 429.4[M+H] + .

[0416] Step 2: Synthesis of intermediate 89-4 Intermediate 89-3 (81 mg, 189 μmol) is dissolved in dichloromethane (2 mL), then hydrochloric acid in dioxane (4 M, 2 mL) is added, and the reaction is stirred for 2 hours at 20° C. Filtration and concentration under reduced pressure give white solid intermediate 89-4 (71 mg, crude), which is used directly in the next step reaction. LCMS(ESI+):m / z 329.3[M+H] + .

[0417] Step 6: Synthesis of Compound 89 Intermediate 89-4 (71 mg, 216 μmol) and intermediate 55-10 (111 mg, 216 μmol) were dissolved in dichloromethane (5 mL), triethylamine (109 mg, 1.08 mmol) was added, and the mixture was stirred at 25 °C for 0.5 h. Acetic acid (64.9 mg, 1.08 mmol) was then added, and the mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (137 mg, 649 μmol) was then added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. High-performance liquid chromatography (acetonitrile / water (2% formic acid)) gave yellow solid compound 89 (20 mg, yield: 11.1%).

[0418] LCMS(ESI+):m / z 848.6[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.52(s,1H),10.15(s,1H),8.82(s,1H),8.05(s,1H),7.75(d,J=7.20Hz,1H),7.50-7.65(m,3H),7.46(d,J=9.20Hz ,1H),6.93(d,J=8.80Hz,3H),6.83(s,1H),5.57-5.76(m,1H),5.33(s,1H),4.99(d,J=10.00Hz,1H),4.82(d,J=17.6H) z,1H),4.68(d,J=6.00Hz,2H),3.86-3.92(m,6H),3.65(d,J=10.80Hz,2H),3.31(s,2H),3.24(s,5H),2.73(t,J=6.8 0Hz,2H),2.59-2.65(m,2H),2.25(d,J=7.20Hz,2H),1.83(d,J=11.20Hz,2H),1.71(s,1H),1.46(s,6H),1.23(s,2H).

[0419] Example 93: Compound 93 [ka]

[0420] Step 1: Synthesis of intermediate 93-2 Intermediate 93-1 (1 g, 4.16 mmol) is dissolved in dichloromethane (5 mL), DMP (2.65 g, 6.24 mmol) is added, and the mixture is stirred for 3 hours at 25° C. The reaction is quenched with aqueous sodium bicarbonate and sodium thiosulfate (1:1, 10 mL), diluted with 20 mL of water, extracted with two 80 mL portions of ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate, filtered, and spun to give crude intermediate 93-2 (956 mg, crude), which is used directly in the next step.

[0421] Step 2: Synthesis of intermediate 93-3 Intermediate 93-2 (500 mg, 2.10 mmol) was dissolved in tetrahydrofuran (5 mL), saturated ammonium chloride solution (1 mL) and reduced iron powder (1.17 g, 21.0 mmol) were added, and the mixture was stirred at 80 °C for 1 h. The reaction mixture was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate, and the combined organic phase was spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain intermediate 93-3 (256 mg, yield: 28.6%).

[0422] Step 3: Synthesis of intermediate 93-5 Intermediate 93-3 (256 mg, 1.23 mmol) and intermediate 80-5 (708 mg, 3.69 mmol) were dissolved in N,N-dimethylformamide (5 mL), sodium bicarbonate (310 mg, 3.69 mmol) was added, and the mixture was stirred at 70 °C for 3 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) gave yellow solid intermediate 93-5 (151 mg, yield: 38.5%). LCMS (ESI+): m / z 320.2 [M+H] + .

[0423] Step 4: Synthesis of Compound 93 Intermediate 93-5 (151 mg, 424 μmol) and intermediate B7-B (165 mg, 315 μmol) were dissolved in dichloromethane (5 mL), triethylamine (95.7 mg, 946 μmol, 132 μL) was added, and the mixture was stirred at 25 °C for 0.5 h. Acetic acid (56.8 mg, 946 μmol, 54.1 μL) was then added, and the mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (134 mg, 630 μmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was spin-dried to obtain the crude product. Separation by high-performance liquid chromatography (acetonitrile / water (2% formic acid)) gave compound 93 (10.6 mg, yield: 4.12%) as a yellow solid.

[0424] LCMS(ESI+):m / z 790.6[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.18(br s,1H),8.83(s,1H),8.06(br s,1H),7.82-7.71(m,1H),7.66-7.46(m,3H),7.00-6.89(m,2H),6.88 -6.78(m,1H),6.55-6.46(m,1H),6.45-6.36(m,1H),5.85-5.76(m,1H) ,5.72-5.59(m,1H),5.35(s,1H),4.99(d,J=9.6Hz,1H),4.86-4.77(m, 1H),4.73-4.59(m,2H),4.30-4.19(m,1H),3.22-3.15(m,2H),3.11(br s,4H),2.80-2.72(m,1H),2.68(br s,4H),2.63-2.56(m,3H),2.33(br s,1H),2.13-2.03(m,1H),1.91-1.78(m,3H),1.66-1.52(m,2H),1.46(s,6H).

[0425] Compound 148 is synthesized using a similar method to compound 93, but with different intermediates. [Table 28]

[0426] Example 100-A and Example 100-B: Compound 100-A and Compound 100-B [ka] Step 1: Synthesis of Compounds 10-A and 100-B The chiral compound 71 (12 mg, 3.13 mmol) was separated by chiral separation chromatography column DAICEL CHIRALPAK IE (250 mm x 30 mm, 10 μm), mobile phase: [IPA-ACN], carbon dioxide %: 50%-50%, 45 mL / min) to give peak 1, yellow solid single enantiomer compound 100-A (1.18 mg, yield: 9.83%) and peak 2, yellow solid single enantiomer compound 100-B (0.76 mg, yield: 6.33%).

[0427] Compound 100-A: Chiral analysis: Analytical column: chiralpak IE-3, 100 × 4.6 mm ID, 3 μm, mobile phase: A: isopropanol (0.05% diethylamine) B: acetonitrile, elution gradient: 50% B, flow rate: 1.0 mL / min, column temperature: 35 °C, detection wavelength: 254 nM, Rt = 1.87 min.

[0428] Compound 100-B: Chiral analysis: Analytical column: chiralpak IE-3, 100 × 4.6 mm ID, 3 μm, mobile phase: A: isopropanol (0.05% diethylamine) B: acetonitrile, elution gradient: 50% B, flow rate: 1.0 mL / min, column temperature: 35 °C, detection wavelength: 254 nM, Rt = 2.43 min. [Table 29]

[0429] Compound 102-A and Compound 102-B: Compounds 102-A and 102-B [ka] Step 1: Synthesis of Compounds 102-A and 102-B The chiral compound 74 (15.20 mg, 18.91 μmol) was separated by a chiral separation chromatography column (DAICEL CHIRALPAK IF, 250 mm x 30 mm, 10 μm, mobile phase: [IPA-ACN], carbon dioxide %: 50%-50%, 45 mL / min) to give peak 1, yellow solid single-configuration compound 102-A (2.10 mg, yield: 13.82%) and peak 2, yellow solid single-configuration compound 102-B (2.20 mg, yield: 14.47%).

[0430] Compound 102-A: Chiral analysis: Analytical column: chiralpak IF-3, 100 × 4.6 mm ID, 3 μm, mobile phase: A: isopropanol (0.05% diethylamine) B: acetonitrile, elution gradient: 50% B, flow rate: 1.0 mL / min, column temperature: 35 °C, detection wavelength: 254 nM, Rt = 3.35 min.

[0431] Compound 102-B: Chiral analysis: Analytical column: chiralpak IF-3, 100 × 4.6 mm ID, 3 μm, mobile phase: A: isopropanol (0.05% diethylamine) B: acetonitrile, elution gradient: 50% B, flow rate: 1.0 mL / min, column temperature: 35 °C, detection wavelength: 254 nM, Rt = 5.89 min. [Table 30]

[0432] Example 104: Synthesis of Compound 104 [ka]

[0433] Step 1: Synthesis of intermediate 104-2 To a dioxane solution (5 mL) of intermediate B23 (500 mg, 1.55 mmol) and intermediate 104-1 (320 mg, 2.01 mmol), cesium carbonate (1.51 g, 4.64 mmol) and RuPhos Pd G3 (388 mg, 464 μmol) were added. The reaction mixture was stirred at 100 °C under nitrogen gas protection for 2 h. The resulting mixture was filtered and spin-dried. Separation by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) gave pale yellow solid intermediate 104-2 (160 mg, yield: 17.8%). LCMS(ESI+):m / z 402.5[M+H] + .

[0434] Step 2: Synthesis of intermediate 104-3 To a solution of intermediate 104-2 (160 mg, 399 μmol) in dichloromethane (5 mL) was added 4 M hydrochloric acid in dioxane (3 mL). The reaction was stirred at 20° C. for 1 h. Spin-drying afforded the crude brown solid 104-3 (160 mg, crude), which was used directly in the next step. LCMS(ESI+):m / z 356.3[M+H] + .

[0435] Step 3: Synthesis of Compound 104 Intermediate 104-3 (80 mg, 225 μmol) and intermediate B8 (109 mg, 225 μmol) were dissolved in dichloromethane (5 mL), triethylamine (68.3 mg, 675 μmol) was added, and after stirring, acetic acid (27 mg, 450 μmol) was added. The reaction mixture was stirred for 30 minutes, and then sodium borohydride acetate (143 mg, 675 μmol) was added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was spin-dried and separated using a high-performance liquid chromatography column (acetonitrile / water (2% formic acid)) to obtain pink solid compound 104 (13 mg, yield: 6.79%).

[0436] LCMS(ESI+):m / z 825.6[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.50(s,1H),10.24(br s,1H),8.87(s,1H),8.10-8.03(m,1H),7.75(d,J=8.0Hz,1H),7.69-7.59(m,3H),7.43(d,J=8.0 Hz,1H),7.22(d,J=12.0Hz,2H),6.91(d,J=8.0Hz,1H),6.80(s,1H),5.72-5.61(m,1H),5.36(br s,1H),4.99(d,J=12.0Hz,1H),4.82(d,J=16.0Hz,1H),4.68(d,J=8.0Hz,2H),3.92-3 .84(m,5H),3.80(d,J=12.0Hz,2H),2.97(d,J=8.0Hz,2H),2.77-2.70(m,4H),2.46(br s,1H),2.21(d,J=8.0Hz,2H),2.04-1.93(m,2H),1.83(d,J=12.0Hz,2H) ,1.77-1.70(m,3H),1.69-1.60(m,2H),1.46(s,6H),1.33-1.19(m,2H).

[0437] Compounds 105, 117, 124, 129 and compound 143 are synthesized using a similar method to compound 104 but with different intermediates. [Table 31-1] [Table 31-2]

[0438] Example 106: Compound 106 [ka]

[0439] Step 1: Synthesis of intermediate 106-2 Intermediate 106-1 (500 mg, 999 μmol) and 1-Boc-piperazine (372 mg, 2.00 mmol) were dissolved in toluene (5 mL), and cesium carbonate (977 mg, 3.00 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (84 mg, 99.9 μmol) were added. The mixture was purged with nitrogen gas three times and stirred under nitrogen gas protection at 100°C for 16 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) gave yellow solid intermediate 106-2 (302 mg, yield: 40.4%). LCMS (ESI+): m / z 606.5 [M+H] + .

[0440] Step 2: Synthesis of intermediate 106-3 Intermediate 106-2 (302 mg, 499 μmol) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL), Pd / C (300 mg, 10%) was added, and the mixture was purged with nitrogen gas three times and stirred under a nitrogen atmosphere at 25°C for 16 hours. The reaction mixture was filtered and spin-dried to obtain the crude product. The product was separated by column chromatography (ethyl acetate:petroleum ether = 1:1 to 0:1) to obtain white solid intermediate 106-3 (118 mg, yield: 53.7%). LCMS (ESI+): m / z 428.2 [M+H] + .

[0441] Step 3: Synthesis of intermediate 106-4 Compound 106-3 (118 mg, 276 μmol) is dissolved in dichloromethane (2 mL), and a solution of hydrochloric acid in dioxane (4 M, 2 mL) is added, and the reaction is stirred for 0.5 h at 25° C. The reaction is spun to dryness to give compound 106-4 (115 mg, crude), a white solid, which is used directly in the next step.

[0442] Step 4: Synthesis of Compound 106 Intermediate 106-4 (115 mg, 316 μmol) and intermediate 55-10 (174 mg, 316 μmol) were dissolved in dichloromethane (5 mL), triethylamine (96.0 mg, 948 μmol, 132 μL) was added, and the mixture was stirred at 25 °C for 0.5 h. Acetic acid (43.7 mg, 727 μmol, 41.6 μL) was then added, and the mixture was stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (134 mg, 632 μmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was spin-dried to obtain the crude product. Separation by high-performance liquid chromatography (acetonitrile / water (2% formic acid)) gave yellow solid compound 106 (65 mg, yield: 24.3%).

[0443] LCMS(ESI+):m / z 825.5[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.87(s,1H),10.16(br s,1H),8.82(s,1H),8.05(br s,1H),7.79-7.71(m,1H),7.63-7.53(m,3H),7.50(d,J=8.8Hz,1H),6.93(d,J=8.8Hz,3H),6.85(s,1H),5.72-5.59(m,1H),5.35(br s,1H),4.99(d,J=10.4Hz,1H),4.86-4.78(m,1H),4.72-4.61(m,2H),4.30-4.23(m,1H),3.89(s,3H),3.69-3.60(m,2H),3.23(br s,3H),2.70-2.59(m,4H),2.54(br s,5H),2.34-2.28(m,1H),2.27-2.21(m,2H),2.20-2.10(m,1H),1.88-1.77(m,2H),1.70(br s, 1H), 1.46 (s, 6H), 1.31-1.19 (m, 2H).

[0444] Compound 118 is synthesized using a similar method to compound 106, but with different intermediates. [Table 32]

[0445] Example 107: Compound 107 [ka]

[0446] Step 1: Synthesis of intermediate 107-3 Potassium carbonate (9.91 g, 71.74 mmol) was added to a solution of intermediate 107-1 (5 g, 23.91 mmol) and intermediate 107-2 (2.75 g, 23.91 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into 30 mL of water, extracted twice with 40 mL of ethyl acetate, and the combined organic phase was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Separation by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) gave yellow solid intermediate 107-3 (7.1 g, yield: 97.6%). 1 H NMR(400MHz,CDCl3)δ 8.51-8.48(m,1H),8.32-8.26(m,1H),7.26-7.22(m,1H),3.62-3.54(m,2H),3.48-3.39(m,2H) ,2.93-2.90(m,1H),2.88-2.84(m,1H),1.92-1.81(m,2H),1.72-1.66(m,1H),1.53-1.41(m,2H)

[0447] Step 2: Synthesis of intermediate 107-4 To a solution of intermediate 107-3 (3.0 g, 9.86 mmol) in ethyl acetate (20 mL) was added palladium on carbon (0.325 g, 985.98 μmol, 10%). The reaction mixture was stirred under hydrogen gas (15 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was spin-dried to give intermediate 107-4 (2.50 g, 92.44% yield), a yellow solid. LCMS(ESI+):m / z 275.9[M+H] + .

[0448] Step 3: Synthesis of intermediate 107-6 Intermediate 107-4 (2.5 g, 9.11 mmol) and intermediate 80-5 (5.25 g, 27.34 mmol) were dissolved in N,N-dimethylformamide (18 mL). Sodium bicarbonate (4.59 g, 54.69 mmol, 2.13 mL) was added to the reaction mixture and stirred at 70 °C for 12 h. The reaction mixture was poured into 100 mL of water and extracted twice with 40 mL of ethyl acetate. The combined organic phase was washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain yellow solid intermediate 107-6 (1.72 g, crude product), which was used directly in the next step.

[0449] Step 4: Synthesis of intermediate 107-7 Intermediate 107-6 (300 mg, 778.45 μmol) was dissolved in dichloromethane (10 mL) and Dess-Martin reagent (660.35 mg, 1.56 mmol) was added. The reaction was stirred at 25 °C for 10 min. The reaction was added to saturated sodium thiosulfate (6 mL) and saturated sodium bicarbonate (8 mL) and extracted twice with 6 mL of ethyl acetate. The combined organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give blue solid intermediate 107-7 (170 mg, crude product), which was used directly in the next step.

[0450] Step 5: Synthesis of Compound 107 Intermediate 107-7 (40 mg, 104.34 μmol...

Claims

1. A compound represented by structural formula (I), or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex, or prodrug thereof, (I): W-L-D where: W has the following structure: 【Chemistry 1】 is a WEE1 kinase binding ligand having the formula: where: 【Chemistry 2】 represents an optionally substituted cyclic group; A １ represents O=, halogen, hydroxyl group, nitro group, cyano group, amino group, mercapto group, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl groups, X ２ Whenever exists, CR ２ ' or N, R ２ ', whenever present, represents an absence, hydrogen, deuterium, halogen, hydroxyl group, carbonyl group, nitro group, cyano group, amino group, mercapto group, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, R １ Each time it is present, it represents absence, hydrogen, deuterium, a halogen, a hydroxyl group, a carbonyl group, a nitro group, a cyano group, an amino group, a mercapto group, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with an alkyl group, R ２ Each time it is present, it represents absence, hydrogen, deuterium, a halogen, a hydroxyl group, a carbonyl group, a nitro group, a cyano group, an amino group, a mercapto group, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, or R １ and R ２ together with the ring atoms to which it is attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and the ring system does not contain 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C １ -C ６ optionally substituted with alkyl groups, R １ , R ２ , R １ and R ２ together, or R １ and R ２ any one of the ring systems formed by these together is bonded to the L group, L has the following structure: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 is a linker having the formula where: 【Chemistry 10】 represents the binding site, D has the following structure: 【Chemistry 11】 and an E3 ubiquitin ligase-binding ligand having the formula: where: 【Chemistry 12】 represents an optionally substituted cyclic group; Y １ Whenever exists, CT １ or N, and T １ is selected from hydrogen or deuterium, The compound as described above, wherein L is bonded to W and / or D through one or more bonds.

2. W is 【Chemistry 13】 and R １ Each time it is present, it represents absence, hydrogen, deuterium, a halogen, a hydroxyl group, a carbonyl group, a nitro group, a cyano group, an amino group, a mercapto group, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, R ２ Each time it is present, it represents absence, hydrogen, deuterium, a halogen, a hydroxyl group, a carbonyl group, a nitro group, a cyano group, an amino group, a mercapto group, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, or R １ and R ２ together with the ring atoms to which it is attached, form a monocyclic, bicyclic or tricyclic saturated or unsaturated ring system having 5 to 14 ring atoms, 0, 1, 2, 3 or 4 of which are heteroatoms selected from N, O and S, and the remainder are carbon atoms, and the ring system does not contain 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, mercapto groups, -COOH, or C １ -C ６ optionally substituted with alkyl groups, R １ , R ２ , R １ and R ２ together, or R １ and R ２ any one of the ring systems formed by these together is bonded to the L group, R ４ Each occurrence of represents an absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, allyl, propenyl, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, R ２１ , R ２２ Each occurrence of any one of the following may be selected from the group consisting of absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, allyl, propenyl, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl group, C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ４ C substituted by a substituent arbitrarily selected from an alkyl group, a cyclopropyl group, a halogen, a hydroxyl group, a carbonyl group, and a nitro group １ -C ６ optionally substituted with an alkyl group, or R ２１ , R ２２ together with the ring atoms to which it is attached form a 5- or 6-membered ring having 0, 1 or 2 heteroatoms selected from N, O or S, said 5- or 6-membered ring being １ -C ４ It is optionally substituted with a substituent selected from an alkyl group, a cyclopropyl group, a halogen, a hydroxyl group, a carbonyl group, and a nitro group. The compound of claim 1.

3. W is 【Chemistry 14】 characterized in that The compound of claim 1.

4. D is 【Chemistry 15】 and Y １ Whenever exists, CT １ or N, T １ Each time it is present, it represents absence, hydrogen, deuterium, a halogen, a hydroxyl group, a carbonyl group, a nitro group, a cyano group, an amino group, a mercapto group, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, Y ４１ Whenever exists, C, CT ４１ T ４１ ', N.T. ４１ ", C=O, or O; Y ４２ Whenever exists, C, CT ４２ T ４２ ', N.T. ４２ ", C=O, or O; Y ４３ Whenever exists, C, CT ４３ T ４３ ', N.T. ４３ ", C=O, or O; or Y ４１ -Y ４２ is -T ４１ (C=C)T ４２ -, -(N=C)T ４２ -, -T ４１ (C=N)- or -(N=N)-, or Y ４２ -Y ４３ is -T ４２ (C=C)T ４３ -, -(N=C)T ４３ -, -T ４２ (C═N)— or —(N═N)—; T ４１ , T ４１ ', T ４１ '', T ４２ , T ４２ ', T ４２ '', T ４３ , T ４３ ', T ４３ Each of "," whenever present, represents an absence, hydrogen, deuterium, halogen, hydroxyl group, carbonyl group, nitro group, cyano group, amino group, mercapto group, -COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, Y ５ Whenever exists, CT ５ or N, Y ６ Whenever exists, CT ６ or N, Y ７ Whenever exists, CT ７ or N, Y ８ Whenever exists, CT ８ or N, T ５ , T ６ , T ７ , T ８ Each of the following, each occurrence, is selected from the group consisting of absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, Y ５ , Y ６ , Y ７ and Y ８ one or more of which are linked to the L group The compound of claim 1.

5. D is 【Chemistry 16】 and where: Y １ is, at each occurrence, independently selected from CH, CD or N; Y ４２ is, at each occurrence, independently selected from CH or N; Y ４３ Whenever exists, CH ２ , —NH, O or N—CH ３ are independently selected from Y ５ Whenever exists, N,CT ５ are independently selected from, where T ５ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y ６ Whenever exists, N,CT ６ are independently selected from, where T ６ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y ７ Whenever exists, N,CT ７ are independently selected from, where T ７ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y ８ Whenever exists, N,CT ８ are independently selected from, where T ８ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; Y ５ , Y ６ , Y ７ and Y ８ one or more of are linked to an L group, or D is 【Chemistry 17】 and Here, Y １ is, at each occurrence, independently selected from CH, CD or N; J １ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J ２ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J ３ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J ４ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J １ , J ２ , J ３ and J ４ one or more of are linked to an L group, or D is [Chemistry 18] and Here, Y １ is, at each occurrence, independently selected from CH, CD or N; J １ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J ２ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J ３ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J ４ is, each occurrence, independently selected from absence, hydrogen, fluorine, chlorine, methyl, and methoxy; J １ , J ２ , J ３ and J ４ one or more of are linked to an L group, or D is 【Chemistry 19】 and Y １ is, at each occurrence, independently selected from CH, CD or N; Y ２１ is, whenever present, NH, N-CH ３ or O, 【Chemistry 20】 is an aromatic ring or a heteroaromatic ring, Y １０ Whenever it exists, it is absent, O, S, N, NH, CT １０ are independently selected from, where T １０ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １０ ', where T １０ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １１ Whenever it exists, it is absent, O, S, N, NH, CT １１ are independently selected from, where T １１ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １１ ', where T １１ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １２ Whenever it exists, it is absent, O, S, N, NH, CT １２ are independently selected from, where T １２ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １２ ', where T １２ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １３ Whenever it exists, it is absent, O, S, N, NH, CT １３ are independently selected from, where T １３ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １３ ', where T １３ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １４ Whenever it exists, it is absent, O, S, N, NH, CT １４ are independently selected from, where T １４ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １４ ', where T １４ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １０ , Y １１ , Y １２ , Y １３ and Y １４ one or more of are linked to an L group, or Y １０ , Y １１ , Y １２ , Y １３ and Y １４ any two adjacent groups together with the atoms to which they are attached form an optionally substituted aryl group or an optionally substituted heteroaryl group, and the optionally substituted aryl group or the optionally substituted heteroaryl group is linked to the L group via one or more bonds, and preferably the aryl group or the heteroaryl group is selected from a phenyl group, a naphthyl group, an anthracenyl group, an indenyl group, an indanyl group, a 1,2-dihydronaphthyl group, a 1,2,3,4-tetrahydronaphthyl group, a pyridyl group, a pyrimidinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a triazinyl group, and the substituents thereon are selected from absence, fluorine, chlorine, methyl, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, or D is 【Chemistry 21】 and where: Y １ is, at each occurrence, independently selected from CH, CD or N; V is hydrogen or a methyl group; 【Chemistry 22】 is an aromatic ring or a heteroaromatic ring, Y １５ Whenever it exists, it is absent, O, S, N, NH, CT １５ are independently selected from, where T １５ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １５ ', where T １５ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １６ Whenever it exists, it is absent, O, S, N, NH, CT １６ are independently selected from, where T １６ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １６ ', where T １６ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １７ Whenever it exists, it is absent, O, S, N, NH, CT １７ are independently selected from, where T １７ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １７ ', where T １７ ' is present whenever absent, hydrogen, fluorine, chlorine, methyl group, haloCH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １８ Whenever it exists, it is absent, O, S, N, NH, CT １８ are independently selected from, where T １８ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １８ ', where T １８ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １９ Whenever it exists, it is absent, O, S, N, NH, CT １９ are independently selected from, where T １９ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, NT １９ ', where T １９ ' is present whenever it is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １５ , Y １６ , Y １７ , Y １８ and Y １９ one or more of are linked to an L group, or Y １５ , Y １６ , Y １７ , Y １８ and Y １９ any two adjacent groups together with the atoms to which they are attached form an optionally substituted aryl group or an optionally substituted heteroaryl group, and the optionally substituted aryl group or the optionally substituted heteroaryl group is linked to the L group via one or more bonds, and preferably the aryl group or the heteroaryl group is selected from a phenyl group, a naphthyl group, an anthracenyl group, an indenyl group, an indanyl group, a 1,2-dihydronaphthyl group, a 1,2,3,4-tetrahydronaphthyl group, a pyridyl group, a pyrimidinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a triazinyl group, and the substituents thereon are selected from absence, fluorine, chlorine, methyl, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , methoxy group, or D is 【Chemistry 23】 where: Y １ is, at each occurrence, independently selected from CH, CD or N; Y ６ Whenever exists, CT ６ or N, Y ８ Whenever exists, CT ８ or N, T ６ , T ８ Each of the following, each occurrence, is selected from the group consisting of absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, E １ , E ２ and E ４ Each of the following, each occurrence, is selected from the group consisting of absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl esters, C １ -C ６ Alkylthio group, C １ -C ６ Halogenated alkyl group, C １ -C ６ Halogenated alkoxy group, hydroxy C １ -C ６ Alkyl group, amino C １ -C ６ Alkyl groups, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), —O—C ０ -C ４ Alkyl (C ３ -C ７ cycloalkyl), C ３ -C １２ Heterocyclyl group, C ６ -C １２ Aryl groups and C ５ -C １０ and heteroaryl groups, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are independently selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, or C １ -C ６ optionally substituted with alkyl groups, E １ , E ２ , Y ６ and Y ８ one or more of are linked to an L group, or D is 【Chemistry 24】 and where: Y １ is, at each occurrence, independently selected from CH, CD or N; Y ２ is, at each occurrence, independently selected from CH, CD, N, or oxygen; E ５ is, each occurrence, independently selected from absence, hydrogen, deuterium, or a methyl group; E ６ , E ７ , E ８ and E ９ Each of the following, whenever present, is selected from the group consisting of: absence, hydrogen, deuterium, fluorine, chlorine, a methyl group, CH ２ F, CHF ２ , C.F. ３ , a methoxy group, or a cyclopropyl group; E ６ , E ７ , E ８ and E ９ one or more of are linked to an L group, or D is 【Chemistry 25】 and Y １ is, at each occurrence, independently selected from CH, CD or N; Y １０ Whenever exists, N,CT １０ are independently selected from, where T １０ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １１ Whenever exists, N,CT １１ are independently selected from, where T １１ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １２ Whenever exists, N,CT １２ are independently selected from, where T １２ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １３ Whenever exists, N,CT １３ are independently selected from, where T １３ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １４ Whenever exists, N,CT １４ are independently selected from, where T １４ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , and methoxy groups; Y １０ , Y １１ , Y １２ , Y １３ and Y １４ one or more of which are linked to the L group The compound of claim 1.

6. D has the following structure: 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 characterized in that it is selected from The compound of claim 1.

7. The compound is a compound represented by structural formula (XXXXI) or structural formula (XXXXVII), 【Chemistry 35】 where: Y １ is, at each occurrence, independently selected from CH, CD or N; Y ２１ is C, N, NH, N-CH each time it occurs. ３ , N.C. ２ H ５ , N.C. ３ H ７ , N.C. ４ H ９ are independently selected from Y １０ , Y １１ , Y １２ , Y １３ , Y １４ Each of N, CT, １０１ are independently selected from, where T １０１ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y １０ , Y １１ , Y １２ , Y １３ and Y １４ is linked to the L group, Y ５０ , Y ５１ , Y ５２ , Y ５２ , Y ５４ Each of N, CT, １０２ are independently selected from, where T １０２ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y ５０ , Y ５１ , Y ５２ , Y ５３ and Y ５４ one or more of are linked to the L group; R ４ Each occurrence of represents an allyl group, a propargyl group, a methylenecyclopropyl group, an ethyl group, a trifluoroethyl group, a difluoroethyl group, an isopropyl group, a cyclopropyl group, a methylene C group, ６ -C １２ aryl group, methylenephenyl group, optionally substituted C １－４ alkyl groups, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ Alkynyl group, optionally substituted C ３－６ Cycloalkyl groups and optionally substituted C ３－６ Cycloalkyl (C １－４ alkyl), wherein said C ６ -C １２ Aryl group, C １－４ Alkyl group, C ２－４ Alkenyl group and C ２－４ The alkynyl group is selected from the group consisting of halogen, C １－４ Alkoxy group, C １－４ Halogenated alkyl group, C １－４ Halogenated alkoxy group, cyano group, amino group, mono-C １－４ Alkylamines and Di-C １－４ alkylamines, and ３－６ Cycloalkyl groups and the C ３－６ Cycloalkyl (C １－４ One or more rings of the alkyl group may be halogen, C １－４ Alkyl group, C １－４ Alkoxy group, C １－４ Halogenated alkyl group, C １－４ Halogenated alkoxy group, cyano group, amino group, mono-C １－４ Alkylamines and Di-C １－４ optionally substituted independently by one or more substituents selected from alkylamines; 【Transformation 36】 is absent, -(NR ８１ )-N=, -(NR ８２ )-(NR ８３ ) -, -(NR ８４ )-(C=O)- or -(C=O)-(NR ８５ )-, where R ８１ , R ８２ , R ８３ , R ８４ and R ８５ each occurrence is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy; R ２１ , R ２２ Each occurrence of any one of the following may be selected from the group consisting of absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, allyl, propenyl, C １ -C ６ Alkyl group, C １ -C ６ alkoxy groups, wherein the alkyl and alkoxy groups are optionally substituted with 1, 2, 3 or 4 halogens, hydroxyl groups, carbonyl groups, nitro groups, cyano groups, amino groups, and mercapto groups, and preferably R ２１ , R ２２ each occurrence is independently selected from hydrogen, a 2-hydroxyisopropyl group, or R ２１ , R ２２ are bonded together to form -(CR ９１ R ９２ )-(CR ９３ R ９４ )-(CR ９５ R ９６ )—, where R ９１ , R ９２ , R ９３ , R ９４ , R ９５ and R ９６ each occurrence is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, allyl, propenyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and preferably R ９１ , R ９２ , R ９３ , R ９４ , R ９５ and R ９６ Each occurrence of R is independently selected from hydrogen, hydroxyl, methyl, ethyl, and propyl, and more preferably, R ２１ , R ２２ are bonded together to form -(CR ９１ R ９２ )-(CH ２ )-(CH ２ ) - or -(CH ２ )-(CH ２ )-(CR ９５ R ９６ )—, where R ９１ , R ９２ , R ９５ and R ９６ each occurrence is independently selected from a hydroxyl group, a methyl group, an ethyl group, and a propyl group; L has the following structure: 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 and where: 【Chemistry 44】 represents a bonding site, and the L group is selected from the group consisting of 1, 2, 3, or 4 halogens, hydroxyl groups, nitro groups, cyano groups, amino groups, mercapto groups, —COOH, or C １ -C ６ optionally substituted with alkyl groups, 【Chemistry 45】 where: Y １０ , Y １１ , Y １２ , Y １３ , Y １４ Each of N, CT, １０１ are independently selected from, where T １０１ is absent, hydrogen, halogen, C whenever present. １ -C ６ Alkyl group, C １ -C ６ Halogenated alkyl group, C １ -C ６ independently selected from an alkoxy group, a hydroxyl group, and a cyano group; Y １０ , Y １１ , Y １２ , Y １３ and Y １４ is linked to the L group, Y ５０ , Y ５１ , Y ５２ , Y ５２ , Y ５４ Each of N, CT, １０２ are independently selected from, where T １０２ is absent, hydrogen, halogen, C whenever present. １ -C ６ Alkyl group, C １ -C ６ Halogenated alkyl group, C １ -C ６ independently selected from an alkoxy group, a hydroxyl group, and a cyano group; Y ５０ , Y ５１ , Y ５２ , Y ５３ and Y ５４ one or more of are linked to the L group; R ４ Each occurrence of represents an allyl group, a propargyl group, a methylenecyclopropyl group, an ethyl group, a trifluoroethyl group, a difluoroethyl group, an isopropyl group, a cyclopropyl group, a methylene C group, ６ -C １２ aryl group, methylenephenyl group, optionally substituted C １－４ alkyl groups, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ Alkynyl group, optionally substituted C ３－６ Cycloalkyl groups and optionally substituted C ３－６ Cycloalkyl (C １－４ alkyl), wherein said C ６ -C １２ Aryl group, C １－４ Alkyl group, C ２－４ Alkenyl group and C ２－４ The alkynyl group is selected from the group consisting of halogen, C １－４ Alkoxy group, C １－４ Halogenated alkyl group, C １－４ Halogenated alkoxy group, cyano group, amino group, mono-C １－４ Alkylamines and Di-C １－４ alkylamines, and ３－６ Cycloalkyl groups and the C ３－６ Cycloalkyl (C １－４ One or more rings of the alkyl group may be halogen, C １－４ Alkyl group, C １－４ Alkoxy group, C １－４ Halogenated alkyl group, C １－４ Halogenated alkoxy group, cyano group, amino group, mono-C １－４ Alkylamines and Di-C １－４ optionally substituted independently by one or more substituents selected from alkylamines; Y ６１ Whenever exists, CH ２ , NH, N(C １ -C ６ alkyl), R ２１ , R ２２ Each occurrence of any one of the following is selected from the group consisting of absence, hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C １ -C ６ Alkyl group, C １ -C ６ Alkenyl group, C １ -C ６ Alkynyl group, C １ -C ６ alkoxy groups, wherein the alkyl, alkenyl, alkynyl, or alkoxy groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, or —COOH; or R ２１ , R ２２ are bonded together to form -(CR ９１ R ９２ )-(CR ９３ R ９４ )-(CR ９５ R ９６ )—, where R ９１ , R ９２ , R ９３ , R ９４ , R ９５ and R ９６ Each of the following, each occurrence, is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, —COOH, C １ -C ６ Alkyl group, C １ -C ６ Alkenyl group, C １ -C ６ Alkynyl group, C １ -C ６ alkoxy groups, wherein the alkyl, alkenyl, alkynyl, and alkoxy groups are optionally substituted with 1, 2, 3, or 4 halogens, hydroxyl, carbonyl, nitro, cyano, amino, mercapto, or —COOH; L has the following structure: 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 is a linker having the formula where: 【Chemistry 53】 represents a bonding site, and the L group is a halogen, a hydroxyl group, a nitro group, a cyano group, an amino group, a mercapto group, or C １ -C ６ optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl groups; The compound of claim 1.

8. The compound is represented by formula (XXXXII) or formula (XXXXIV), 【Chemistry 54】 where: Y １ is, at each occurrence, independently selected from CH, CD or N; Y ２１ is, whenever present, NH, N-CH ３ , N.C. ２ H ５ , N.C. ３ H ７ , N.C. ４ H ９ are independently selected from Y １０ , Y １１ , Y １２ , Y １３ , Y １４ Each of N, CT, １０１ are independently selected from, where T １０１ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y １０ , Y １１ , Y １２ , Y １３ and Y １４ is linked to the L group, Y ５０ , Y ５１ , Y ５２ , Y ５２ , Y ５４ Each of N, CT, １０２ are independently selected from, where T １０２ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y ５０ , Y ５１ , Y ５２ , Y ５３ and Y ５４ one or more of are linked to the L group; R ４ each occurrence is independently selected from allyl, propargyl, methylenecyclopropyl, ethyl, trifluoroethyl, difluoroethyl, isopropyl, and cyclopropyl; R ２１ , R ２２ each occurrence is independently selected from hydrogen or a 2-hydroxyisopropyl group; or ２１ , R ２２ are bonded together to form -(CR ９１ R ９２ )-(CH ２ )-(CH ２ ) - or -(CH ２ )-(CH ２ )-(CR ９５ R ９６ )—, where R ９１ , R ９２ , R ９５ and R ９６ each occurrence is independently selected from hydrogen, hydroxyl, methyl, ethyl, and propyl; L has the following structure: 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 is a linker having the formula where: 【Transformation 62】 represents a bonding site, and the L group is a halogen, a hydroxyl group, a nitro group, a cyano group, an amino group, a mercapto group, or C １ -C ６ optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl groups; 【Transformation 63】 where: Y １ is, at each occurrence, independently selected from CH, CD or N; Y ２１ each occurrence is independently selected from C, CH, CD, and N; Y １０ , Y １１ , Y １２ , Y １３ , Y １４ Each of N, CT, １０１ are independently selected from, where T １０１ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y １０ , Y １１ , Y １２ , Y １３ and Y １４ is linked to the L group, Y ５０ , Y ５１ , Y ５２ , Y ５２ , Y ５４ Each of N, CT, １０２ are independently selected from, where T １０２ is absent, hydrogen, fluorine, chlorine, methyl group, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, hydroxyl, and cyano; Y ５０ , Y ５１ , Y ５２ , Y ５３ and Y ５４ one or more of are linked to the L group; Y ６２ each occurrence is N, NH, —(C═O)— or —CH ２ are independently selected from R ７０ each occurrence is independently selected from hydrogen, methyl, ethyl, or propyl; 【Chemistry 64】 represents a single bond or a double bond, R ４ each occurrence is independently selected from allyl, propargyl, methylenecyclopropyl, ethyl, trifluoroethyl, difluoroethyl, isopropyl, and cyclopropyl; R ２１ , R ２２ each occurrence is independently selected from hydrogen or a 2-hydroxyisopropyl group; or ２１ , R ２２ are bonded together to form -(CR ９１ R ９２ )-(CH ２ )-(CH ２ ) - or -(CH ２ )-(CH ２ )-(CR ９５ R ９７６ )—, where R ９１ , R ９２ , R ９５ and R ９６ each occurrence is independently selected from hydrogen, hydroxyl, methyl, ethyl, and propyl; L has the following structure: 【Transformation 65】 【Chemical 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 is a linker having the formula where: 【Chemistry 72】 represents a bonding site, and the L group is a halogen, a hydroxyl group, a nitro group, a cyano group, an amino group, a mercapto group, —COOH, or C １ -C ６ optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl groups; The compound of claim 7.

9. The compounds are represented by the following formula (XXIII), formula (XXIV), formula (XXV), and formula (XXVIII): 【Transformation 73】 The compound is characterized by being represented by a structural formula selected from the group consisting of The compound of claim 1.

10. The compound has formula (XXXXIII), formula (XXXXV) or formula (XXXXVI): 【Chemistry 74】 The compound is characterized in that it is represented by The compound of claim 1.

11. The compound has the formula: 【Chemistry 75】 【Transformation 76】 【Chemical 77】 【Transformation 78】 【Chemistry 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Transformation 87】 【Chemical 88】 【Chemical 89】 [Chemical 90] 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 【Chemical 95】 【Chemistry 96】 【Chemistry 97】 【Chem.98】 【Chem.99】 【Chemistry 100】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemical 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemistry 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 【Chemistry 121】 【Chemistry 122】 【Chemical 123】 The compound is characterized in that it has a structure selected from The compound of claim 1.

12. The compound has the formula: 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 The compound is characterized in that it has a structure selected from The compound of claim 1.

13. 1. A pharmaceutical composition comprising:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug thereof, and a pharmaceutically acceptable carrier.

14. 13. Use of a compound according to any one of claims 1 to 12, or a derivative, pharmaceutically acceptable salt, isomer, solvate, hydrate, adduct, complex or prodrug thereof, in the manufacture of a medicament for treating a proliferative disease.

15. 15. The use according to claim 14, The proliferative disorders include breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neurocytoma, cancers of the lymphoid organs, and myeloid malignancies including leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HML), and the like). CL), T-cell prolymphocytic leukemia (T-PLL), giant lymphocytic leukemia, adult T-cell leukemia), lymphomas (small lymphocytic lymphoma (SLL), Hodgkin's lymphoma (nodular sclerosis, mixed cytology, lymphocyte-rich, lymphopenic or non-reduced and nodular lymphocyte-predominant Hodgkin's lymphoma), non-Hodgkin's lymphoma (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic leukemia (e.g., Waldenstrom's macroglobulinemia), Splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition disease, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), nodal marginal zone B-cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell giant lymphocytic leukemia, grade of malignancy NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary intercutaneous CD30-positive T-cell lymphoproliferative disorder, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (nonspecific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or Kahler's disease), malignant melanoma (malignant melanoma, gliomas, ovarian carcinoma, uterine serous carcinoma (USC), triple negative breast cancerThe above use, characterized in that the cancers include Breast Cancer (TNBC), Head and Neck Squamous Cell Carcinoma (HNSCC).

Images