Heterocyclic compound

Abstract

The present disclosure provides a heterocyclic compound.　The disclosure relates to a compound in which a ligand of a specific E3 ligase is bound to an intracellular target protein ligand via a linker. More specifically, the disclosure relates to a compound that induces the degradation of a target protein using a ligand of an inhibitor of apoptosis protein (IAP) that is an E3 ligase. The compound of the disclosure exhibits an effect of inducing protein degradation by using the ligand of the inhibitor of apoptosis protein (IAP). Therefore, the compound of the disclosure is useful as a therapeutic agent and / or a prophylactic agent.

Description

heterocyclic compounds

[0001] The present disclosure relates to a compound in which a ligand for a specific E3 ligase is linked to a ligand for an intracellular target protein via a linker. More particularly, the present disclosure relates to a compound that induces degradation of a target protein using a ligand for an Inhibitor of Apoptosis Protein (IAP) as the E3 ligase.

[0002] For the purpose of treatment by reducing pathology-related proteins, attempts have been made to develop compounds that induce ubiquitination and proteasomal degradation of target proteins by E3 ligase (specifically, Inhibitor of Apoptosis Protein (IAP)). For example, compounds have been proposed that contain MV1, MeBS, Nutlin-3, IκBα peptide, HIF-1α peptide, or VHL ligand as a ligand that binds to E3 ligase, and target proteins such as CRABP2, RIPK2, ERα, TACC3, AR, ERRα, FRS2α, or PI3K.

[0003] The present disclosure provides compounds that induce the degradation of a target protein.

[0004] As a result of intensive research, the present inventors have found that compounds represented by the following formula A and related structural formulas, or pharmaceutically acceptable salts thereof (hereinafter sometimes referred to as "compounds of the present disclosure" or "the compound(s) of the disclosure") solve the above-mentioned problems, and have completed the technical matters of the present disclosure. That is, the present disclosure is as follows: (Item 1) A compound represented by formula (A) Z-L-X or an isomer thereof, or a salt thereof, wherein Z is a ligand moiety that specifically binds to an intracellular protein, L is a linker moiety or a single bond, and X is a group represented by the following formula: A is N or CR ８ and B is N, CR ９ , or C.L. ２ and Q is N or CR １０ and R １ and L that is not used for bonding with L １are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), -(CH ２ ) ｓ -C ３－１２ Carbocyclyl, —C(═O)—(3- to 12-membered heterocyclyl), and —C(═O)—C ３－１２ carbocyclyl, or R １ and L that is not used for bonding with L １ can form, together with the carbon atoms to which they are attached, a 3- to 10-membered saturated carbocyclyl or heterocyclyl group, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl and carbocyclyl groups may be formed by one or more R ｂ optionally substituted with a group; ２ａ and R ２ｂ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), and -(CH ２ ) ｓ -C ３－１２ carbocyclyl, or R ２ａ and R ２ｂ can form, together with the carbon atoms to which they are attached, a 3- to 10-membered saturated carbocyclyl or heterocyclyl group, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl and carbocyclyl groups may be formed by one or more R ｂ optionally substituted with a group; ３is C １－４ Alkyl, C ２－４ Alkenyl and -(CH ２ ) ｓ -C ３－８ cycloalkyl, wherein said C １－４ Alkyl, C ２－４ alkenyl, and C ３－８ Cycloalkyl is one or more R ａ optionally substituted with a group; ａ represents halogen, —OH and —O—C １－６ alkyl; R ４ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl and -(CH ２ ) ｓ -C ３－８ cycloalkenyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl and C ３－８ Cycloalkenyl is one or more R ａ optionally substituted with a group; ５ａ and R ５ｂ are each independently hydrogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN, -S(O) ｑ -R ｘ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)Rｘ 、-(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ 、-(CR ｘ R ｙ ) ｓ -O-C(=O)-R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ 、-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ 、-(CH ２ ) ｓ -NR ｘ R ｙ 、-NR ｘ -(CH ２ ) ｓ -R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ 、-(CR ｘ R ｙ ) ｓ -C(=N)NR ｚ 、-(CH ２ ) ｓ -O-C(=O)-C １－４ アルキル-NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｎ -O-C(=O)-R ｚ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｓ -SO ２ -R ｙ 、-(CH２ ) ｓ -NH-SO ２ -NR ｘ R ｙ and -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ or R ５ａ and R ５ｂ can form, together with the carbon atom to which they are attached, a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group, wherein said C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ An alkynyl group is one or more R ｂ groups, and the carbocyclyl and heterocyclyl groups may be substituted with one or more R ｂ optionally substituted with a group; ６ is hydrogen, halogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , =O, =S, nitro, Si(R ｘ ) ４ , -(CH ２ ) ｓ -CN, -S(O) ｑ - (CR ｘ R ｙ ) ｓ -R ｚ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ-O-C(=O)-R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ 、-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ 、-(CH ２ ) ｓ -NR ｘ R ｙ 、-NR ｘ -(CH ２ ) ｓ -R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ 、-(CR ｘ R ｙ ) ｓ -C(=N)NR ｘ 、-S(O)(=NR ｘ )R ｙ 、-(CH ２ ) ｓ -O-C(=O)-C １－４ アルキル-NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｎ -O-C(=O)-R ｚ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｓ -SO ２ -R ｙ 、-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ 、-(CH２ ) ｓ -SO ２ NR ｘ R ｙ group, -P(=O)(R ｘ ) ２ , -Y-C ５－１０ Aryl, —Y—(5- to 10-membered heteroaryl), an optionally fused 5- to 10-membered carbocyclyl group, an optionally fused 5- to 10-membered heterocyclyl group, and (E represents the point of attachment), and L ３ and L ３ ' together with the carbon atom to which they are attached can form a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group connected with a linker, wherein said C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl groups, carbocyclyl groups, heterocyclyl groups, and (E represents the point of attachment) is one or more R ｂ optionally substituted with a group; R ７ , R ８ and R ９ are each independently hydrogen, halogen, or C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , =O, =S, nitro, Si(R ｘ ) ４ , -(CH ２ ) ｓ -CN, -S(O) ｑ - (CR ｘ R ｙ ) ｓ -R ｚ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ , -(CR ｘR ｙ ) ｓ -C(=O)OR ｚ 、-(CR ｘ R ｙ ) ｓ -O-C(=O)-R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ 、-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ 、-(CH ２ ) ｓ -NR ｘ R ｙ 、-NR ｘ -(CH ２ ) ｓ -R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ 、-(CR ｘ R ｙ ) ｓ -C(=N)NR ｘ 、-S(O)(=NR ｘ )R ｙ 、-(CH ２ ) ｓ -O-C(=O)-C １－４ アルキル-NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｎ -O-C(=O)-R ｚ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｓ -SO ２ -R ｙ, -(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ , -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ group, -P(=O)(R ｘ ) ２ and -Y-C ５－１０ aryl, wherein said C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ An alkynyl group is one or more R ｂ groups, and the carbocyclyl and heterocyclyl groups may be substituted with one or more (e.g., 1, 2, or 3) R ｂ optionally substituted with a group; ｂ are each independently a halogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(5- to 10-membered heteroaryl), -(CH ２ ) ｓ -(4- to 7-membered saturated heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , Halo C １－６ Alkyl, haloC １－６ Alkoxy, hydroxy, hydroxy C １－６ Alkyl, ═O, ═S, nitro, Si(Rx) ４ , -(CH ２ ) ｓ -CN, -S(O)ｑ -R ｘ 、-C(=O)R ｘ 、-(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ 、-(CR ｘ R ｙ ) ｓ -O-C(=O)-R ｚ 、-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ 、-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ -(CH ２ ) ｓ -NR ｘ R ｙ 、-NR ｘ -(CH ２ ) ｓ -R ｚ 、-(CH ２ ) ｓ -O-C(=O)-C １－４ アルキル-NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｎ -O-C(=O)-R ｚ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｓ -SO ２ -R ｙ 、-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ 、-(CH ２ )ｓ -SO ２ NR ｘ R ｙ group and —P(═O)(R ｘ ) ２ wherein said C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, heterocyclyl, phenyl and heteroaryl can be one or more R ｘ optionally substituted with a group; ｘ , R ｙ and R ｚ are each independently a halogen, hydrogen, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(4- to 7-membered saturated heterocyclyl), hydroxy C optionally substituted with one or more halo １－６ Alkyl, —C(═O)OC １－６ Alkyl, hydroxy, C １－６ Alkoxy, HaloC １－６ Alkyl, -(CH ２ ) ｎ -O-C １－６ Alkyl, —C(═O)—(CH ２ ) ｎ -C １－６ Alkoxy, —C(═O)—C １－６ Alkyl, -(CH ２ ) ｓ -CN, C １－６ Alkyl-N(H) ２－ｑ (C １－６ alkyl) ｑ , -N(H) ２－ｑ (C １－６ alkyl) ｑ, -C(=O)-N(H) ２－ｑ (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -NH-SO ２ -N(H) ２－ｑ (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -N(C １－４ (alkyl)-SO ２ -N(H) ２－ｑ (C １－６ alkyl) ｑ and -(CH ２ ) ｓ -O-C(=O)-C １－４ Alkyl-N(H) ２－ｑ (C １－６ alkyl) ｑ and when attached to a nitrogen, carbon, silicon or phosphorus atom, R ｘ and R ｙ may, together with the atoms to which they are attached, form a 3- to 7-membered ring which may contain one or two additional heteroatoms selected from O, N, S, and oxidized forms of N and S; Y and W each independently represent a bond, -(CR ｘ R ｙ ) ｍ -, -C(=CR ｘ )-, -C(=O)-, -NR ｘ , —C(═O)NR ｘ -, -NR ｘ C(=O)-,-(CR ｘ R ｙ ) ｑ -O-, -O-(CR ｘ R ｙ ) ｑ -, -S(O) ２ -NH,NH-S(O) ２ - and -S(O) ｑ - selected from; R １０ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ, -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), -(CH ２ ) ｓ -C ３－１２ Carbocyclyl, —C(═O)—(3- to 12-membered heterocyclyl), and —C(═O)—C ３－１２ carbocyclyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl, and carbocyclyl groups can be one or more R ｂ group; s independently represents an integer of 0 to 4; n independently represents an integer of 1 to 4; q independently represents an integer of 0 to 2; m independently represents an integer of 1 to 2; L １ ~L ３ and L ３and X is bonded to L. (Item 2) The compound according to item 1, or an isomer thereof, or a salt thereof, wherein the intracellular protein in Z is a serine / threonine kinase, a receptor tyrosine kinase, a non-receptor tyrosine kinase, or a non-kinase. (Item 3) The compound according to item 1, or an isomer thereof, or a salt thereof, which has inhibitory activity or binding activity to the intracellular protein in Z. (Item 4) The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein the intracellular protein in Z is a serine / threonine kinase, and the serine / threonine kinase is selected from the group consisting of the AGC group, the CAMK group, the CK1 group, the CMGC group, the STE group, the TKL group, and other serine / threonine kinases. (Item 5) The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein the serine / threonine kinase is ROCK2. (Item 6) The compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein the intracellular protein represented by Z is a receptor tyrosine kinase selected from the group consisting of the epidermal growth factor receptor family, insulin receptor family, platelet-derived growth factor receptor family, vascular endothelial growth factor receptor family, fibroblast growth factor receptor family, CCK family, nerve growth factor receptor family, hepatocyte growth factor receptor family, Eph receptor family, AXL receptor family, TIE receptor family, RYK receptor family, DDR receptor family, RET receptor family, ROS receptor family, LTK receptor family, ROR receptor family, MuSK receptor family, LMR receptor family, and other receptor tyrosine kinases. (Item 7) The compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein the receptor tyrosine kinase is ALK.(Item 8) The compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein the intracellular protein in Z is a non-receptor tyrosine kinase selected from the group consisting of the ABL family, ACK family, CSK family, FAK family, FES family, FRK family, JAK family, SRC family, TEC family and SYK family. (Item 9) The compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein the non-receptor tyrosine kinase is FAK. (Item 10) X is L. １ , L ２ , L ３ or L ３ A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein Q is connected to L at any one of (a) and (b). (Item 11) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein Q is N. (Item 12) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein Q is CH. (Item 13) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein A is N. (Item 14) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein A is CH. (Item 15) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein B is N. (Item 16) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein B is CH. (Item 17) A compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein R １ and L that is not used for bonding with L １ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 7-membered heterocyclyl), -(CH ２ ) ｓ -C ３－７ Carbocyclyl, —C(═O)—(3- to 7-membered heterocyclyl), and —C(═O)—C ３－７ carbocyclyl, or R１ and L that is not used for bonding with L １ can form, together with the carbon atoms to which they are attached, a 3- to 6-membered saturated carbocyclyl group or a 4- to 6-membered heterocyclyl group, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl and carbocyclyl groups may be formed by one or more R ｂ group, and the R ｂ are each independently a halogen, C １－４ Alkyl, C ３－４ Alkynyl, -(CH ２ ) ｑ -C ３－６ Cycloalkyl, -(CH ２ ) ｑ -phenyl, -(CH ２ ) ｑ -(5- to 6-membered heteroaryl), -(CH ２ ) ｑ -O-C １－４ Alkyl, haloC １－４ Alkyl, haloC １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, ═O, —S(O) ｑ -C １－４ Alkyl, —C(═O)C １－４ Alkyl, -(CH ２ ) ｑ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｑ -NR ｘ C(=O)C １－４ Alkyl, -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｑ -C １－４ Alkyl, -(CH ２ ) ｑ -NR ｘ - (CH ２ ) ｑ -SO ２ -C １－４Alkyl, and -(CH ２ ) ｑ -SO ２ NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ R ｘ and R ｙ are each independently a halogen, hydrogen, or C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ may form, together with the atom to which they are attached, a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N, or a salt thereof. (Item 18) A compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R １ and L that is not used for bonding with L １ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 7-membered heterocyclyl), -(CH ２ ) ｓ -C ３－７ Carbocyclyl, —C(═O)—(3- to 7-membered heterocyclyl), and —C(═O)—C ３－７ carbocyclyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl, and carbocyclyl groups can be one or more R ｂ may be substituted with a group, R ｂ are each independently fluorine, methyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—C １－２ Alkyl, fluoromethyl, fluoromethoxy, hydroxy, ═O, —S(O) ２ -C１－４ Alkyl, —C(═O)C １－４ Alkyl, —C(═O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl, and —NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ R ｘ and R ｙ are each independently chlorine, fluorine, hydrogen, C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ may form, together with the atom to which they are attached, a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N, or a salt thereof. (Item 19) A compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R ２ａ and R ２ｂ are each independently hydrogen, C １－３ Alkyl, C ２－３ Alkenyl and C ２－３ alkynyl, or R ２ａ and R ２ｂ and R can form a 3- to 4-membered saturated carbocyclyl group together with the carbon atom to which they are attached, or an isomer thereof, or a salt thereof, according to the preceding item. (Item 20) ２ａ and R ２ｂ (Item 21) The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R is hydrogen. ３ is C １－４ alkyl, wherein said C １－４ Alkyl is one or more R ａ (Item 22) A compound according to the preceding item, an isomer thereof, or a salt thereof, which may be substituted by a group. ３(Item 23) The compound or an isomer thereof, or a salt thereof, according to the preceding item, wherein R is methyl, wherein the methyl may be substituted with one or more fluorines. ４ (Item 24) The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R is hydrogen. ５ａ and R ５ｂ are each independently hydrogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－６ carbocyclyl, -W-(3- to 6-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN and -C(=O)R ｘ or R ５ａ and R ５ｂ can form, together with the carbon atom to which they are attached, a 3- to 5-membered carbocyclyl group or a 5- to 6-membered heterocyclyl group, wherein said C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ An alkynyl group is one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, C １－４ Alkyl, C ３－４ Alkynyl, —C ３－６ Cycloalkyl, —O—C １－４ Alkyl, Fluoro C １－４ Alkyl, haloC １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, —C(═O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl, and —NR ｘ R ｙ(Item 25) A compound according to the preceding item, or an isomer thereof, or a salt thereof, selected from the group consisting of R ５ａ and R ５ｂ are each independently hydrogen or methyl, or R ５ａ and R ５ｂ and R can form a cyclopropyl group together with the carbon atom to which they are attached, or an isomer thereof, or a salt thereof, according to the preceding item. (Item 26) ６ But hydrogen, halogen, C １－４ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, -(CR ｘ R ｙ )-C ３－７ Carbocyclyl, -(CR ｘ R ｙ )-(3- to 7-membered heterocyclyl), -(CR ｘ R ｙ )-O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN, -S(O) ２ - (CH ２ ) ｓ -R ｚ , -C(=O)R ｘ , -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ , -(CH ２ ) ｎ -C ５－１０ Aryl, -(CH ２ ) ｎ -(5- to 10-membered heteroaryl), an optionally fused 5- to 7-membered carbocyclyl group, an optionally fused 5- to 7-membered heterocyclyl group, and (E represents the point of attachment), and L ３ and L ３' together with the carbon atom to which they are attached can form a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group which can be connected with a linker, wherein said C １－４ Alkyl, C ２－５ Alkenyl and C ２－５ Alkynyl groups, carbocyclyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and (E represents the point of attachment) is one or more R ｂ may be substituted with a group, and the R ｂ are each independently a halogen, C １－４ Alkyl, C ３－４ Alkynyl, -(CH ２ ) ｑ -C ３－６ Cycloalkyl, -(CH ２ ) ｑ -phenyl, -(CH ２ ) ｑ -(5- to 6-membered heteroaryl), -(CH ２ ) ｑ -O-C １－４ Alkyl, haloC １－４ Alkyl, haloC １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, ═O, —S(O) ｑ -C １－４ Alkyl, —C(═O)C １－４ Alkyl, -(CH ２ ) ｑ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｑ -NR ｘ C(=O)C １－４ Alkyl, -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｑ -C １－４ Alkyl, -(CH ２ ) ｑ -NR ｘ - (CH ２ ) ｑ -SO ２ -C１－４ Alkyl, and -(CH ２ ) ｑ -SO ２ NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ CR ｘ R ｙ is CH ２ or CF ２ and other R ｘ , R ｙ and R ｚ are each independently hydrogen, C １－４ Alkyl, C ３－４ Alkynyl, Fluoro C １－４ Alkyl, and C １－４ alkoxy; R ｂ R as a substituent of ｘ The group is halogen, hydrogen, C １－４ Alkyl, and C １－４ 27. The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R is selected from the group consisting of alkoxy, ... ６ But, -(CR ｘ R ｙ ) -H, -(CR ｘ R ｙ )-F, -(CR ｘ R ｙ ) - C １－２ Alkyl, -(CR ｘ R ｙ ) —O-phenyl, —S(O) ２ -CH ２ -R ｚ , -C(=O)C １－４ Alkyl, —C(═O)-phenyl, —C(═O)-(5-6 membered heteroaryl), —CH ２ -phenyl, -CH ２ -(5-6 membered heteroaryl), and (E represents the point of attachment), and L ３ and L ３' together with the carbon atom to which they are attached can form a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group which can be connected with a linker, wherein said C １－２ Alkyl, C １－４ Alkyl, phenyl, heteroaryl and (E represents a point of attachment) is one or more C １－３ an alkyl group, fluorine, chlorine, or —O—C １－３ may be substituted with an alkyl group, ｘ R ｙ is CH ２ or CF ２ and other R ｘ , R ｙ and R ｚ are each independently hydrogen, C １－４ Alkyl, C ３－４ Alkynyl, Fluoro C １－４ Alkyl, and C １－４ 28. The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R is selected from the group consisting of alkoxy, ... ７ is hydrogen, halogen, C １－３ Alkyl, C ２－３ Alkenyl, C ２－３ Alkynyl and C ３－４ carbocyclyl, wherein said C １－３ Alkyl, C ２－３ Alkenyl, C ２－３ Alkynyl and C ３－４ Carbocyclyl is a group consisting of one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, —O—C １－４ Alkyl, Fluoro C １－４ Alkoxy, hydroxy, and —NR ｘ R ｙ R is selected from the group ｘ and R ｙ are each independently hydrogen, and C １－４ alkyl, and when attached to a nitrogen, R ｘ and R ｙmay form, together with the atom to which they are attached, a 4- to 6-membered ring which may contain one additional heteroatom selected from O and N, or a salt thereof. (Item 29) A compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R ７ (Item 30) The compound or an isomer thereof, or a salt thereof according to the preceding item, wherein R is hydrogen or fluorine. ８ (Item 31) The compound according to the preceding item, or an isomer thereof, or a salt thereof, wherein R is hydrogen. ９ is hydrogen, halogen, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, -Y-C ３－６ carbocyclyl, -W-(4- to 6-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , ═O, -(CH ２ ) ｓ -CN, -C(=O)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ -NR ｘ R ｙ , -(CH ２ ) ｓ -O-C(=O)-C １－４ Alkyl-NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ , -(CH ２ ) ｓ -NH-SO２ -NR ｘ R ｙ , -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ , and -Y-C ５－１０ aryl, wherein said C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, carbocyclyl and heterocyclyl groups are each formed by one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, C １－４ Alkyl, C ３－４ Alkynyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—C １－４ Alkyl, Fluoro C １－４ Alkyl, Fluoro C １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, ═O, —C(═O)C １－４ Alkyl, —C(═O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl, and —NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ group, and the R ｘ , R ｙ and R ｚ are each independently chlorine, fluorine, hydrogen, C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ and R may, together with the atom to which they are attached, form a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N. ９ is hydrogen, C １－４ Alkyl, C ２－４ Alkenyl, C２－４ Alkynyl, —CH ２ -C ３－６ Carbocyclyl, -CH ２ -(4- to 6-membered heterocyclyl), -CH ２ -O-R ｚ -C(=O)R ｘ , and -CH ２ -NR ｘ R ｙ wherein said C is selected from １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, carbocyclyl and heterocyclyl groups are each formed by one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, C １－４ Alkyl, C ３－４ Alkynyl, phenyl, 5- to 6-membered heteroaryl, —O—C １－４ Alkyl, Fluoro C １－４ Alkyl, Fluoro C １－４ Alkoxy, hydroxy, and —NR ｘ R ｙ groups, wherein the phenyl and heteroaryl groups are selected from one or more R ｘ group, and the R ｘ , R ｙ and R ｚ are each independently chlorine, fluorine, hydrogen, C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ and R may, together with the atom to which they are attached, form a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N. １０ is hydrogen or methyl. (Item 34) The compound according to any one of the preceding items, represented by the following structure: (Item 35) A pharmaceutical composition comprising the compound according to any one of the preceding items or an isomer thereof, or a salt thereof. (Item 36) A target protein modulator comprising the compound according to any one of the preceding items or an isomer thereof, or a salt thereof. (Item 37) A process for producing a compound of formula (I) defined in any one of the preceding items, comprising: (a) reacting a compound of formula (III) (In the formula, A, B, R ５ａ , R ５ｂ , R ６ , R ７ is as defined in any of the preceding paragraphs) with a compound of formula (IV): (In the formula R ４ is as defined in any of the preceding items, and L Ａ and L Ｂ each independently represent a leaving group), followed by reacting with a compound of formula (V): (In the formula R １ , R ２ａ , R ２ｂ , R ３ is as defined in any of the preceding items, and L １ is L that is not used to bond with L １ and P １ represents hydrogen or a protecting group), followed by the following reaction with a compound of formula P １and / or (b) (i) reacting Z of the preceding item with L of the preceding item to form Z-L, and reacting said Z-L with X to form a compound of formula (I), (ii) reacting X of the preceding item with L of the preceding item to form X-L, and reacting said X-L with Z to form a compound of formula (I), and / or (iii) reacting Z of the preceding item with La, which is part of L of the preceding item, to form Z-La, and reacting X of the preceding item with Lb, which is the remaining part of L, to form X-Lb, and reacting said Z-La with X-Lb to form a compound of formula (I). It is intended that in the present disclosure, one or more of the above features may be provided in further combinations in addition to the combinations explicitly stated. Still further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary.

[0005] The present disclosure provides compounds in which a specific E3 ligase ligand and an intracellular target protein ligand are linked via a linker. The compounds of the present disclosure exhibit proteolysis-inducing activity when used with an Inhibitor of Apoptosis Protein (IAP) ligand. Therefore, the compounds of the present disclosure are useful as therapeutic and / or prophylactic agents.

[0006] The present disclosure will be described in more detail below. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0007] (Definitions) First, the terms and general techniques used in this disclosure will be explained. In this specification, the term "group" means a monovalent group unless otherwise specified. Examples of non-monovalent groups include alkylene groups (divalent). In addition, in the following explanations of substituents, etc., the term "group" may be omitted.

[0008] In this specification, when defined as "optionally substituted" or "substituted," the number of substituents is not particularly limited as long as substitution is possible, and is one or more. Furthermore, unless otherwise specified, the description of each substituent also applies when that substituent is a part of or a substituent for another substituent.

[0009] As used herein, the "maximum number of possible substitutions" refers to the maximum number of substituents that a group can have, and may vary for each group. For example, the maximum number of possible substitutions is 3 for a methyl group, 5 for an ethyl group, 7 for a benzyl group, and 11 for a naphthalenylethyl group.

[0010] In the present specification, any part of a group modified with "optionally substituted" or "substituted" may be substituted. For example, in "optionally substituted arylalkyl" and "substituted arylalkyl," the aryl moiety, the alkyl moiety, or both the aryl and alkyl moieties may be substituted.

[0011] In the present specification, the substituents in the case of "optionally substituted" may be one or more of the same or different substituents selected from any of the following substituent groups I to III. The type of atom in the substituent participating in the bond is not particularly limited depending on the type of the substituent, but when the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the bond point in the following substituent is limited to a carbon atom, and the substituent is selected from those.

[0012] Substituent Group I includes halogen, hydroxy, oxo, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted alkyloxy, unsubstituted or substituted alkenyloxy, unsubstituted or substituted alkynyloxy, unsubstituted or substituted aryl-L Ｘ -oxy, unsubstituted or substituted cycloalkyl-L Ｘ -oxy, unsubstituted or substituted heteroaryl-L Ｘ -oxy, unsubstituted or substituted heterocycloalkyl-L Ｘ -oxy, unsubstituted or substituted alkyloxyalkyl, unsubstituted or substituted alkenyloxyalkyl, unsubstituted or substituted alkynyloxyalkyl, unsubstituted or substituted aryloxyalkyl, unsubstituted or substituted cycloalkyloxyalkyl, unsubstituted or substituted heteroaryloxyalkyl, unsubstituted or substituted heterocycloalkyloxyalkyl, unsubstituted or substituted alkyloxyalkyloxy, unsubstituted or substituted alkenyloxyalkyloxy, unsubstituted or substituted alkynyloxyalkyloxy, unsubstituted or substituted aryloxyalkyloxy, unsubstituted or substituted cycloalkyloxyalkyloxy, unsubstituted or substituted heteroaryloxyalkyloxy, unsubstituted or substituted heterocycloalkyloxyalkyloxy, unsubstituted or substituted alkylcarbonyl, unsubstituted or substituted alkenylcarbonyl, unsubstituted or substituted alkynylcarbonyl, unsubstituted or substituted aryl-L Ｘ -carbonyl, unsubstituted or substituted cycloalkyl-L Ｘ -carbonyl, unsubstituted or substituted heteroaryl-L Ｘ-carbonyl, unsubstituted or substituted heterocycloalkyl-L Ｘ -carbonyl, unsubstituted or substituted alkylcarbonyloxy, unsubstituted or substituted alkenylcarbonyloxy, unsubstituted or substituted alkynylcarbonyloxy, unsubstituted or substituted aryl-L Ｘ -carbonyloxy, unsubstituted or substituted cycloalkyl-L Ｘ -carbonyloxy, unsubstituted or substituted heteroaryl-L Ｘ -carbonyloxy, unsubstituted or substituted heterocycloalkyl-L Ｘ -carbonyloxy, unsubstituted or substituted alkylcarbonylamino, unsubstituted or substituted alkenylcarbonylamino, unsubstituted or substituted alkynylcarbonylamino, unsubstituted or substituted aryl-L Ｘ -carbonylamino, unsubstituted or substituted cycloalkyl-L Ｘ -carbonylamino, unsubstituted or substituted heteroaryl-L Ｘ -carbonylamino, unsubstituted or substituted heterocycloalkyl-L Ｘ -carbonylamino, unsubstituted or substituted alkylcarbonylthio, unsubstituted or substituted alkenylcarbonylthio, unsubstituted or substituted alkynylcarbonylthio, unsubstituted or substituted aryl-L Ｘ -carbonylthio, unsubstituted or substituted cycloalkyl-L Ｘ -carbonylthio, unsubstituted or substituted heteroaryl-L Ｘ -carbonylthio, unsubstituted or substituted heterocycloalkyl-L Ｘ -carbonylthio, unsubstituted or substituted alkylcarbonylimino, unsubstituted or substituted alkenylcarbonylimino, unsubstituted or substituted alkynylcarbonylimino, unsubstituted or substituted aryl-L Ｘ -carbonylimino, unsubstituted or substituted cycloalkyl-L Ｘ -carbonylimino, unsubstituted or substituted heteroaryl-L Ｘ -carbonylimino, unsubstituted or substituted heterocycloalkyl-L Ｘ-carbonylimino, unsubstituted or substituted alkylthio, unsubstituted or substituted alkenylthio, unsubstituted or substituted alkynylthio, unsubstituted or substituted aryl-L Ｘ -thio, unsubstituted or substituted cycloalkyl-L Ｘ -thio, unsubstituted or substituted heteroaryl-L Ｘ -thio, unsubstituted or substituted heterocycloalkyl-L Ｘ -thio, unsubstituted or substituted alkylamino, unsubstituted or substituted alkenylamino, unsubstituted or substituted alkynylamino, unsubstituted or substituted alkynylamino, unsubstituted or substituted aryl-L Ｘ -amino, unsubstituted or substituted cycloalkyl-L Ｘ -amino, unsubstituted or substituted heteroaryl-L Ｘ -amino, unsubstituted or substituted heterocycloalkyl-L Ｘ -amino, unsubstituted or substituted alkylsulfonyl, unsubstituted or substituted alkenylsulfonyl, unsubstituted or substituted alkynylsulfonyl, unsubstituted or substituted aryl-L Ｘ -sulfonyl, unsubstituted or substituted cycloalkyl-L Ｘ -sulfonyl, unsubstituted or substituted heteroaryl-L Ｘ -sulfonyl, unsubstituted or substituted heterocycloalkyl-L Ｘ -sulfonyl, unsubstituted or substituted alkylsulfonylamino, unsubstituted or substituted alkenylsulfonylamino, unsubstituted or substituted alkynylsulfonylamino, unsubstituted or substituted aryl-L Ｘ -sulfonylamino, unsubstituted or substituted cycloalkyl-L Ｘ -sulfonylamino, unsubstituted or substituted heteroaryl-L Ｘ -sulfonylamino, unsubstituted or substituted heterocycloalkyl-L Ｘ -sulfonylamino, unsubstituted or substituted alkylimino, unsubstituted or substituted alkenylimino, unsubstituted or substituted alkynylimino, unsubstituted or substituted aryl-L Ｘ -imino, unsubstituted or substituted cycloalkyl-L Ｘ -imino, unsubstituted or substituted heteroaryl-LＸ -imino, unsubstituted or substituted heterocycloalkyl-L Ｘ -imino, unsubstituted or substituted alkyloxyimino, unsubstituted or substituted alkenyloxyimino, unsubstituted or substituted alkynyloxyimino, unsubstituted or substituted aryl-L Ｘ -oximino, unsubstituted or substituted cycloalkyl-L Ｘ -oximino, unsubstituted or substituted heteroaryl-L Ｘ -oximino, unsubstituted or substituted heterocycloalkyl-L Ｘ -oximino, unsubstituted or substituted alkyloxycarbonyl, unsubstituted or substituted alkenyloxycarbonyl, unsubstituted or substituted alkynyloxycarbonyl, unsubstituted or substituted aryl-L Ｘ -oxycarbonyl, unsubstituted or substituted cycloalkyl-L Ｘ -oxycarbonyl, unsubstituted or substituted heteroaryl-L Ｘ -oxycarbonyl, unsubstituted or substituted heterocycloalkyl-L Ｘ -oxycarbonyl, unsubstituted or substituted alkyloxycarbonylamino, unsubstituted or substituted alkenyloxycarbonylamino, unsubstituted or substituted alkynyloxycarbonylamino, unsubstituted or substituted aryl-L Ｘ -oxycarbonylamino, unsubstituted or substituted cycloalkyl-L Ｘ -oxycarbonylamino, unsubstituted or substituted heteroaryl-L Ｘ -oxycarbonylamino, unsubstituted or substituted heterocycloalkyl-L Ｘ -oxycarbonylamino, unsubstituted or substituted alkylsulfanyl, unsubstituted or substituted alkenylsulfanyl, unsubstituted or substituted alkynylsulfanyl, unsubstituted or substituted aryl-L Ｘ -sulfanyl, unsubstituted or substituted cycloalkyl-L Ｘ -sulfanyl, unsubstituted or substituted heteroaryl-L Ｘ -sulfanyl, unsubstituted or substituted heterocycloalkyl-L Ｘ-sulfanyl, unsubstituted or substituted alkylsulfinyl, unsubstituted or substituted alkenylsulfinyl, unsubstituted or substituted alkynylsulfinyl, unsubstituted or substituted aryl-L Ｘ -sulfinyl, unsubstituted or substituted cycloalkyl-L Ｘ -sulfinyl, unsubstituted or substituted heteroaryl-L Ｘ -sulfinyl, unsubstituted or substituted heterocycloalkyl-L Ｘ -sulfinyl, unsubstituted or substituted alkylcarbamoyl, unsubstituted or substituted alkenylcarbamoyl, unsubstituted or substituted alkynylcarbamoyl, unsubstituted or substituted aryl-L Ｘ -carbamoyl, unsubstituted or substituted cycloalkyl-L Ｘ -carbamoyl, unsubstituted or substituted heteroaryl-L Ｘ -carbamoyl, unsubstituted or substituted heterocycloalkyl-L Ｘ -carbamoyl, unsubstituted or substituted alkylsulfamoyl, unsubstituted or substituted alkenylsulfamoyl, unsubstituted or substituted alkynylsulfamoyl, unsubstituted or substituted aryl-L Ｘ -sulfamoyl, unsubstituted or substituted cycloalkyl-L Ｘ -sulfamoyl, unsubstituted or substituted heteroaryl-L Ｘ -sulfamoyl, and unsubstituted or substituted heterocycloalkyl-L Ｘ -sulfamoyl, where L Ｘis a single bond or unsubstituted or substituted alkylene, and the substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted cycloalkyl, substituted heteroaryl, substituted heterocycloalkyl, and substituted alkylene moieties (in whole or in part) in the above substituent groups each independently represent halogen, hydroxy, oxo, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, alkyloxy, alkenyloxy, alkynyloxy, aryl-L Ｘ -oxy, cycloalkyl-L Ｘ -oxy, heteroaryl-L Ｘ -oxy, heterocycloalkyl-L Ｘ -oxy, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, cycloalkyloxyalkyl, heteroaryloxyalkyl, heterocycloalkyloxyalkyl, alkyloxyalkyloxy, alkenyloxyalkyloxy, alkynyloxyalkyloxy, aryloxyalkyloxy, cycloalkyloxyalkyloxy, heteroaryloxyalkyloxy, heterocycloalkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aryl-L Ｘ -carbonyl, cycloalkyl-L Ｘ -carbonyl, heteroaryl-L Ｘ -carbonyl, heterocycloalkyl-L Ｘ -carbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, aryl-L Ｘ -carbonyloxy, cycloalkyl-L Ｘ -carbonyloxy, heteroaryl-L Ｘ -carbonyloxy, heterocycloalkyl-L Ｘ-carbonyloxy, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, aryl-L Ｘ -carbonylamino, cycloalkyl-L Ｘ -carbonylamino, heteroaryl-L Ｘ -carbonylamino, heterocycloalkyl-L Ｘ -carbonylamino, alkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, aryl-L Ｘ -carbonylthio, cycloalkyl-L Ｘ -carbonylthio, heteroaryl-L Ｘ -carbonylthio, heterocycloalkyl-L Ｘ -carbonylthio, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, aryl-L Ｘ -carbonylimino, cycloalkyl-L Ｘ -carbonylimino, heteroaryl-L Ｘ -carbonylimino, heterocycloalkyl-L Ｘ -carbonylimino, alkylthio, alkenylthio, alkynylthio, aryl-L Ｘ -thio, cycloalkyl-L Ｘ -thio, heteroaryl-L Ｘ -thio, heterocycloalkyl-L Ｘ -thio, alkylamino, alkenylamino, alkynylamino, alkynylamino, aryl-L Ｘ -amino, cycloalkyl-L Ｘ -amino, heteroaryl-L Ｘ -amino, heterocycloalkyl-L Ｘ -amino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, aryl-L Ｘ -sulfonyl, cycloalkyl-L Ｘ -sulfonyl, heteroaryl-L Ｘ -sulfonyl, heterocycloalkyl-L Ｘ -sulfonyl, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aryl-L Ｘ-sulfonylamino, cycloalkyl-L Ｘ -sulfonylamino, heteroaryl-L Ｘ -sulfonylamino, heterocycloalkyl-L Ｘ -sulfonylamino, alkylimino, alkenylimino, alkynylimino, aryl-L Ｘ -imino, cycloalkyl-L Ｘ -imino, heteroaryl-L Ｘ -imino, heterocycloalkyl-L Ｘ -imino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, aryl-L Ｘ -oximino, cycloalkyl-L Ｘ -oximino, heteroaryl-L Ｘ -oximino, heterocycloalkyl-L Ｘ -oximino, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryl-L Ｘ -oxycarbonyl, cycloalkyl-L Ｘ -oxycarbonyl, heteroaryl-L Ｘ -oxycarbonyl, heterocycloalkyl-L Ｘ -oxycarbonyl, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryl-L Ｘ -oxycarbonylamino, cycloalkyl-L Ｘ -oxycarbonylamino, heteroaryl-L Ｘ -oxycarbonylamino, heterocycloalkyl-L Ｘ -oxycarbonylamino, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, aryl-L Ｘ -sulfanyl, cycloalkyl-L Ｘ -sulfanyl, heteroaryl-L Ｘ -sulfanyl, heterocycloalkyl-L Ｘ -sulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, aryl-L Ｘ -sulfinyl, cycloalkyl-L Ｘ-sulfinyl, heteroaryl-L Ｘ -sulfinyl, heterocycloalkyl-L Ｘ -sulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, aryl-L Ｘ -carbamoyl, cycloalkyl-L Ｘ -carbamoyl, heteroaryl-L Ｘ -carbamoyl, heterocycloalkyl-L Ｘ -carbamoyl, alkylsulfamoyl, alkenylsulfamoyl, alkynylsulfamoyl, aryl-L Ｘ -sulfamoyl, cycloalkyl-L Ｘ -sulfamoyl, heteroaryl-L Ｘ -sulfamoyl, and heterocycloalkyl-L Ｘ -sulfamoyl, and the like.

[0013] Substituent group II includes halogen, hydroxy, oxo, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, unsubstituted or substituted C １－１２ Alkyl, unsubstituted or substituted C ２－１２ Alkenyl, unsubstituted or substituted C ２－１２ Alkynyl, unsubstituted or substituted C ６－１０ Aryl, unsubstituted or substituted C ３－１０ Cycloalkyl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl, unsubstituted or substituted C １－１２ Alkyloxy, unsubstituted or substituted C ２－１２ Alkenyloxy, unsubstituted or substituted C ２－１２ Alkynyloxy, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -oxy, unsubstituted or substituted C ３－１０ Cycloalkyl-LＸ -oxy, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -oxy, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -oxy, unsubstituted or substituted C １－１２ Alkyloxy C １－１２ Alkyl, unsubstituted or substituted C ２－１２ Alkenyloxy C １－１２ Alkyl, unsubstituted or substituted C ２－１２ Alkynyloxy C １－１２ Alkyl, unsubstituted or substituted C ６－１０ Aryloxy C １－１２ Alkyl, unsubstituted or substituted C ３－１０ Cycloalkyloxy C １－１２ Alkyl, unsubstituted or substituted 5-10 membered heteroaryloxy C １－１２ Alkyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyloxy C １－１２ Alkyl, unsubstituted or substituted C １－１２ Alkyloxy C １－１２ Alkyloxy, unsubstituted or substituted C ２－１２ Alkenyloxy C １－１２ Alkyloxy, unsubstituted or substituted C ２－１２ Alkynyloxy C １－１２ Alkyloxy, unsubstituted or substituted C ６－１０ Aryloxy C １－１２ Alkyloxy, unsubstituted or substituted C ３－１０ Cycloalkyloxy C １－１２ Alkyloxy, unsubstituted or substituted 5- to 10-membered heteroaryloxy C １－１２ Alkyloxy, unsubstituted or substituted 5- to 10-membered heterocycloalkyloxy C １－１２ Alkyloxy, unsubstituted or substituted C １－１２ Alkylcarbonyl, unsubstituted or substituted C ２－１２ Alkenylcarbonyl, unsubstituted or substituted C ２－１２ Alkynylcarbonyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -carbonyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ-carbonyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -carbonyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -carbonyl, unsubstituted or substituted C １－１２ Alkylcarbonyloxy, unsubstituted or substituted C ２－１２ Alkenylcarbonyloxy, unsubstituted or substituted C ２－１２ Alkynylcarbonyloxy, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -carbonyloxy, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -carbonyloxy, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -carbonyloxy, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -carbonyloxy, unsubstituted or substituted C １－１２ Alkylcarbonylamino, unsubstituted or substituted C ２－１２ Alkenylcarbonylamino, unsubstituted or substituted C ２－１２ Alkynylcarbonylamino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -carbonylamino, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -carbonylamino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -carbonylamino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -carbonylamino, unsubstituted or substituted C １－１２ Alkylcarbonylthio, unsubstituted or substituted C ２－１２ Alkenylcarbonylthio, unsubstituted or substituted C ２－１２ Alkynylcarbonylthio, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -carbonylthio, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -carbonylthio, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ-carbonylthio, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -carbonylthio, unsubstituted or substituted C １－１２ Alkylcarbonylimino, unsubstituted or substituted C ２－１２ Alkenylcarbonylimino, unsubstituted or substituted C ２－１２ Alkynylcarbonylimino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -carbonylimino, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -carbonylimino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -carbonylimino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -carbonylimino, unsubstituted or substituted C １－１２ Alkylthio, unsubstituted or substituted C ２－１２ Alkenylthio, unsubstituted or substituted C ２－１２ Alkynylthio, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -thio, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -thio, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -thio, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -thio, unsubstituted or substituted C １－１２ Alkylamino, unsubstituted or substituted C ２－１２ Alkenylamino, unsubstituted or substituted C ２－１２ Alkynylamino, unsubstituted or substituted C ２－１２ Alkynylamino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -amino, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -amino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -amino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -amino, unsubstituted or substituted C １－１２ Alkylsulfonyl, unsubstituted or substituted C２－１２ Alkenylsulfonyl, unsubstituted or substituted C ２－１２ Alkynylsulfonyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -sulfonyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -sulfonyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -sulfonyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -sulfonyl, unsubstituted or substituted C １－１２ Alkylsulfonylamino, unsubstituted or substituted C ２－１２ Alkenylsulfonylamino, unsubstituted or substituted C ２－１２ Alkynylsulfonylamino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -sulfonylamino, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -sulfonylamino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -sulfonylamino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -sulfonylamino, unsubstituted or substituted C １－１２ Alkylimino, unsubstituted or substituted C ２－１２ Alkenylimino, unsubstituted or substituted C ２－１２ Alkynylimino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -imino, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -imino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -imino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -imino, unsubstituted or substituted C １－１２ Alkyloxyimino, unsubstituted or substituted C ２－１２ Alkenyloxyimino, unsubstituted or substituted C ２－１２ Alkynyloxyimino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -oximino, unsubstituted or substituted C３－１０ Cycloalkyl-L Ｘ -oximino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -oximino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -oximino, unsubstituted or substituted C １－１２ Alkyloxycarbonyl, unsubstituted or substituted C ２－１２ Alkenyloxycarbonyl, unsubstituted or substituted C ２－１２ Alkynyloxycarbonyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -oxycarbonyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -oxycarbonyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -oxycarbonyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -oxycarbonyl, unsubstituted or substituted C １－１２ Alkyloxycarbonylamino, unsubstituted or substituted C ２－１２ Alkenyloxycarbonylamino, unsubstituted or substituted C ２－１２ Alkynyloxycarbonylamino, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -oxycarbonylamino, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -oxycarbonylamino, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -oxycarbonylamino, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -oxycarbonylamino, unsubstituted or substituted C １－１２ Alkylsulfanyl, unsubstituted or substituted C ２－１２ Alkenylsulfanyl, unsubstituted or substituted C ２－１２ Alkynylsulfanyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -sulfanyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ-sulfanyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -sulfanyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -sulfanyl, unsubstituted or substituted C １－１２ Alkylsulfinyl, unsubstituted or substituted C ２－１２ Alkenylsulfinyl, unsubstituted or substituted C ２－１２ Alkynylsulfinyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -sulfinyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -sulfinyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -sulfinyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -sulfinyl, unsubstituted or substituted C １－１２ Alkylcarbamoyl, unsubstituted or substituted C ２－１２ Alkenylcarbamoyl, unsubstituted or substituted C ２－１２ Alkynylcarbamoyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -carbamoyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -carbamoyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -carbamoyl, unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ -carbamoyl, unsubstituted or substituted C １－１２ Alkylsulfamoyl, unsubstituted or substituted C ２－１２ Alkenylsulfamoyl, unsubstituted or substituted C ２－１２ Alkynylsulfamoyl, unsubstituted or substituted C ６－１０ Aryl-L Ｘ -sulfamoyl, unsubstituted or substituted C ３－１０ Cycloalkyl-L Ｘ -sulfamoyl, unsubstituted or substituted 5- to 10-membered heteroaryl-L Ｘ -sulfamoyl, and unsubstituted or substituted 5- to 10-membered heterocycloalkyl-L Ｘ-sulfamoyl, where L Ｘ is a single bond or an unsubstituted or substituted C １－１２ alkylene, and the substituent C １－１２ Alkyl, substituted C ２－１２ Alkenyl, substituted C ２－１２ Alkynyl, substituted C ６－１０ Aryl, substituted C ３－１０ The cycloalkyl, substituted 5- to 10-membered heteroaryl, substituted 5- to 10-membered heterocycloalkyl, and substituted alkylene moieties (in whole or in part) each independently represent halogen, hydroxy, oxo, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, C １－１２ Alkyl, C １－１２ Haloalkyl, C ２－１２ Alkenyl, C ２－１２ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C １－１２ Alkyloxy, C １－１２ Haloalkyloxy, C ２－１２ Alkenyloxy, C ２－１２ Alkynyloxy, C ６－１０ Aryl-L Ｘ -oxy, C ３－１０ Cycloalkyl-L Ｘ -oxy, 5- to 10-membered heteroaryl-L Ｘ -oxy, 5- to 10-membered heterocycloalkyl-L Ｘ -oxy, C １－１２ Alkyloxyalkyl, C ２－１２ Alkenyloxyalkyl, C ２－１２ Alkynyloxyalkyl, C ６－１０ Aryloxyalkyl, C ３－１０ cycloalkyloxyalkyl, 5- to 10-membered heteroaryloxyalkyl, 5- to 10-membered heterocycloalkyloxyalkyl, C １－１２Alkyloxy alkyloxy, C ２－１２ Alkenyloxyalkyloxy, C ２－１２ Alkynyloxyalkyloxy, C ６－１０ Aryloxyalkyloxy, C ３－１０ Cycloalkyloxyalkyloxy, 5- to 10-membered heteroaryloxyalkyloxy, 5- to 10-membered heterocycloalkyloxyalkyloxy, C １－１２ Alkylcarbonyl, C ２－１２ Alkenylcarbonyl, C ２－１２ Alkynylcarbonyl, C ６－１０ Aryl-L Ｘ -carbonyl, C ３－１０ Cycloalkyl-L Ｘ -carbonyl, 5- to 10-membered heteroaryl-L Ｘ -carbonyl, 5- to 10-membered heterocycloalkyl-L Ｘ -carbonyl, C １－１２ Alkylcarbonyloxy, C ２－１２ Alkenylcarbonyloxy, C ２－１２ Alkynylcarbonyloxy, C ６－１０ Aryl-L Ｘ -carbonyloxy, C ３－１０ Cycloalkyl-L Ｘ -carbonyloxy, 5- to 10-membered heteroaryl-L Ｘ -carbonyloxy, 5- to 10-membered heterocycloalkyl-L Ｘ -carbonyloxy, C １－１２ Alkylcarbonylamino, C ２－１２ Alkenylcarbonylamino, C ２－１２ Alkynylcarbonylamino, C ６－１０ Aryl-L Ｘ -carbonylamino, C ３－１０ Cycloalkyl-L Ｘ -carbonylamino, 5- to 10-membered heteroaryl-L Ｘ -carbonylamino, 5- to 10-membered heterocycloalkyl-L Ｘ -carbonylamino, C １－１２ Alkylcarbonylthio, C ２－１２ Alkenylcarbonylthio, C ２－１２ Alkynylcarbonylthio, C６－１０ Aryl-L Ｘ -carbonylthio, C ３－１０ Cycloalkyl-L Ｘ -carbonylthio, 5- to 10-membered heteroaryl-L Ｘ -carbonylthio, 5- to 10-membered heterocycloalkyl-L Ｘ -carbonylthio, C １－１２ Alkylcarbonylimino, C ２－１２ Alkenylcarbonylimino, C ２－１２ Alkynylcarbonylimino, C ６－１０ Aryl-L Ｘ -carbonylimino, C ３－１０ Cycloalkyl-L Ｘ -carbonylimino, 5- to 10-membered heteroaryl-L Ｘ -carbonylimino, 5- to 10-membered heterocycloalkyl-L Ｘ -carbonylimino, C １－１２ Alkylthio, C ２－１２ Alkenylthio, C ２－１２ Alkynylthio, C ６－１０ Aryl-L Ｘ - Thio, C ３－１０ Cycloalkyl-L Ｘ -thio, 5- to 10-membered heteroaryl-L Ｘ -thio, 5- to 10-membered heterocycloalkyl-L Ｘ - Thio, C １－１２ Alkylamino, C ２－１２ Alkenylamino, C ２－１２ Alkynylamino, C ２－１２ Alkynylamino, C ６－１０ Aryl-L Ｘ - Amino, C ３－１０ Cycloalkyl-L Ｘ -amino, 5- to 10-membered heteroaryl-L Ｘ -amino, 5- to 10-membered heterocycloalkyl-L Ｘ - Amino, C １－１２ Alkylsulfonyl, C ２－１２ Alkenylsulfonyl, C ２－１２ Alkynylsulfonyl, C ６－１０ Aryl-L Ｘ -sulfonyl, C ３－１０ Cycloalkyl-L Ｘ-sulfonyl, 5- to 10-membered heteroaryl-L Ｘ -sulfonyl, 5- to 10-membered heterocycloalkyl-L Ｘ -sulfonyl, C １－１２ Alkylsulfonylamino, C ２－１２ Alkenylsulfonylamino, C ２－１２ Alkynylsulfonylamino, C ６－１０ Aryl-L Ｘ -sulfonylamino, C ３－１０ Cycloalkyl-L Ｘ -sulfonylamino, 5- to 10-membered heteroaryl-L Ｘ -sulfonylamino, 5- to 10-membered heterocycloalkyl-L Ｘ -sulfonylamino, C １－１２ Alkylimino, C ２－１２ Alkenylimino, C ２－１２ Alkynylimino, C ６－１０ Aryl-L Ｘ -Imino, C ３－１０ Cycloalkyl-L Ｘ -imino, 5- to 10-membered heteroaryl-L Ｘ -imino, 5- to 10-membered heterocycloalkyl-L Ｘ -Imino, C １－１２ Alkyloxyimino, C ２－１２ Alkenyloxyimino, C ２－１２ Alkynyloxyimino, C ６－１０ Aryl-L Ｘ -oximino, C ３－１０ Cycloalkyl-L Ｘ -oximino, 5- to 10-membered heteroaryl-L Ｘ -oximino, 5- to 10-membered heterocycloalkyl-L Ｘ -oximino, C １－１２ Alkyloxycarbonyl, C ２－１２ Alkenyloxycarbonyl, C ２－１２ Alkynyloxycarbonyl, C ６－１０ Aryl-L Ｘ -oxycarbonyl, C ３－１０ Cycloalkyl-L Ｘ -oxycarbonyl, 5- to 10-membered heteroaryl-L Ｘ-oxycarbonyl, 5- to 10-membered heterocycloalkyl-L Ｘ -oxycarbonyl, C １－１２ Alkyloxycarbonylamino, C ２－１２ Alkenyloxycarbonylamino, C ２－１２ Alkynyloxycarbonylamino, C ６－１０ Aryl-L Ｘ -oxycarbonylamino, C ３－１０ Cycloalkyl-L Ｘ -oxycarbonylamino, 5- to 10-membered heteroaryl-L Ｘ -oxycarbonylamino, 5- to 10-membered heterocycloalkyl-L Ｘ -oxycarbonylamino, C １－１２ Alkylsulfanyl, C ２－１２ Alkenylsulfanyl, C ２－１２ Alkynylsulfanyl, C ６－１０ Aryl-L Ｘ -sulfanyl, C ３－１０ Cycloalkyl-L Ｘ -sulfanyl, 5- to 10-membered heteroaryl-L Ｘ -sulfanyl, 5- to 10-membered heterocycloalkyl-L Ｘ -sulfanyl, C １－１２ Alkylsulfinyl, C ２－１２ Alkenylsulfinyl, C ２－１２ Alkynylsulfinyl, C ６－１０ Aryl-L Ｘ -sulfinyl, C ３－１０ Cycloalkyl-L Ｘ -sulfinyl, 5- to 10-membered heteroaryl-L Ｘ -sulfinyl, 5- to 10-membered heterocycloalkyl-L Ｘ -sulfinyl, C １－１２ Alkylcarbamoyl, C ２－１２ Alkenylcarbamoyl, C ２－１２ Alkynylcarbamoyl, C ６－１０ Aryl-L Ｘ -carbamoyl, C ３－１０ Cycloalkyl-L Ｘ -carbamoyl, 5- to 10-membered heteroaryl-L Ｘ-carbamoyl, 5- to 10-membered heterocycloalkyl-L Ｘ -carbamoyl, C １－１２ Alkylsulfamoyl, C ２－１２ Alkenylsulfamoyl, C ２－１２ Alkynylsulfamoyl, C ６－１０ Aryl-L Ｘ -sulfamoyl, C ３－１０ Cycloalkyl-L Ｘ -sulfamoyl, 5- to 10-membered heteroaryl-L Ｘ -sulfamoyl, and 5- to 10-membered heterocycloalkyl-L Ｘ -sulfamoyl, and the like.

[0014] Substituent group III consists of halogen, hydroxy, carboxy, amino, carbamoyl, nitro, guanidino, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkyloxy, alkylcarbonyl, cycloalkylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylamino, cycloalkylalkylamino, alkyloxycarbonyl, and trialkylsilyloxy, and these groups in the substituent group may be substituted with one to the maximum possible number of identical or different substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, carbamoyl, nitro, alkyl, haloalkyl, alkyloxy, haloalkyloxy, and alkyloxycarbonyl. Substituent group III is preferably substituent group III', which consists of halogen, hydroxy, carboxy, amino, carbamoyl, nitro, guanidino, C １－１２ Alkyl, C １－１２ Alkenyl, C １－１２ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, C １－１２ Alkyloxy, C １－１２ Alkylcarbonyl, C ３－１０ Cycloalkylcarbonyl, C １－１２ Alkylcarbonylamino, C ３－１０Cycloalkylcarbonylamino, C １－１２ Alkylamino, C ３－１０ Cycloalkyl C １－６ Alkylamino, C １－１２ Alkyloxycarbonyl, and triC １－６ These groups in the above substituent group are halogen, hydroxy, carboxy, amino, carbamoyl, nitro, C １－１２ Alkyl, C １－１２ Haloalkyl, C １－１２ Alkyloxy, C １－１２ Haloalkyloxy, and C １－１２ It may be substituted with one to the maximum possible number of identical or different substituents selected from the group consisting of alkyloxycarbonyl.

[0015] In the present specification, examples of substituents that are "substituted as needed" include substituent group α and substituent group β. Substituent group α may be substituent group α1, substituent group α2, substituent group α3, or substituent group α4, and substituent group β may be substituent group β1, substituent group β2, substituent group β3, or substituent group β4. Substituents that are "substituted as needed" may be selected from substituent group α1, and may be substituted with 1 to 5 identical or different substituents. The type of atom in the substituent participating in the bond is not particularly limited by the type of substituent, but when the atom to which the substituent is bonded is an oxygen atom, nitrogen atom, or sulfur atom, the bonded atom is limited to those of the following substituents whose atom is a carbon atom. Substituent group α1 includes: 1) halogen atoms 2) hydroxyl groups 3) carboxyl groups 4) cyano groups 5) C 1－6 Alkyl 6) C 2－6 Alkenyl 7) C 2－6 Alkynyl 8) C 1－6 Alkoxy 9) C 1－6 Alkylthio 10) C 1－6 Alkylcarbonyl 11) C 1－6 Alkylsulfonyl (wherein each of the substituents 5) to 11) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β1). 12) C 3－10 Carbocyclyl group 13) C3－10 Carbocyclyloxy 14) C 6－10 Aryloxy 15) 5- or 6-membered heteroaryloxy 16) 4- to 10-membered heterocyclyloxy 17) C 3－10 Carbocyclylthio 18) C 6－10 Arylthio 19) 5- or 6-membered heteroarylthio 20) 4- to 10-membered heterocyclylthio 21) C 6－10 Aryl 22) 5- or 6-membered heteroaryl 23) 4- to 10-membered heterocyclyl 24) C 3－10 Carbocyclylcarbonyl 25) C 6－10 26) 5- or 6-membered heteroarylcarbonyl 27) 4- to 10-membered heterocyclylcarbonyl 28) C 3－10 Carbocyclylsulfonyl 29) C 6－10 30) 5- or 6-membered heteroarylsulfonyl; 31) 4- to 10-membered heterocyclylsulfonyl (provided that each of the substituents in 12) to 31) is 1 to 5 of the substituent group β1 or the above 5) C 1－6 32) -NR, optionally substituted with alkyl １０ａ R １１ａ 33) -SO ２ -NR １０ｂ R １１ｂ 34)-NR １０ｃ -C(=O)R １１ｃ 35)-NR １０ｄ -C(=O)OR １１ｄ 36)-NR １２ａ -C(=O)NR １０ｅ R １１ｅ 37) -NR １０ｉ -SO ２ -R １１ｉ 38)-NR １２ｃ -SO ２ -NR １０ｊ R １１ｊ 39)-C(=O)OR １０ｋ 40)-C(=O)NR １０ｌ R １１ｋ 41)-C(=O)NR １０ｍ OR １１ｌ 42)-C(=O)NR １２ｄ -NR １０ｎ R１１ｍ 43)-C(=NR １３ａ ) R １０ｓ 44)-C(=NR １３ｃ ) NR １０ｔ R １１ｑ 45)-C(=NR １３ｄ ) NR １２ｆ -NR １０ｕ R １１ｒ 46)-NR １７ｃ -C(=NR １３ｋ ) R １７ｄ 47)-NR １２ｇ -C(=NR １３ｅ )-NR １０ｖ R １１ｓ 48)-NR １４ -C(=NR １３ｆ )-NR １２ｈ -NR １０ｗ R １１ｔ 49)-OC(=O)R １０ｘ 50)-OC(=O)OR １０ｙ 51)-OC(=O)NR １０ｚ１ R １１ｕ 52)-NR １２ｉ -NR １０ｚ２ R １１ｖ 53)-NR １０ｚ３ OR １１ｗ 54) Protecting group, and the substituent group β1 includes 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) C 3－10 Carbocyclyl group, 6) C 1－6 Alkoxy, 7) C 3－10 Carbocyclyloxy, 8) C 1－6 alkylthio, 9) 5- or 6-membered heteroarylthio, 10) C 6－10 aryl, 11) 5- or 6-membered heteroaryl, 12) 4- to 10-membered heterocyclyl, 13) C 1－6 Alkylcarbonyl, 14) C 3－10 Carbocyclylcarbonyl, 15) C 6－10 arylcarbonyl, 16) 5- or 6-membered heteroarylcarbonyl, 17) 4- to 10-membered heterocyclylcarbonyl, 18) —NR １５ａ R １６ａ , 19)-SO ２ -NR １５ｂR １６ｂ , 20)-NR １５ｃ -C(=O)R １６ｃ 21) -NR １７ａ -C(=O)NR １５ｄ R １６ｄ , 22)-C(=O)NR １５ｅ R １６ｅ , 23)-C(=NR １３ｇ ) R １５ｆ , 24)-C(=NR １３ｈ ) NR １５ｇ R １６ｆ 25)-NR １６ｇ -C(=NR １３ｉ ) R １５ｈ 26) -NR １７ｂ -C(=NR １３ｊ )-NR １５ｉ R １６ｈ 27) Protecting group (provided that, among the substituent group β1, each of the substituents 5) to 17) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, and —NR １８ａ R １８ｂ and R １３ａ , R １３ａ２ , R １３ｃ , R １３ｃ２ , R １３ｄ , R １３ｄ２ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｇ２ , R １３ｈ , R １３ｈ２ , R １３ｉ , R １３ｊ , R １３ｋ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C 1－6 Alkyl, C 1－6 Alkoxy, or C 1－6 alkoxycarbonyl, R １０ａ , R １０ｂ , R １０ｃ , R １０ｄ , R １０ｅ , R １０ｉ , R １０ｊ , R １０ｋ , R １０ｌ , R １０ｍ , R １０ｎ , R１０ｓ , R １０ｓ２ , R １０ｔ , R １０ｔ２ , R １０ｕ , R １０ｕ２ , R １０ｖ , R １０ｗ , R １０ｘ , R １０ｙ , R １０ｚ１ , R １０ｚ２ , R １０ｚ３ , R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １１ｅ , R １１ｉ , R １１ｊ , R １１ｋ , R １１ｌ , R １１ｍ , R １１ｑ , R １１ｑ２ , R １１ｒ , R １１ｒ２ , R １１ｓ , R １１ｔ , R １１ｕ , R １１ｖ , R １１ｗ , R １２ａ , R １２ｃ , R １２ｄ , R １２ｆ , R １２ｆ２ , R １２ｇ , R １２ｈ , R １２ｉ , R １４ , R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｅ , R １５ｆ , R １５ｆ２ , R １５ｇ , R １５ｇ２ , R １５ｈ , R １５ｉ , R １６ａ , R １６ｂ , R １６ｃ , R １６ｄ , R １６ｅ , R １６ｆ , R １６ｆ２ , R １６ｇ , R １６ｈ , R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ are each independently the same or different and represent a hydrogen atom, C1－6 Alkyl (C 1－6 Alkyl is a hydroxyl group, a cyano group, C 1－6 Alkoxy, —NR １８ａ R １８ｂ may be substituted with 1 to 3 identical or different substituents selected from the following, or C 1－6 alkoxycarbonyl, R １８ａ and R １８ｂ are each independently the same or different and represent a hydrogen atom or C 1－6 In an exemplary embodiment, any hydrogen atom of the hydroxyl group and amino group in the substituent groups α1 and β1 may be substituted with a protecting group.

[0016] In the present specification, the substituents in the case of being "optionally substituted" preferably include the following substituents. The substituent group α2 preferably includes: 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) a C 1－6 Alkyl 6) C 1－6 Alkoxy 7) C 1－6 Alkylthio 8) C 1－6 Alkylcarbonyl (wherein each of the substituents 5) to 8) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β2) 9) C 3－10 Carbocyclyl group 10) C 3－10 Carbocyclyloxy 11) C 6－10 Aryloxy 12) 5- or 6-membered heteroaryloxy 13) 4- to 10-membered heterocyclyloxy 14) C 3－10 Carbocyclylthio 15) C 6－10 Arylthio 16) 5- or 6-membered heteroarylthio 17) 4- to 10-membered heterocyclylthio 18) C 6－10 Aryl 19) 5- or 6-membered heteroaryl 20) 4- to 10-membered heterocyclyl 21) C 3－10 Carbocyclylcarbonyl 22) C 6－10 23) 5- or 6-membered heteroarylcarbonyl; 24) 4- to 10-membered heterocyclylcarbonyl (provided that each of the substituents in 9) to 24) is 1 to 5 of the substituent group β2 or the above 1) C1－6 25) -NR, optionally substituted with alkyl １０ａ R １１ａ 26) -SO ２ -NR １０ｂ R １１ｂ 27) -NR １０ｃ -C(=O)R １１ｃ 28)-NR １２ａ -C(=O)NR １０ｄ R １１ｄ 29) -NR １０ｅ -SO ２ -R １１ｅ 30)-NR １２ｂ -SO ２ -NR １０ｆ R １１ｆ 31)-C(=O)NR １０ｇ R １１ｇ 32) -C(=NR １３ａ ) R １０ｈ 33) -C(=NR １３ｂ ) NR １０ｉ R １１ｈ 34)-NR １１ｆ２ -C(=NR １３ｃ ) R １０ｇ２ 35)-NR １２ｃ -C(=NR １３ｄ )-NR １０ｊ R １１ｉ The substituent group β2 is preferably a halogen atom, a hydroxyl group, a cyano group, or a C 3－10 Carbocyclyl group 5) C 1－6 Alkoxy 6) C 1－6 Alkylthio 7) 5- or 6-membered heteroarylthio 8) 5- or 6-membered heteroaryl 9) 4- to 10-membered heterocyclyl 10) C 1－6 Alkylcarbonyl 11) C 3－10 Carbocyclylcarbonyl 12) C 6－10 13) 5- or 6-membered heteroarylcarbonyl; 14) 4- to 10-membered heterocyclylcarbonyl; 15) —NR １５ａ R １６ａ 16) -NR １５ｂ -C(=O)R １６ｂ 17) -NR １７ａ -C(=O)NR １５ｃ R１６ｃ 18)-C(=O)NR １５ｄ R １６ｄ 19) -C(=NR １３ｅ ) R １５ｅ 20) -C(=NR １３ｆ ) NR １５ｆ R １６ｅ 21) -NR １６ｆ -C(=NR １３ｇ ) R １５ｇ 22)-NR １７ｂ -C(=NR １３ｈ )-NR １５ｈ R １６ｇ 23)-C(=N-OR １３ｅ２ ) R １５ｅ２ 24)-C(=N-OR １３ｆ２ ) NR １５ｆ２ R １６ｅ２ (However, in the substituent group β2, each of the substituents 4) to 14) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, and —NR １８ａ R １８ｂ and R １３ａ , R １３ａ２ , R １３ｂ , R １３ｂ２ , R １３ｃ , R １３ｄ , R １３ｅ , R １３ｅ２ , R １３ｆ , R １３ｆ２ , R １３ｇ , R １３ｈ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C 1－6 Alkyl, C 1－6 Alkoxy, or C 1－6 alkoxycarbonyl, R １０ａ , R １０ｂ , R １０ｃ , R １０ｄ , R １０ｅ , R １０ｆ , R １０ｇ , R １０ｇ２ , R １０ｈ , R １０ｈ２ , R １０ｉ , R １０ｉ２ , R １０ｊ , R １１ａ , R １１ｂ , R１１ｃ , R １１ｄ , R １１ｅ , R １１ｆ , R １１ｆ２ , R １１ｇ , R １１ｈ , R １１ｈ２ , R １１ｉ , R １２ａ , R １２ｂ , R １２ｃ , R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｅ , R １５ｅ２ , R １５ｆ , R １５ｆ２ , R １５ｇ , R １５ｈ , R １６ａ , R １６ｂ , R １６ｃ , R １６ｄ , R １６ｅ , R １６ｅ２ , R １６ｆ , R １６ｇ , R １７ａ , R １７ｂ are each independently the same or different and represent a hydrogen atom, C 1－6 Alkyl (C 1－6 Alkyl is a hydroxyl group, a cyano group, C 1－6 Alkoxy, —NR １８ａ R １８ｂ may be substituted with 1 to 3 identical or different substituents selected from the following, or C 1－6 alkoxycarbonyl, R １８ａ , R １８ｂ are each independently the same or different and represent a hydrogen atom or C 1－6 In an exemplary embodiment, any hydrogen atom of the hydroxyl group and amino group in the substituent groups α2 and β2 may be substituted with a protecting group.

[0017] As used herein, the substituents "optionally substituted" are more preferably the following: 1) halogen atoms, 2) hydroxyl groups, 3) cyano groups, 4) C 1－6 Alkyl 5) C 1－6 Alkoxy 6) C 1－6Alkylthio 7) C 1－6 Alkylcarbonyl (wherein each of the substituents 4) to 7) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β3) 8) C 3－10 Carbocyclyl group 9) 5- or 6-membered heteroaryloxy 10) 4- to 10-membered heterocyclyloxy 11) 5- or 6-membered heteroarylthio 12) 4- to 10-membered heterocyclylthio 13) C 6－10 14) 5- or 6-membered heteroaryl; 15) 4- to 10-membered heterocyclyl (provided that each of the substituents in 8) to 15) is 1 to 5 of the substituent group β3 or the above 4) C 1－6 16) -NR, optionally substituted with alkyl １０ａ R １１ａ 17) -NR １１ｂ -C(=O)R １０ｂ 18)-NR １２ａ -C(=O)NR １０ｃ R １１ｃ 19)-C(=O)NR １０ｄ R １１ｄ 20) -C(=NR １３ａ ) R １０ｅ 21) -C(=NR １３ｂ ) NR １０ｆ R １１ｅ 22)-NR １１ｆ -C(=NR １３ｃ ) R １０ｇ 23) -NR １２ｂ -C(=NR １３ｄ )-NR １０ｈ R １１ｇ The substituent group β3 is more preferably 1) a halogen atom, 2) a hydroxyl group, 3) a cyano group, or 4) —NR １５ａ R １６ａ , 5)-NR １５ｂ -C(=O)R １６ｂ , 6)-NR １７ａ -C(=O)NR １５ｃ R １６ｃ , 7)-C(=O)NR １５ｄ R １６ｄ , 8)-C(=NR １３ｅ ) R １５ｅ , 9)-C(=NR １３ｆ ) NR １５ｆ R１６ｅ , 10)-NR １６ｆ -C(=NR １３ｇ ) R １５ｇ , 11)-NR １７ｂ -C(=NR １３ｈ )-NR １５ｈ R １６ｇ and R １３ａ , R １３ａ２ , R １３ｂ , R １３ｂ２ , R １３ｃ , R １３ｄ , R １３ｅ , R １３ｅ２ , R １３ｆ , R １３ｆ２ , R １３ｇ , R １３ｈ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C 1－6 Alkyl, C 1－6 Alkoxy, or C 1－6 alkoxycarbonyl, R １０ａ , R １０ｂ , R １０ｃ , R １０ｄ , R １０ｅ , R １０ｆ , R １０ｅ２ , R １０ｆ２ , R １０ｇ , R １０ｈ , R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １１ｅ , R １１ｅ２ , R １１ｆ , R １１ｇ , R １２ａ , R １２ｂ , R １５ａ , R １５ｂ , R １５ｃ , R １５ｄ , R １５ｅ , R １５ｅ２ , R １５ｆ , R １５ｆ２ , R １５ｇ , R １５ｈ , R １６ａ , R １６ｂ , R １６ｃ , R １６ｄ , R １６ｅ , R １６ｅ２ , R １６ｆ , R １６ｇ , R１７ａ , R １７ｂ are each independently the same or different and represent a hydrogen atom, C 1－6 Alkyl (C 1－6 Alkyl is a hydroxyl group, a cyano group, C 1－6 Alkoxy, —NR １８ａ R １８ｂ may be substituted with 1 to 3 identical or different substituents selected from the following, or C 1－6 alkoxycarbonyl, R １８ａ , R １８ｂ are each independently the same or different and represent a hydrogen atom or C 1－6 In an exemplary embodiment, any hydrogen atom of the hydroxyl group and amino group in the substituent groups α3 and β3 may be substituted with a protecting group.

[0018] As used herein, the substituents "optionally substituted" are more preferably the following substituents. The substituent group α4 is more preferably: 1) a halogen atom; 2) C 1－6 Alkyl 3) C 1－6 Alkylcarbonyl (wherein each of the substituents 2) to 3) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β4) 4) C 3－10 Carbocyclyl group 5) C 6－10 aryl; 6) 5- or 6-membered heteroaryl; 7) 4- to 10-membered heterocyclyl (provided that each of the substituents in 4) to 7) is 1 to 5 of the substituent group β4 or the above-mentioned 2) C 1－6 8) -NR １０ａ R １１ａ 9)-C(=O)NR １０ｄ R １１ｄ 10) -NR １２ｂ -C(=NR １３ｄ )-NR １０ｈ R １１ｇ The substituent group β4 is more preferably: 1) a halogen atom, 2) —NR １５ａ R １６ａ , 3)-NR １５ｂ -C(=O)R １６ｂ , 4)-C(=O)NR １５ｄR １６ｄ , 5)-NR １７ｂ -C(=NR １３ｈ )-NR １５ｈ R １６ｇ and R １３ｄ , R １３ｈ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C 1－6 Alkyl, C 1－6 Alkoxy, or C 1－6 alkoxycarbonyl, R １０ａ , R １０ｄ , R １０ｈ , R １１ａ , R １１ｄ , R １１ｇ , R １２ｂ , R １５ａ , R １５ｂ , R １５ｄ , R １５ｈ , R １６ａ , R １６ｂ , R １６ｄ , R １６ｇ , R １７ｂ are each independently the same or different and represent a hydrogen atom, C 1－6 Alkyl (C 1－6 Alkyl is C 1－6 Alkoxy, —NR １８ａ R １８ｂ may be substituted with 1 to 3 identical or different substituents selected from the following, or C 1－6 In an exemplary embodiment, any hydrogen atom of the hydroxyl group and amino group in the substituent groups α4 and β4 may be substituted with a protecting group.

[0019] In an exemplary embodiment, the hydroxyl group in the above substituent groups (e.g., α (e.g., α1), β (e.g., β1), I to III) may be further protected with a silyl protecting group. In an exemplary embodiment, the amino group in the above substituent groups (e.g., α (e.g., α1), β (e.g., β1), I to III) may be further protected with a nitrogen protecting group.

[0020] As used herein, "C １－６ " means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C １－４" means that the number of carbon atoms is 1 to 4, and "C １－３ " means that the number of carbon atoms is 1 to 3. In this specification, descriptions limiting the number of carbon atoms are merely preferred numerical ranges, and it is intended that groups having substituents with carbon atoms other than the specified number of carbon atoms also fall within the scope of the present disclosure.

[0021] As used herein, substituent names ending in the suffix "ene" refer to a biradical derived from the removal of an additional hydrogen atom from a monoradical group, as defined herein. Thus, for example, a monoradical alkyl, as defined herein, becomes a biradical alkylene by the removal of an additional hydrogen atom. Similarly, an alkenyl is an alkenylene, an alkynyl is an alkynylene, a heteroalkyl is a heteroalkylene, a heteroalkenyl is a heteroalkenylene, a heteroalkynyl is a heteroalkynylene, a carbocyclyl is a carbocyclylene, a heterocyclyl is a heterocyclylene, an aryl is an arylene, and a heteroaryl is a heteroarylene.

[0022] As used herein, the term "hydrocarbon group," also referred to as a hydrocarbyl group, refers to a group formed by removing at least one hydrogen from a "hydrocarbon" containing at least one carbon and at least one hydrogen.

[0023] In this specification, the term "functional group" refers to any group that imparts some functionality, and includes a carboxyl group, a nitrile group, a carbonyl group, a hydroxy group, an amino group, an imino group, a nitro group, a halogen group, as well as an alkyl group, and in a broad sense also includes groups formed by bonds such as acid anhydrides, ester bonds, amide bonds, and ether bonds.

[0024] As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen atoms, such as an oxygen atom, nitrogen atom, or sulfur atom. A group containing a heteroatom may be referred to as a hetero... group (for example, a heteroaryl group (meaning that an aryl group contains at least a heteroatom)) or a hetero... group (for example, a heterocyclic group (meaning that a ring group (carbocyclic group) contains at least one heteroatom)).

[0025] As used herein, a "halogen atom" refers to an atom belonging to the halogen group, such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A fluorine atom or a chlorine atom is preferred. A fluorine atom is more preferred. A "halogen atom" may also be referred to as "halogen" or "halo".

[0026] As used herein, a "hydroxyl group" refers to a monovalent group of -OH. This group may also be called a "hydroxy group" or "hydroxy."

[0027] As used herein, a "carboxyl group" refers to a monovalent group of -COOH. This group may also be called a "carboxy group," "carboxy," or "carboxyl."

[0028] As used herein, a "cyano group" is a monovalent group of -CN.

[0029] As used herein, "amino" refers to -NH ２ This group is sometimes called an "amino group."

[0030] As used herein, the term "imino" refers to a monovalent group of formula ═N or a divalent group of formula —N—.

[0031] As used herein, "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. １－１２ "Alkyl" refers to an alkyl group having 1 to 12 carbon atoms, examples of which include C １－６ Examples of alkyl include, but are not limited to, alkyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, and isododecyl. １－６"Alkyl" is an alkyl group having 1 to 6 carbon atoms, and preferred examples include "C １－４ alkyl", and more preferably "C １－３ alkyl," and more preferably "C １－２ "C alkyl". １－４ Specific examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. １－６ Specific examples of "alkyl" include C １－４ Examples include, but are not limited to, alkyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, n-hexyl, and the like.

[0032] As used herein, "alkenyl" refers to a straight- or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond. ２－１２ "Alkenyl" refers to an alkenyl group having 2 to 12 carbon atoms, and examples include, but are not limited to, heptenyl, isoheptenyl, octenyl, isooctenyl, nonenyl, isononenyl, decenyl, isodecenyl, undecenyl, isoundecenyl, dodecenyl, isododecenyl, and the like. ２－６ "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms, and preferred examples include "C ２－４ "C alkenyl" is an example. ２－６ Specific examples of "alkenyl" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and the like.

[0033] As used herein, "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. ２－１２"Alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms, and examples include, but are not limited to, heptynyl, isoheptynyl, octynyl, isooctynyl, nonynyl, isononynyl, decynyl, isodecynyl, undecynyl, isoundecynyl, dodecynyl, isododecynyl, and the like. ２－６ "Alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, and preferred examples include "C ２－４ "C alkynyl" is an example. ２－６ Examples of "alkynyl" include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, and the like.

[0034] As used herein, "aryl" means a monovalent radical of a monocyclic or bicyclic aromatic hydrocarbon ring, and "C ５－１０ "Aryl" means an aryl group having 5 to 10 carbon atoms. Examples of "aryl" include C ６ Aryl, C １０ Examples include, but are not limited to, aryl and the like. ６ Specific examples of aryl include, but are not limited to, phenyl. １０ Specific examples of aryl include, but are not limited to, 1-naphthyl, 2-naphthyl, and the like.

[0035] An aryl group as a substituent or part thereof may be fused with a carbocyclyl group. For example, a phenyl group may be fused with a cyclohexane ring to form a 1,2,3,4-tetrahydronaphthalenyl group, in which case any available carbon atom on the benzene ring is bonded to the parent skeleton or to a group or atom thereof close to the parent skeleton. Aryl groups include 5,6,7,8-tetrahydronaphthalen-1-yl and 5,6,7,8-tetrahydronaphthalen-2-yl.

[0036] As used herein, "arylalkyl" refers to an alkyl substituted with at least one aryl. ６－１０ Aryl C １－６ "Alkyl" means a group having at least one C ６－１０Aryl-substituted C １－６ It means alkyl. ６－１０ Aryl C １－６ Specific examples of alkyl include benzyl (phenyl-CH ２ -), phenethyl (phenyl-CH ２ CH ２ -), naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, 2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl and the like.

[0037] As used herein, "(optionally substituted amino)-arylalkyl" refers to an arylalkyl substituted with an optionally substituted amino group, where the alkyl group, the aryl group, or both are substituted with an amino group. The amino group of the arylalkyl group may be unsubstituted or may have one, two, or three substituents, such as an optionally substituted alkyl (e.g., an unsubstituted C １－６ Alkyl, C ３－６ Cycloalkyl-C １－６ Alkyl, C ３－６ (Optionally substituted amino)-C ６－１０ Aryl C １－６ Examples of alkyl include, but are not limited to, (di(alkyl)amino)benzyl, ((cycloalkylalkyl)amino)benzyl, ((cycloalkylcarbonyl)amino)benzyl, ((carbamoylalkyl)carbonylamino)benzyl, ((carboxyalkyl)carbonyl)aminobenzyl, (di(alkyl)amino)naphthalenylmethyl, ((cycloalkylalkyl)amino)naphthalenylmethyl, ((cycloalkylcarbonyl)amino)naphthalenylmethyl, ((carbamoylalkyl)carbonylamino)naphthalenylmethyl, or ((carboxyalkyl)carbonyl)aminonaphthalenylmethyl, and the like.

[0038] As used herein, the aryl moiety of "arylthio" has the same meaning as the aryl defined above. ６－１０ As "arylthio", preferably "C ６Or C １０ "C" is an example of an arylthio group. ６－１０ Specific examples of "aryloxy" include, but are not limited to, phenylthio, 1-naphthylthio, 2-naphthylthio, and the like.

[0039] As used herein, "arylsulfonyl" refers to a sulfonyl substituted with the above-mentioned "aryl". ６－１０ As "arylsulfonyl", preferably "C ６ or C １０ "C is an arylsulfonyl group. ６－１０ Specific examples of "arylsulfonyl" include, but are not limited to, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

[0040] As used herein, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms.

[0041] As used herein, "5- or 6-membered heteroaryl" refers to a monovalent group of a monocyclic aromatic heterocycle consisting of 5 to 6 atoms, containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. Specific examples of "5- or 6-membered heteroaryl" include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, pyridyl, furyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0042] As used herein, the term "5- to 10-membered heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms, containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. Specific examples of "5- to 10-membered heteroaryl" include 5- or 6-membered heteroaryl, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridyl, imidazothiazolyl, imidazooxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridyl, thienopyridyl, furopyridyl, benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuryl, benzothienyl, benzo[1,3]dioxole, thienofuryl, chromenyl, chromanyl, coumarinyl, quinolonyl, and the like, but are not limited to these.

[0043] As used herein, "heteroarylalkyl" refers to an alkyl substituted with at least one heteroaryl. １－６ "Alkyl" refers to a C alkyl substituted with at least one 5- to 10-membered heteroaryl. １－６ alkyl; 5- to 10-membered heteroaryl C １－６ Specific examples of alkyl include, but are not limited to, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-(quinolin-8-yl)ethyl, 2-(quinolin-5-yl)ethyl, 2-(quinoxalin-5-yl)ethyl, 2-(1H-indol-3-yl)ethyl, and the like.

[0044] As used herein, "carbocyclyl" refers to a monovalent group of a monocyclic, bicyclic, or tricyclic non-aromatic hydrocarbon ring, including those having a partially unsaturated bond, a partially bridged structure, a partially spiro-bonded structure, and one, two, or more carbonyl structures. "Carbocyclyl" encompasses cycloalkyl, cycloalkenyl, and cycloalkynyl. ３－２０ As "carbocyclyl", preferably "C ３－１０carbocyclyl," and more preferably "C ３－６ "C carbocyclyl". ３－２０ Examples of "carbocyclyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexadinyl, cycloheptadinyl, cyclooctadinyl, adamantyl, norbornyl, and the like.

[0045] A carbocyclyl may be a fused ring of a non-aryl ring with an aryl and / or heteroaryl ring. For example, C ６－１０ Cycloalkyl fused with an aryl or a 5- or 6-membered heteroaryl is encompassed by carbocyclyl. Examples of fused carbocyclyls include monovalent groups formed by removing one hydrogen atom from 1,2,3,4-tetrahydronaphthalene, indan, 1,2,3,4-tetrahydroanthracene, and 5,6,7,8-tetrahydroquinoline, and specific examples include 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, indan-1-yl, indan-2-yl, 5,6,7,8-tetrahydroquinolin-5-yl, and 5,6,7,8-tetrahydroquinolin-6-yl. A fused carbocyclyl is bonded to the parent skeleton from any one of the possible ring-constituting atoms on the non-aryl ring.

[0046] As used herein, "C ３－１０ "Carbocyclyl" means the same as "C" above. ３－２０ Among "carbocyclyl", "C ３－１０ "Carbocyclyl" means a monovalent substituent.

[0047] As used herein, "carbocyclyloxy" refers to a (carbocyclyl)-O- group, and the carbocyclyl moiety has the same meaning as a carbocyclyl group. ３－６ "Carbocyclyloxy" means (C ３－６ carbocyclyl)-O- group, ３－６ The carbocyclyl moiety is C ３－６ It is synonymous with carbocyclyl. ３－６ As "carbocyclyloxy", preferably "C３－５ carbocyclyloxy". ３－６ Specific examples of "carbocyclyloxy" include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0048] As used herein, "carbocyclylcarbonyl" means a carbonyl substituted with the above-mentioned "carbocyclyl". ３－１０ As the "carbocyclylcarbonyl", preferably "C ３－６ "Carbocyclylcarbonyl". ３－１０ Specific examples of "carbocyclylcarbonyl" include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and the like.

[0049] As used herein, "carbocyclylthio" refers to the group (carbocyclyl)-S-, wherein the carbocyclyl moiety is as defined above. ３－１０ As "carbocyclylthio", preferably "C ３－６ Carbocyclylthio. ３－６ Specific examples of "carbocyclylthio" include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

[0050] As used herein, "carbocyclylsulfonyl" refers to a sulfonyl group substituted with the above-mentioned "carbocyclyl". ３－１０ As "carbocyclylsulfonyl", preferably "C ３－６ "C carbocyclylsulfonyl". ３－１０ Specific examples of "carbocyclylsulfonyl" include, but are not limited to, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, and the like.

[0051] As used herein, "cycloalkyl" refers to a non-aromatic saturated hydrocarbon ring group, including those having a partially bridged structure, those having a partially spiro structure, and those having one, two, or more carbonyl structures. ３－２０ "Cycloalkyl" means a monocyclic or bicyclic cycloalkyl having 3 to 20 carbon atoms. ３－６ "Cycloalkyl" means a monocyclic cycloalkyl having 3 to 6 carbon atoms. ３－６ Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] A cycloalkyl group as a substituent or part thereof may be fused with an aryl and / or heteroaryl ring. For example, a cyclohexyl group may be fused with a benzene ring to form a 1,2,3,4-tetrahydronaphthalenyl group, in which case any available carbon atom on the cyclohexane ring is bonded to the parent skeleton or to a group or atom thereof close to the parent skeleton. Cycloalkyl groups include 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, indan-1-yl, indan-2-yl, 5,6,7,8-tetrahydroquinolin-5-yl, and 5,6,7,8-tetrahydroquinolin-6-yl.

[0053] As used herein, "cycloalkylalkyl" refers to an alkyl substituted with at least one cycloalkyl. ３－６ Cycloalkyl C １－６ "Alkyl" means a group having at least one C ３－６ Cycloalkyl-substituted C １－６ It means alkyl. ３－６ Cycloalkyl C １－６Specific examples of alkyl include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, and the like.

[0054] As used herein, "heterocycloalkyl" refers to a non-aromatic saturated or partially unsaturated heterocycle composed of three or more atoms, including one, two, or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and includes those having a partially bridged structure and those having a partially spiro-type structure. "Heterocycloalkyl" encompasses "heterocyclyl." Heterocycloalkyl may have a structure in which a non-aromatic heterocycle is fused with an aryl ring and / or a heteroaryl ring.

[0055] As used herein, "heterocyclyl" refers to a monocyclic or bicyclic non-aromatic heterocycle composed of three or more atoms, including one, two, or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and includes saturated heterocyclyls, those having a partially unsaturated bond, those having a partially bridged structure, and those having a partially spiro-substituted structure. The heterocyclyl may form a fused ring with an aryl or heteroaryl. For example, C ６－１０ A heterocycle also includes a ring fused with an aryl or a 5- or 6-membered heteroaryl. The heterocyclyl may contain one, two, or more carbonyls, thiocarbonyls, sulfinyls, or sulfonyls, and cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the heterocyclyl. Here, the oxygen atom of a carbonyl, sulfinyl, or sulfonyl and the sulfur atom of a thiocarbonyl are not included in the number of ring members (ring size) or the number of heteroatoms constituting the ring.

[0056] As used herein, "4- to 10-membered heterocyclyl" refers to a substituent of the above-mentioned "heterocyclyl" in which "4- to 10-membered heterocyclyl" is a monovalent group.

[0057] As used herein, the heterocyclyl moiety of "heterocyclyloxy" has the same meaning as the above-mentioned "heterocyclyl". "4- to 10-membered heterocyclyloxy" is preferably "4- to 6-membered heterocyclyloxy". Specific examples of "4- to 10-membered heterocyclyloxy" include, but are not limited to, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, and the like.

[0058] As used herein, the heterocyclyl moiety of "heterocyclylthio" has the same meaning as the above-mentioned "heterocyclyl". "4- to 10-membered heterocyclylthio" is preferably "4- to 6-membered heterocyclylthio". Specific examples of "4- to 10-membered heterocyclylthio" include, but are not limited to, tetrahydropyranylthio, piperidinylthio, and the like.

[0059] As used herein, "heterocyclylcarbonyl" refers to a carbonyl group substituted with the above-mentioned "heterocyclyl". The "4- to 10-membered heterocyclylcarbonyl" is preferably a "4- to 6-membered heterocyclylcarbonyl". Specific examples of the "4- to 10-membered heterocyclylcarbonyl" include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, and the like.

[0060] As used herein, "heterocyclylsulfonyl" refers to a sulfonyl group substituted with the above-mentioned "heterocyclyl". The "4- to 10-membered heterocyclylsulfonyl" is preferably a "4- to 6-membered heterocyclylsulfonyl". Specific examples of the "4- to 10-membered heterocyclylsulfonyl" include, but are not limited to, azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, and the like.

[0061] As used herein, "5- to 6-membered heterocycloalkyl" refers to a heterocycloalkyl consisting of 5 to 6 ring atoms containing one or more identical or different heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms.

[0062] As used herein, "heterocycloalkylalkyl" refers to an alkyl substituted with at least one heterocycloalkyl.

[0063] As used herein, "alkylcarbonyl" refers to a monovalent group of -C(=O)-alkyl. Preferred examples of alkylcarbonyl include C １－６ Examples include alkylcarbonyl. １－６ Specific examples of alkylcarbonyl include acetyl (CH ３ C(=O)-), n-propanoyl (CH ３ CH ２ C(=O)-), n-butanoyl (CH ３ CH ２ CH ２ C(=O)-), n-pentanoyl (CH ３ (CH ２ ) ３ C(=O)-), n-hexanoyl (CH ３ (CH ２ ) ４ C(=O)-), n-heptanoyl (CH ３ (CH ２ ) ５ Examples include, but are not limited to, C(═O)—.

[0064] As used herein, "alkoxy" refers to a monovalent group of -O-alkyl. Preferred examples of alkoxy include C １－６ Alkoxy (i.e., C １－６ alkyl-O-), C １－４ Alkoxy (i.e., C １－４ alkyl-O-) and the like. １－４ Specific examples of alkoxy include methoxy (CH ３ O-), ethoxy (CH ３ CH ２ O-), n-propoxy (CH ３ (CH ２ )２ O-), isopropoxy ((CH ３ ) ２ CHO-), n-butoxy (CH ３ (CH ２ ) ３ O-), isobutoxy ((CH ３ ) ２ CHCH ２ O-), tert-butoxy ((CH ３ ) ３ CO-), sec-butoxy (CH ３ CH ２ CH (CH ３ ) O-) and the like. １－６ Specific examples of alkoxy include C １－４ Alkoxy, n-pentyloxy (CH ３ (CH ２ ) ４ O-), isopentyloxy ((CH ３ ) ２ CHCH ２ CH ２ O-), neopentyloxy ((CH ３ ) ３ CCH ２ O-), tert-pentyloxy (CH ３ CH ２ C(CH ３ ) ２ O-), 1,2-dimethylpropoxy (CH ３ CH (CH ３ ) CH(CH ３ )O-) and the like, but are not limited to these.

[0065] As used herein, an "alkoxycarbonyl" is a monovalent radical of -C(=O)-O-alkyl. Examples of alkoxycarbonyl include C １－６ Alkoxycarbonyl, preferably C １－４ Examples include, but are not limited to, alkoxycarbonyl. １－４ Specific examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl.１－６ Specific examples of the alkoxycarbonyl include C １－４ Examples include, but are not limited to, alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, n-hexyloxycarbonyl, and the like.

[0066] As used herein, "alkoxycarbonylamino" refers to a monovalent group of -NH-C(=O)-O-alkyl. Examples of alkoxycarbonylamino include C １－６ Alkoxycarbonylamino, preferably C １－４ Examples include, but are not limited to, alkoxycarbonylamino. １－４ Specific examples of alkoxycarbonylamino include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, and isobutoxycarbonylamino. １－６ Specific examples of alkoxycarbonylamino include C １－４ Examples include, but are not limited to, alkoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, tert-pentyloxycarbonylamino, 1,2-dimethylpropyloxycarbonylamino, n-hexyloxycarbonylamino, and the like.

[0067] As used herein, a "haloalkyl" is a monovalent halogenated alkyl group in which one or more hydrogen atoms on the alkyl group have been replaced with halogen atoms. The term "perhaloalkyl" refers to a haloalkyl group in which all hydrogen atoms on the alkyl group have been replaced with halogen atoms. For example, perfluoroethyl is -CF ２ CF ３ and perchloro-n-propyl is —CCl ２ CCl ２ CCl ３ Examples of haloalkyl include C１－６ Haloalkyl, C １－４ Haloalkyl, C １－３ The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with a fluoro group. １－３ Specific examples of alkyl include fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, fluorochloromethyl, difluorochloromethyl, fluorodichloromethyl, fluoroethyl, chloroethyl, bromoethyl, trifluoroethyl, trichloroethyl, tribromoethyl, perfluoroethyl, perchloroethyl, perbromoethyl, perfluoropropyl, perchloropropyl, perbromopropyl, perfluoroisopropyl, perchloroisopropyl, perbromoisopropyl, and the like, but are not limited to these. １－４ Specific examples of alkyl include C １－３ Examples include, but are not limited to, haloalkyl, perfluorobutyl, perchlorobutyl, perbromobutyl, perfluoroisobutyl, perfluoro-t-butyl, and the like. １－６ Specific examples of alkyl include C １－４ These include, but are not limited to, haloalkyl, perfluoro-n-pentyl, perfluoroisopentyl, perfluoroneopentyl, perfluorotert-pentyl, perfluoro-1,2-dimethylpropyl, and the like.

[0068] As used herein, "haloalkoxy" and "haloalkyloxy" refer to a monovalent group of -O-haloalkyl in which one or more hydrogen atoms on the alkyl group have been replaced with halogen atoms. The term "perhaloalkoxy" refers to a haloalkoxy in which all hydrogen atoms on the alkyl group have been replaced with halogen atoms. For example, perfluoroethoxy is -OCF ２ CF ３ and perchloro-n-propoxy is —OCCl ２ CCl ２ CCl ３ Preferred examples of haloalkoxy include C １－６Haloalkoxy, C １－４ Haloalkoxy, C １－３ haloalkoxy and the like. １－３ Specific examples of alkoxy include fluoromethoxy, chloromethoxy, bromomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, fluorochloromethoxy, difluorochloromethoxy, fluorodichloromethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, trifluoroethoxy, trichloroethoxy, tribromoethoxy, perfluoroethoxy, perchloroethoxy, perbromoethoxy, perfluoropropoxy, perchloropropoxy, perbromopropoxy, perfluoroisopropoxy, perchloroisopropoxy, perbromoisopropoxy, and the like, but are not limited to these. １－４ Specific examples of alkoxy include C １－３ Examples include, but are not limited to, haloalkoxy, perfluorobutoxy, perchlorobutoxy, perbromobutoxy, perfluoroisobutoxy, perfluoro-t-butoxy, and the like. １－６ Specific examples of alkoxy include C １－４ These include, but are not limited to, haloalkoxy, perfluoro-n-pentyloxy, perfluoroisopentyloxy, perfluoroneopentyloxy, perfluorotert-pentyloxy, perfluoro-1,2-dimethylpropoxy, and the like.

[0069] As used herein, "alkylsulfonyl" refers to a sulfonyl group substituted with the above-mentioned "alkyl". １－６ As "alkylsulfonyl", preferably "C １－４ "C alkylsulfonyl". １－６ Specific examples of "alkylsulfonyl" include, but are not limited to, methylsulfonyl, propionylsulfonyl, butyrylsulfonyl, and the like.

[0070] As used herein, the alkyl portion of "alkylthio" has the same meaning as the alkyl defined above. １－６ An example of "alkylthio" is "C１－４ alkylthio", preferably "C １－３ "Alkylthio" is an example. １－６ Specific examples of "alkylthio" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2-dimethylpropylthio, and the like.

[0071] As used herein, "arylcarbonyl" refers to a monovalent group of -C(=O)-aryl. Preferred examples of arylcarbonyl include C ６－１０ Examples of the arylcarbonyl include C. ６－１０ Illustrative examples of arylcarbonyl include, but are not limited to, benzoyl (ie, phenyl-C(=O)-), 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like.

[0072] As used herein, the aryl moiety of "aryloxy" has the same meaning as the aryl defined above. ６－１０ As the "aryloxy", preferably "C ６ Or C １０ "C aryloxy" is an example. ６－１０ Specific examples of the "aryloxy group" include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

[0073] As used herein, a "heteroarylcarbonyl" is a monovalent radical of -C(=O)-heteroaryl.

[0074] As used herein, the term "heteroarylcarbonyl group" refers to a carbonyl group substituted with the above-mentioned "heteroaryl." Specific examples of the "5- or 6-membered heteroarylcarbonyl group" include, but are not limited to, a pyrazolylcarbonyl group, a triazolylcarbonyl group, a thiazolylcarbonyl group, a thiadiazolylcarbonyl group, a pyridylcarbonyl group, and a pyridazinylcarbonyl group.

[0075] As used herein, the heteroaryl portion of a "heteroaryloxy group" has the same meaning as the above-mentioned "heteroaryl." The 5- or 6-membered heteroaryl portion of a "5- or 6-membered heteroaryloxy group" has the same meaning as a "5-membered heteroaryl" or a "6-membered heteroaryl," respectively. Specific examples of a "5- or 6-membered heteroaryloxy group" include, but are not limited to, a pyrazolyloxy group, a triazolyloxy group, a thiazolyloxy group, a thiadiazolyloxy group, a pyridyloxy group, a pyridazinyloxy group, and the like.

[0076] As used herein, the heteroaryl portion of a "heteroarylthio group" has the same meaning as the above-mentioned "heteroaryl." The 5- or 6-membered heteroaryl portion of a "5- or 6-membered heteroarylthio group" has the same meaning as a "5-membered heteroaryl" or a "6-membered heteroaryl," respectively. Specific examples of the "5- or 6-membered heteroarylthio group" include, but are not limited to, a pyrazolylthio group, a triazolylthio group, a thiazolylthio group, a thiadiazolylthio group, a pyridylthio group, a pyridazinylthio group, and the like.

[0077] As used herein, the heteroaryl moiety of a "heteroarylsulfonyl group" has the same meaning as the above-mentioned "heteroaryl". A "5- or 6-membered heteroarylsulfonyl group" means a sulfonyl group substituted with a "5- or 6-membered heteroaryl". Specific examples of the "5- or 6-membered heteroarylsulfonyl group" include, but are not limited to, a pyrazolylsulfonyl group, a triazolylsulfonyl group, a thiazolylsulfonyl group, a thiadiazolylsulfonyl group, a pyridylsulfonyl group, and a pyridazinylsulfonyl group.

[0078] As used herein, "acyl" refers to -C(=O)-R acyl where R acylis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. Specific examples of acyl include, but are not limited to, formyl, and the exemplified groups of alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl.

[0079] As used herein, an "optionally substituted carbonyl" group refers to a monovalent group of -C(=O)- (hydrogen or any group selected from the substituent group described herein). Examples of "optionally substituted carbonyl" groups include, but are not limited to, formyl, optionally substituted carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkenylcarbonyl, alkenyloxycarbonyl, alkynylcarbonyl, alkynyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkyloxycarbonyl, and the like. A carbonyl group substituted with hydrogen is a formyl group. A carbonyl group substituted with amino is a carbamoyl group.

[0080] As used herein, an "optionally substituted oxy" group refers to a monovalent group of -O- (hydrogen or any group selected from the substituent group described herein). Examples of "optionally substituted oxy" groups include, but are not limited to, hydroxy, optionally substituted alkyloxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, heterocycloalkylcarbonyloxy, and the like. An oxy group substituted with hydrogen is a hydroxy group.

[0081] As used herein, "carbamoyl" refers to -C(=O)-NH ２ is a monovalent group.

[0082] In this specification, the phrase "a group substituted with a substituent" means that the group is substituted with at least one substituent. For example, "hydroxy-substituted C １－６ "Alkyl" is C １－６ It means that the alkyl is substituted with at least one hydroxy.

[0083] As used herein, "carbamoyl-substituted C １－６ "Alkyl" means at least one -C(=O)-NH ２ C substituted with a group １－６ "Carbamoyl-substituted C １－６ Examples of "alkyl" include carbamoyl-substituted C １－４ "Carbamoyl-substituted C alkyl" includes, but is not limited to, １－４ A specific example of "alkyl" is 2-amino-2-oxoethyl (i.e., H ２ NC(=O)-CH ２ -, or carbamoylmethyl), 3-amino-3-oxopropyl (i.e., H ２ NC(=O)-CH ２ CH ２ -, or carbamoylethyl), 4-amino-4-oxobutyl (i.e., H ２ NC(=O)-(CH ２ ) ３ -, or carbamoylpropyl), 5-amino-5-oxopentyl (i.e., H ２ NC(=O)-(CH ２ ) ４ -, or carbamoylbutyl), etc. １－６ Specific examples of "alkyl" include carbamoyl-substituted C １－４ alkyl, 6-amino-6-oxohexyl (i.e., H ２ NC(=O)-(CH ２ ) ５ -, or carbamoylpentyl), 7-amino-7-oxoheptyl (i.e., H２ NC(=O)-(CH ２ ) ６ -, or carbamoylhexyl), and the like.

[0084] As used herein, an "arylalkyl substituted with an alkyl-substituted amino" refers to an arylalkyl substituted with at least one alkyl-substituted amino. １－６ Specific examples of alkyl-substituted amino include —NH(CH ３ ), -N(CH ３ ) ２ , -NH(CH ２ CH ３ ), -N(CH ２ CH ３ ) ２ , -NH((CH ２ ) ２ CH ３ ), -N((CH ２ ) ２ CH ３ ) ２ , -NH(CH(CH ３ ) ２ ), -N(CH(CH ３ ) ２ ) ２ , -NH((CH ２ ) ３ CH ３ ), -N((CH ２ ) ３ CH ３ ) ２ , -NH(CH ２ CH (CH ３ ) ２ ), -N(CH ２ CH (CH ３ ) ２ ) ２ , -NH((CH ２ ) ４ CH ３ ), -N((CH ２ ) ４ CH ３ ) ２ , -NH((CH ２ ) ５ CH ３ ), -N((CH ２ ) ５ CH ３ )２ Examples include, but are not limited to, the following. In this specification, "alkyl-substituted amino" has the same meaning as "alkylamino".

[0085] As used herein, a "carboxy-substituted alkyl" is an alkyl substituted with at least one -COOH group. １－６ Examples of "alkyl" include "carboxy-substituted C １－４ Examples include, but are not limited to, "carboxy-substituted C alkyl" and the like. １－４ Specific examples of "alkyl" include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, etc. １－６ Specific examples of "alkyl" include carboxy-substituted C １－４ Examples include, but are not limited to, alkyl, 5-carboxypentyl, 6-carboxyhexyl, and the like.

[0086] A "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. The compounds of the present disclosure may be prepared by any R １ ~R ４or any position of these or other substituents may be substituted with a protecting group as appropriate or necessary, and compounds containing such protecting groups are also within the scope of the present disclosure. Typically, the protecting group can be selectively removed during the synthesis process if desired. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 5th Edition, 2014, John Wiley & Sons, NY, and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, John Wiley & Sons, NY, etc. As used herein, "protecting group" can fall within the definitions of 1) to 53) of substituent α and 1) to 26) of substituent β. In this case, in substituent group α1, "54) protecting group" may be written as "54) protecting group other than 1) to 53)," and in substituent group β1, "27) protecting group" may be written as "protecting group other than 1) to 26)." Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl and substituted benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), 2-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, and groups represented herein by "Protect."Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS, triethylsilyl, t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkyldiarylsilyl ethers (e.g., t-butyldiphenylsilyl (TBDPS)), triarylsilyl ethers (e.g., triphenylsilyl), glycol ethers (e.g., ethylene glycol ether, propylene glycol ether, etc.), and allyl ethers.

[0087] An amino group possessed by a compound of the present disclosure (e.g., an amino group possessed by the parent skeleton, an amino group as a substituent, an amino group in a substituent possessed by the compound, etc.) may be protected with a nitrogen-protecting group or a group represented by "Protect." An amino group in a substituent listed in a substituent group may be further protected with a nitrogen-protecting group or a group represented by "Protect," and the protected substituent may be used as a substituent.

[0088] The hydroxy group of the compound of the present disclosure (for example, a hydroxy group as a substituent, a hydroxy group in a substituent of the compound, a hydroxy group in the above-mentioned substituent group, etc.) may also be protected with a protecting group for the hydroxy group. The hydroxy group in the substituent listed in the substituent group may be further protected with a hydroxyl-protecting group described herein, and the protected substituent may be used as a substituent.

[0089] (Biosystem, infection system) As used herein, the term "serine / threonine kinase" refers to a protein kinase (protein kinase) that phosphorylates a specific site in a protein to change its function, phosphorylating a serine or threonine residue in the protein.

[0090] As used herein, "receptor tyrosine kinase" refers to a well-known family of membrane receptors that phosphorylate tyrosine residues. Many play important roles during development or cell division. Receptor tyrosine kinases have an extracellular ligand-binding domain, a transmembrane domain, and an intracellular catalytic domain. The extracellular domain binds to cytokines, growth factors, or other ligands and generally consists of one or more identifiable structural motifs, including a cysteine-rich region, a fibronectin III-like domain, an immunoglobulin-like domain, an EGF-like domain, a cadherin-like domain, a kringle-like domain, a factor VIII-like domain, a glycine-rich region, a leucine-rich region, an acidic region, and a discoidin-like domain. Activation of the intracellular kinase domain is achieved by ligand binding to the extracellular domain, which induces receptor dimerization. This activated receptor can autophosphorylate tyrosine residues outside the catalytic domain to promote stabilization of the active receptor conformation. The phosphorylated residues then serve as binding sites for proteins that transduce signals within the cell.

[0091] As used herein, the term "non-receptor tyrosine kinase" refers to a well-known family of kinases that do not have a transmembrane domain and phosphorylate tyrosine residues.

[0092] (Pharmaceuticals) In this specification, the term "pharmaceutically acceptable salts" refers to acid addition salts and base addition salts that are acceptable for pharmaceutically use. Specific examples of "pharmaceutically acceptable salts" include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, paratoluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharate, xinafoate, pamoate, ketone ... Examples of the salts include, but are not limited to, acid addition salts such as arsenate, adipate, cysteine ​​salt, N-acetylcysteine ​​salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; and addition salts with amino acids such as aspartic acid and glutamic acid.

[0093] The phrase "a compound or an isomer thereof or a salt thereof" means a compound, an isomer of said compound, a salt of said compound, or a salt of said isomer.

[0094] The term "target protein modulator" refers to a substance that can control the activity of a target protein. Target protein modulators include target protein degradation inducers, inhibitors, agonists, etc., and can cause changes in protein function or expression level.

[0095] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic and / or therapeutic" treatment is art-recognized and includes administration to a host of one or more compounds or pharmaceutical compositions of the present disclosure. When administered prior to clinical manifestation of an undesired condition (e.g., a disease, disorder, or symptom or other undesired condition in a host animal), the treatment is prophylactic (i.e., protects the host from the onset of the undesired condition), whereas when administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., intended to attenuate, ameliorate, or stabilize an existing undesired condition or its side effects).

[0096] The term "prodrug" is intended to encompass compounds that are converted under physiological conditions into therapeutically active agents of the present disclosure (e.g., compounds of Formula A). A common method for making prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present disclosure. In certain embodiments, some or all of the compounds of Formula A in the formulations depicted above can be replaced with the corresponding appropriate prodrug, for example, where a hydroxyl in the parent compound is provided as an ester or carbonate, or a carboxylic acid present in the parent compound is provided as an ester.

[0097] Pharmaceutical Compositions The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for administration to humans, particularly via an invasive route (i.e., a route such as injection or implantation that avoids transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient can be selected, for example, to effect delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized for reconstitution, powder, liquid, syrup, suppository, or injection. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a liquid suitable for topical administration, such as eye drops.

[0098] A pharmaceutically acceptable carrier can contain a physiologically acceptable agent that acts, for example, to stabilize, increase the solubility, or increase the absorption of a compound, such as a compound of the present disclosure. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins, or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which, for example, a compound of the present disclosure can be incorporated. Liposomes, such as liposomes containing phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0099] The phrase "pharmaceutically acceptable," as employed herein, refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0100] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations.

[0101] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, etc., in aqueous or non-aqueous solutions or suspensions); absorbed through the oral mucosa (e.g., sublingually); anally, rectally, or vaginally (e.g., as pessaries, creams, or foams, etc.); parenterally (e.g., as a sterile solution or suspension, including intramuscularly, intravenously, subcutaneously, or intrathecally); nasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds can also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and the patents cited therein.

[0102] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent active ingredient, and most preferably from about 10 percent to about 30 percent active ingredient, out of one hundred percent.

[0103] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0104] Formulations of the present disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilized, powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each of which contains a predetermined amount of a compound of the present disclosure as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0105] To prepare solid dosage forms for oral administration, such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, and granules, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents. Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0106] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0107] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in different proportions to provide a desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain emulsifying agents, and may be compositions that release the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the excipients described above.

[0108] Useful liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0109] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0110] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0111] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0112] Formulations of the pharmaceutical composition for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0113] Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0114] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0115] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0116] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats and oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0117] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0118] Transdermal patch has the added advantage of providing controlled delivery of the compound of the present disclosure to the body.Such dosage forms can be prepared by dissolving or dispersing active compound in a suitable medium.The flux of compound across the skin can also be increased by using an absorption enhancer.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0119] Ophthalmic formulations, eye ointments, powders, solutions, and the like are also contemplated within the scope of the present disclosure. Exemplary ophthalmic formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0120] The phrases "parenteral administration" and "parenterally administered," as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharmaceutically acceptable sterile, isotonic, aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0121] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, etc. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0122] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol sorbic acid. It is also desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0123] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous injection or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.Therefore, the absorption rate of the drug depends on its dissolution rate, and the rate can also depend on the crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0124] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0125] For use in the methods of the present disclosure, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0126] The method of introduction can also be provided by a rechargeable or biodegradable device. In recent years, various sustained release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biologics. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at a specific target site.

[0127] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the particular patient.

[0128] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds employed, or their esters, salts, or amides, the route of administration, the time of administration, the rate of excretion of the particular compound(s) employed, the duration of treatment, other drugs, compounds, and / or substances used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0129] A physician or veterinarian skilled in the art can easily determine and prescribe the required therapeutically effective amount of the pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered together with the compound of the present disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine, 13th ed., pp. 1814-1882, incorporated herein by reference).

[0130] Generally, a suitable daily dose of an active compound used in the compositions and methods of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0131] If desired, the effective daily amount of the active compound may be administered as 1, 2, 3, 4, 5, or 6 or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In a preferred embodiment, the active compound is administered once daily.

[0132] The patient for this treatment may be any animal in need of treatment, including primates, particularly humans, and other mammals such as horses, cattle, pigs and sheep; as well as poultry and pets in general.

[0133] In certain embodiments, the compounds of the present disclosure may be used alone or may be administered in combination with another type of therapeutic agent. As used herein, the phrase "co-administered" refers to any form of administration of two or more different therapeutic compounds, such that a second compound is administered while a previously administered therapeutic compound is still effective in the body (e.g., the two compounds are effective in the patient's body simultaneously, which may involve a synergistic effect of the two compounds). For example, different therapeutic compounds can be administered simultaneously or sequentially in either the same formulation or separate formulations. In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or within 1 week of each other. Thus, individuals receiving such treatment can benefit from the combined effects of different therapeutic compounds.

[0134] In certain embodiments, co-administration of a compound of the present disclosure with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy compared to the individual administration of either the compound of the present disclosure (e.g., a compound of Formula A) or the one or more additional therapeutic agent(s). In certain such embodiments, the co-administration provides an additive effect, where additive effect refers to the sum of the effects of the individual administration of the compound of the present disclosure and the one or more additional therapeutic agent(s).

[0135] In one embodiment, the compounds of the present disclosure can be administered orally or parenterally, either directly or in the form of a formulation, medicament, or pharmaceutical composition using an appropriate dosage form. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These formulations can be manufactured by known methods using additives commonly used as pharmaceutical additives.

[0136] Depending on the purpose, these additives may include excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0137] The dose of the compound of the present disclosure is appropriately selected depending on the subject to be administered, the administration route, the target disease, disorder or symptom, the age or weight of the subject, or a combination thereof, etc. For example, in the case of oral administration, the lower limit per day for an adult is 0.01 mg (preferably 100 mg) and the upper limit is 10,000 mg (preferably 6,000 mg), and this amount can be administered once a day or in divided doses several times a day.

[0138] The administration timing of the compounds of the present disclosure and the therapeutic agents thereof is not limited, and they may be administered to the subject simultaneously or at different times. The compounds of the present disclosure and the therapeutic agents may also be combined. The dosage of the therapeutic agents may be appropriately selected based on clinically used doses. The compounding ratio of the compounds of the present disclosure and the therapeutic agents may be appropriately selected depending on the subject to be administered, the administration route, the target disease, disorder or symptom, the age or weight of the subject, or a combination thereof.

[0139] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination at the same time or at different times, and such pharmaceutical compositions are also within the scope of the present disclosure.

[0140] Such medicines, formulations, and pharmaceutical compositions can be manufactured using any technique known in the art by mixing the compounds of the present disclosure and / or additional drugs (e.g., antibacterial agents, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.) together or separately, as a combination drug or as separate drugs, with any appropriate ingredients, and can be formulated into appropriate preparations, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices, using any technique known in the art. When the compound of the present disclosure and / or the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.) are prepared as separate drugs, they may be provided as a kit of two drugs, or one component may be provided as a single drug along with instructions (such as a package insert) instructing that the other component (which is the additional drug in the case of the compound of the present disclosure, and the compound of the present disclosure in the case of the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.)) be administered in combination at the same time or at different times.

[0141] When the compounds of the present disclosure are used as active ingredients in medicines, they are not intended for use only in humans, but can also be used in other animals other than humans (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.).

[0142] (Medicine) In one aspect, the present disclosure provides a medicament (composition) for regulating the activity of a target protein. Such a medicament or pharmaceutical composition can be used to prepare an individual single-unit dosage form. The pharmaceutical composition and dosage form of the present disclosure contain a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and optionally further active substances. The pharmaceutical composition and dosage form of the present disclosure can further contain one or more carriers, excipients, or diluents.

[0143] The pharmaceutical compositions and dosage forms of the present disclosure can also contain one or more additional active substances or ingredients. As a result, the pharmaceutical compositions and dosage forms of the present disclosure can contain a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one second active substance. Examples of optional second active substances are disclosed herein.

[0144] In one embodiment, the compounds of the present disclosure can be administered orally or parenterally (e.g., transmucosally (e.g., sublingually, nasally, vaginally, intravesically, rectally, transpreputially, intraocularly, buccally, or intraauricularly), parenterally (e.g., subcutaneously, intravenously, by bolus injection, intramuscularly, or intraarterially), topically (e.g., eye drops or other ophthalmic preparations), transdermally, or transepidermally), either directly or in a suitable dosage form, formulated into a medicament, or pharmaceutical composition. Specific examples of these dosage forms include, but are not limited to, tablets, caplets, capsules (e.g., elastic soft gelatin capsules), cachets, troches, powders, electuaries, granules, solutions, dispersions, suppositories, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water liquid emulsions, or water-in-oil liquid emulsions), elixirs, injections, patches, poultices, and the like. These formulations can be manufactured by known methods using additives commonly used as pharmaceutical additives. The present disclosure may also be in the form of a liquid dosage form suitable for oral or transmucosal administration to a patient, such as an elixir, a liquid dosage form suitable for parenteral administration to a patient, an ophthalmic preparation suitable for eye drops or other topical administration; and a sterile solid (e.g., a crystalline or amorphous solid) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a patient. The present disclosure may be administered as a single-unit dosage form.

[0145] Additives that can be used in the present disclosure include, depending on the purpose, excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavorings, etc. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0146] The composition, shape, and type of the compositions and dosage forms of the present disclosure typically vary depending on their intended use. For example, a dosage form used for the rapid treatment of a disease, disorder, or condition may contain a larger amount of one or more active ingredients than a dosage form used for the chronic treatment of the disease, disorder, or condition. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients than an oral dosage form used to treat the disease, disorder, or condition. These and other ways in which specific dosage forms encompassed by the present disclosure differ from one another are readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing, Easton, PA (1990).

[0147] In one embodiment, pharmaceutical compositions of the present disclosure suitable for oral administration can be presented as individual dosage forms, including, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Typical oral dosage forms of the present disclosure are prepared by combining at least one excipient and the active ingredient into a thorough blend according to conventional pharmaceutical compounding techniques. Excipients can take a variety of forms depending on the form of preparation desired for administration. Non-limiting examples of excipients suitable for use in oral liquid or aerosol dosage forms include water, glycols, oils, alcohol, flavoring agents, preservatives, and coloring agents. Non-limiting examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0148] Non-limiting examples of excipients that can be used in the oral dosage form of the present disclosure include binder, filler, disintegrant and lubricant.Non-limiting examples of binders that are suitable for use in pharmaceutical compositions and dosage forms include corn starch, potato starch or other starches, gelatin, natural and synthetic gums, such as gum acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose, microcrystalline cellulose and their mixtures.

[0149] Non-limiting examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the present disclosure is typically present in from about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

[0150] Non-limiting examples of disintegrants that can be used in pharmaceutical compositions and dosage forms of the present disclosure include agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0151] Non-limiting examples of lubricants that can be used in the pharmaceutical compositions and dosage forms of the present disclosure include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional examples of lubricants include syloid silica gel, coagulated aerosol of synthetic silica, CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, MA), and mixtures thereof. When used, lubricants are typically used in an amount of less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

[0152] The active ingredient or active component of the present disclosure can be administered by controlled-release means or by delivery device or dosage form that is well known to those skilled in the art.The non-limiting example of controlled-release means or delivery device includes those disclosed in United States Patent No. 3,845,770; United States Patent No. 3,916,899; United States Patent No. 3,536,809; United States Patent No. 3,598,123; United States Patent No. 4,008,719; United States Patent No. 5,674,533; United States Patent No. 5,059,595; United States Patent No. 5,591,767; United States Patent No. 5,120,548; United States Patent No. 5,073,543; United States Patent No. 5,639,476; United States Patent No. 5,354,556 and United States Patent No. 5,733,566, which are incorporated herein by reference. Such dosage forms can be used to provide delayed or controlled release of one or more active ingredients, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres or their combinations, to provide desired release profiles at various rates.Suitable controlled-release formulations known to those skilled in the art, including those disclosed herein, can be easily selected for use with the active ingredient or active ingredients of the present disclosure.Therefore, the present disclosure encompasses, but is not limited to, the unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel caps and caplets, adapted for controlled release.

[0153] Parenteral dosage forms can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized before administration to a patient. Non-limiting examples of parenteral dosage forms include ready-to-inject solutions, dry products that are easily dissolved or suspended in a pharmaceutically acceptable vehicle for injection, ready-to-inject suspensions, and emulsions. Suitable vehicles that can be used to provide the parenteral dosage forms of the present disclosure are well known to those skilled in the art. Non-limiting examples of suitable vehicles include Water for Injection (USP); aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0154] Drugs can be applied topically to the skin and its appendages or to various mucous membranes. Usable routes include sublingual, nasal, vaginal, intravesical, rectal, transpreputial, intraocular, buccal, or intraauricular. Many dosage forms have been developed to deliver active ingredients to the application site for localized effects. Non-limiting examples of topical and mucosal dosage forms of the present disclosure include ointments, creams, gels, pastes, powders, lotions, sprays, liniments, poultices, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other dosage forms known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing, Easton, PA (1990), Introduction to Pharmaceutical Dosage Forms, Lea & Febiger, Philadelphia (1985), etc. Dosage forms suitable for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels.

[0155] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed by the present disclosure are well known to those skilled in the pharmaceutical arts and depend on the specific tissue to which a given pharmaceutical composition or dosage form is to be applied. Non-limiting examples of typical excipients for forming solutions, emulsions, or gels include water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, which are non-toxic and pharmaceutically acceptable.

[0156] Moisturizing agents, such as occlusives, humectants, emollients, and protein rejuvenators, can also be added to pharmaceutical compositions and dosage forms if desired.

[0157] Occlusive agent is a substance that physically blocks the loss of moisture in the stratum corneum.Non-limiting examples of occlusive agent include petrolatum, lanolin, mineral oil, silicones such as dimethicone, zinc oxide, and combinations thereof.Preferred occlusive agent is petrolatum and lanolin, more preferably petrolatum at a minimum concentration of 5%.

[0158] A moisturizer is a substance that, when applied to the skin, attracts water to the skin and theoretically improves the hydration of the stratum corneum. However, the water attracted to the skin is water from other cells, not water from the atmosphere. Depending on this type of moisturizer, evaporation from the skin may continue and actually worsen dryness. Non-limiting examples of moisturizers include glycerin, sorbitol, urea, alpha hydroxy acids, sugars, and combinations thereof. Preferred moisturizers include alpha hydroxy acids, such as glycolic acid, lactic acid, malic acid, citric acid, tartaric acid, etc.

[0159] Emollients are substances that lubricate the skin by filling the spaces between skin flakes with oil droplets, and usually do not cause occlusion unless applied thickly. When used in combination with emulsifiers, they can help retain oil and moisture within the stratum corneum. Vitamin E is a common additive that does not appear to have any effect other than as an emollient. Other vitamins, such as vitamin A and vitamin D, are also added, but their effects are questionable. Non-limiting examples of emollients include mineral oil, lanolin, fatty acids, cholesterol, squalene, structured lipids, and combinations thereof.

[0160] The administration timing of the compounds of the present disclosure and the therapeutic agents thereof is not limited, and they may be administered to the subject simultaneously or at intervals (i.e., at different times). The compounds of the present disclosure and the therapeutic agents may also be combined. The dosage of the therapeutic agents may be appropriately selected based on clinically used doses. The compounding ratio of the compounds of the present disclosure and the therapeutic agents may be appropriately selected depending on the subject to be administered, the administration route, the target disease, disorder, or symptom, the age or weight of the subject, or a combination thereof.

[0161] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination at the same time or at different times, and such pharmaceutical compositions are also within the scope of the present disclosure.

[0162] Such medicines, formulations, and pharmaceutical compositions can be manufactured using any technique known in the art by mixing the compounds of the present disclosure and / or additional drugs (e.g., antibacterial agents, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.) together or separately, as a combination drug or as separate drugs, with any appropriate ingredients, and can be formulated into appropriate preparations, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices, using any technique known in the art. When the compound of the present disclosure and / or the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.) are prepared as separate drugs, they may be provided as a kit of two drugs, or one component may be provided as a single drug along with instructions (such as a package insert) instructing that the other component (which is the additional drug in the case of the compound of the present disclosure, and the compound of the present disclosure in the case of the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.)) be administered in combination at the same time or at different times.

[0163] When the compounds of the present disclosure are used as active ingredients in medicines, they are not intended for use only in humans, but can also be used in other animals other than humans (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.).

[0164] The toxicity and therapeutic efficacy of the compounds of the present disclosure can be measured, for example, by LD 50 (the dose that is lethal to 50% of the population) and ED 50The LD 200 mg / kg dose can be determined by standard pharmaceutical procedures in cell cultures or experimental animals by measuring the LD 200 mg / kg dose (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the ratio LD 200 mg / kg. 50 / ED 5O The therapeutic index can be expressed as: Compounds that exhibit large therapeutic indices are preferred. Compounds that exhibit toxic side effects can be used, but the design of delivery systems that target such compounds to the affected tissue site must be done carefully to minimize potential damage to uninfected cells, thereby reducing side effects.

[0165] The data obtained from cell culture assays and animal studies can be used to formulate a range of dosage for use in humans. Such a compound can be administered at a dose that is consistent with little or no toxicity, ED 50 Preferably, the circulating concentration range includes: (Ic) 0.5 to 1.5; ... 50 A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the concentration of the test compound that achieves a half-maximal inhibition of symptoms (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography.

[0166] The compounds of the present disclosure can be administered orally in a single or divided daily dose of about 0.10 to about 150 mg / day of active ingredient, or parenterally, topically, or transmucosally, for example, nasally, rectally, or transdermally, or topically. The amount of pharmaceutical composition administered in the methods of the present disclosure will depend on the subject being treated, the disorder or severity of the disorder's symptoms, the method and frequency of administration, and the judgment of the physician. Dosage frequency ranges from about hourly to monthly. In specific embodiments, administration is from 8 times daily to once every other day, or from 1 to 3 times daily. In specific embodiments, the pharmaceutical compositions of the present disclosure are administered chronically, for example, daily.

[0167] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." In this specification, when it is stated that "within a range of two values," the range includes the two values ​​themselves.

[0168] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0169] (Preferred Embodiments) Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. It is also understood that the following embodiments of the present disclosure can be used alone or in combination.

[0170] (Compounds and Compositions of the Present Disclosure) In one aspect, the compounds of the present disclosure are compounds represented by the following formula (A): Z-L-X or an isomer thereof, or a salt thereof, wherein Z is a ligand moiety that specifically binds to an intracellular protein, L is a linker moiety or a single bond, and X is a group represented by the following formula: A is N or CR８ and B is N, CR ９ , or C.L. ２ and Q is N or CR １０ and R １ and L that is not used for bonding with L １ are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted carbocyclyl; or R １ and L that is not used for bonding with L １ can form, together with the carbon atoms to which they are attached, an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group; R ２ａ and R ２ｂ are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted carbocyclyl; or R ２ａ and R ２ｂ can form, together with the carbon atoms to which they are attached, an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group; R ３ is selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted carbocyclyl; R ４ is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted carbocyclyl; R ５ａ and R ５ are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted carbocyclyl; or R ５ａ and R５ｂ can form, together with the carbon atoms to which they are attached, an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group; R ６ is hydrogen, halogen, ═O, ═S, nitro, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbonyl, optionally substituted amino, optionally substituted hydroxy, optionally substituted heterocyclyl, optionally substituted carbocyclyl, optionally substituted aryl and optionally substituted heteroaryl and (wherein E represents the point of attachment), and L ３ and L ３ R ' together with the carbon atom to which they are attached can form an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group connected with a linker; ７ , R ８ and R ９ are each independently selected from hydrogen, halogen, ═O, ═S, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted carbocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R １０ is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted carbocyclyl; L １ ~L ３ and L ３ and X is bonded to L, or an isomer thereof, or a salt thereof.

[0171] The compound of the present disclosure has a structure in which X, which specifically binds to an E3 ligase (specifically, an Inhibitor of Apoptosis Protein (IAP)), and Z, which specifically binds to a target protein, are linked via a linker (L). By binding to both the IAP and the target protein in cells, the compound can induce ubiquitination of the target protein by the IAP and activity regulation by the proteasome. Therefore, the Z moiety itself does not need to have "functional activity" such as inhibitory activity or agonist activity of the target protein; as long as it has "binding activity" that allows it to specifically bind to the target protein, activity regulation of the compound of the present disclosure can be achieved. For this reason, the Z moiety can be used not only to bind to the active site of a target protein such as an enzyme, but also to any other moiety. For example, when the compound of the present disclosure is used as an anticancer agent, by administering it to patients with breast cancer, cervical cancer, ovarian cancer, or the like, it can inhibit cancer cell proliferation and induce cancer cell suicide by controlling protein regulatory activity in cancer tissues, and can be used as a preventive and therapeutic agent for breast cancer, etc.

[0172] In one embodiment, R １ , L that is not used for bonding with L １ , R ２ａ , R ２ｂ , R ３、 R ４ , R ５ａ、 R ５ｂ and R １０ The alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl in the formula (I) are each independently substituted as needed with one to the maximum possible number of identical or different substituents selected from Substituent Group I, ６ , R ７ , R ８ and R ９ The alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl, aryl, and heteroaryl are each independently substituted as needed with one to the maximum possible number of identical or different substituents selected from Substituent Group I, and L ３ and L ３The carbocyclyl and heterocyclyl groups of the formula (I) are each independently substituted as needed with one to the maximum possible number of identical or different substituents selected from Substituent Group I.

[0173] In one embodiment, R １ , L that is not used for bonding with L １ , R ２ａ , R ２ｂ , R ３、 R ４ , R ５ａ、 R ５ｂ and R １０ are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbonylalkyl, optionally substituted carbamoylalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbonylcarbocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkylcarbamoyl, optionally substituted alkoxycarbamoyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylcarbamoyl, optionally substituted cycloalkylcarbamoyl, or optionally substituted heterocycloalkylcarbamoyl; or R １ and L that is not used for bonding with L １ together with the carbon atoms to which they are attached can form an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group, R ２ａ and R ２ｂ together with the carbon atom to which they are attached can form an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group, R ５ａ and R ５ｂ together with the carbon atom to which they are attached can form an optionally substituted carbocyclyl group or an optionally substituted heterocyclyl group, where R１ , L that is not used for bonding with L １ , R ２ａ , R ２ｂ , R ３、 R ４ , R ５ａ、 R ５ｂ and R １０ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group II.

[0174] In one embodiment, R ６ is hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cyanoalkyl, optionally substituted alkoxyalkyl, optionally substituted carbonyl, optionally substituted alkylamino, optionally substituted aminoalkyl, optionally substituted alkoxy, optionally substituted alkylcarbonyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and (wherein E represents the point of attachment), and L ３ and L ３ ' together with the carbon atom to which they are attached can form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl connected with a linker, where R ６ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group II.

[0175] In one embodiment, R ７ , R ８ and R ９is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, optionally substituted cyanoalkyl, optionally substituted carboxyalkyl, optionally substituted carboxy, optionally substituted carbonyl, optionally substituted carbamoylalkyl, optionally substituted carbamoyl, optionally substituted alkylamino, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkylcarbamoyl, optionally substituted alkoxycarbamoyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylcarbamoyl, optionally substituted cycloalkylcarbamoyl, or optionally substituted heterocycloalkylcarbamoyl, wherein R ７ , R ８ and R ９ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group II.

[0176] In one embodiment, R １０ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylcarbamoyl, optionally substituted carbamoyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylcarbonyl or optionally substituted carbocyclylcarbonyl, where R １０ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group II.

[0177] In one embodiment, R １ , L that is not used for bonding with L １ , R ２ａ , R ２ｂ , R ３、 R ４ , R ５ａ、 R ５ｂ and R １０ are each independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ２－６ alkylcarbamoyl, optionally substituted 3- to 12-membered heterocyclylalkyl, optionally substituted C ３－１２ carbocyclylalkyl, optionally substituted 3- to 12-membered heterocyclylcarbonyl, optionally substituted C ３－１２ carbocyclylcarbonyl, or R １ and L that is not used for bonding with L １ together with the carbon atoms to which they are attached can form an optionally substituted 3- to 10-membered carbocyclyl group or an optionally substituted 3- to 10-membered heterocyclyl group, where R １ and L that is not used for bonding with L １ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0178] In one embodiment, R ２ａ and R ２ｂ are each independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ２－６ alkylcarbamoyl, optionally substituted 3- to 12-membered heterocyclylalkyl and optionally substituted C ３－１２ carbocyclylalkyl, or R ２ａ and R ２ｂtogether with the carbon atoms to which they are attached can form an optionally substituted 3- to 10-membered carbocyclyl group or an optionally substituted 3- to 10-membered heterocyclyl group, where R ２ａ and R ２ｂ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0179] In one embodiment, R ３ is hydrogen, optionally substituted hydroxy, optionally substituted hydroxy C １－６ alkyl, where R ３ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0180] In one embodiment, R ４ represents hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ３－８ cycloalkylalkyl or optionally substituted C ３－８ cycloalkenylalkyl, where R ４ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0181] In one embodiment, R ５ａ and R ５ｂ are each independently hydrogen, optionally substituted C １－８ Alkyl, optionally substituted C ２－８ Alkenyl, optionally substituted C ２－８ Alkynyl, optionally substituted C １－８ Alkoxy, optionally substituted cyano C １－８ Alkyl, optionally substituted carbonyl C １－８ Alkyl, optionally substituted, C １－８alkylcarbonyloxy, optionally substituted carboxy C １－８ Alkyl, optionally substituted hydroxy C １－８ Alkyl, optionally substituted amino C １－８ Alkyl, optionally substituted C １－８ Alkylamino, optionally substituted imino C １－８ Alkyl, optionally substituted C １－８ Alkylimino, C １－８ alkylcarbonylamino, or R ５ａ and R ５ｂ together with the carbon atoms to which they are attached can form an optionally substituted 3- to 6-membered carbocyclyl group or an optionally substituted 4- to 6-membered heterocyclyl group, where R ５ａ and R ５ｂ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0182] In one embodiment, R ６ represents hydrogen, halogen, optionally substituted C １－８ Alkyl, optionally substituted C ２－８ Alkenyl, optionally substituted C ２－８ Alkynyl, optionally substituted C １－８ Alkoxy, optionally substituted cyano C １－８ Alkyl, optionally substituted carbonyl C １－８ Alkyl, optionally substituted, C １－８ alkylcarbonyloxy, optionally substituted carboxy C １－８ Alkyl, optionally substituted hydroxy C １－８ Alkyl, optionally substituted amino C １－８ Alkyl, optionally substituted C １－８ Alkylamino, optionally substituted imino C １－８ Alkyl, optionally substituted C １－８ Alkylimino, C １－８ alkylcarbonylamino or (E indicates the point of attachment), and L ３ and L ３ ' together with the carbon atom to which they are attached can form an optionally substituted 3- to 6-membered carbocyclyl group or an optionally substituted 4- to 6-membered heterocyclyl group connected with a linker, where R ６ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0183] In one embodiment, R ７ , R ８ and R ９ are each independently hydrogen, halogen, or optionally substituted C １－８ Alkyl, optionally substituted C ２－８ Alkenyl, optionally substituted C ２－８ Alkynyl, optionally substituted C １－８ Alkoxy, optionally substituted cyano C １－８ Alkyl, optionally substituted carbonyl C １－８ Alkyl, optionally substituted, C １－８ alkylcarbonyloxy, optionally substituted carboxy C １－８ Alkyl, optionally substituted hydroxy C １－８ Alkyl, optionally substituted amino C １－８ Alkyl, optionally substituted C １－８ Alkylamino, optionally substituted imino C １－８ Alkyl, optionally substituted C １－８ Alkylimino, C １－８ alkylcarbonylamino, or R ７ , R ８ and R ９ together with the carbon atoms to which they are attached can form an optionally substituted 3- to 6-membered carbocyclyl group or an optionally substituted 4- to 6-membered heterocyclyl group, where R ７ , R ８ and R ９The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0184] In one embodiment, R １０ represents hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ alkylcarbamoyl, optionally substituted 3- to 12-membered heterocyclylalkyl, optionally substituted C ３－１２ carbocyclylalkyl, optionally substituted 3- to 12-membered heterocyclylcarbonyl or optionally substituted C ３－１２ carbocyclylcarbonyl, where R ４ The above groups may be optionally substituted with one to the maximum possible number of identical or different substituents selected from Substituent Group III.

[0185] In one aspect, the compound of the present disclosure is a compound represented by the following formula (A): Z-L-X or an isomer thereof, or a salt thereof, wherein Z is a ligand moiety that specifically binds to an intracellular protein, L is a linker moiety or a single bond, and X is a group represented by the following formula: A is N or CR ８ and B is N, CR ９ , or C.L. ２ and Q is N or CR １０ and R １ and L that is not used for bonding with L １ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), -(CH ２ ) ｓ -C ３－１２Carbocyclyl, —C(═O)—(3- to 12-membered heterocyclyl), and —C(═O)—C ３－１２ carbocyclyl, or R １ and L that is not used for bonding with L １ can form, together with the carbon atoms to which they are attached, a 3- to 10-membered saturated carbocyclyl or heterocyclyl group, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl and carbocyclyl groups may be formed by one or more R ｂ optionally substituted with a group; ２ａ and R ２ｂ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), and -(CH ２ ) ｓ -C ３－１２ carbocyclyl, or R ２ａ and R ２ｂ can form, together with the carbon atoms to which they are attached, a 3- to 10-membered saturated carbocyclyl or heterocyclyl group, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl and carbocyclyl groups may be formed by one or more R ｂ optionally substituted with a group; ３ is C １－４ Alkyl, C ２－４ Alkenyl and -(CH ２ ) ｓ -C ３－８ cycloalkyl, wherein said C １－４ Alkyl, C ２－４ alkenyl, and C ３－８ Cycloalkyl is one or more R ａ optionally substituted with a group; ａrepresents halogen, —OH and —O—C １－６ alkyl; R ４ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl and -(CH ２ ) ｓ -C ３－８ cycloalkenyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl and C ３－８ Cycloalkenyl is one or more R ａ optionally substituted with a group; ５ａ and R ５ｂ are each independently hydrogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN, -S(O) ｑ -R ｘ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ, -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ , -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ , -(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ , -(CR ｘ R ｙ ) ｓ -C(=N)NR ｚ , -(CH ２ ) ｓ -O-C(=O)-C １－４ Alkyl-NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ , -(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ and -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ or R ５ａ and R ５ｂcan form, together with the carbon atom to which they are attached, a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group, wherein said C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ An alkynyl group is one or more R ｂ groups, and the carbocyclyl and heterocyclyl groups may be substituted with one or more R ｂ optionally substituted with a group; ６ is hydrogen, halogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , =O, =S, nitro, Si(R ｘ ) ４ , -(CH ２ ) ｓ -CN, -S(O) ｑ - (CR ｘ R ｙ ) ｓ -R ｚ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ-OC(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ , -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ , -(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ , -(CR ｘ R ｙ ) ｓ -C(=N)NR ｘ , -S(O)(=NR ｘ ) R ｙ , -(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ , -(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ , -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ group, -P(=O)(R ｘ ) ２ , -Y-C ５－１０ Aryl, —Y—(5- to 10-membered heteroaryl), an optionally fused 5- to 10-membered carbocyclyl group, an optionally fused 5- to 10-membered heterocyclyl group, and (E represents the point of attachment), and L ３ and L ３ ' together with the carbon atom to which they are attached can form a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group connected with a linker, wherein said C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl groups, carbocyclyl groups, heterocyclyl groups, and (E represents the point of attachment) is one or more R ｂ optionally substituted with a group; R ７ , R ８ and R ９ are each independently hydrogen, halogen, or C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , =O, =S, nitro, Si(R ｘ ) ４ , -(CH ２ ) ｓ -CN, -S(O) ｑ - (CR ｘ R ｙ ) ｓ -R ｚ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH２ ) ｓ -NR ｘ C(=O)R ｙ 、-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ 、-(CH ２ ) ｓ -NR ｘ [[ID=२९]]R ｙ 、-NR ｘ -(CH ２ ) ｓ -R ｚ 、-(CR<00०2913>R ｙ [[ID=४३]]) ｓ -C(=S)NR ｚ 、-(CR ｘ R ｙ ) ｓ -C(=N)NR ｘ 、-S(O)(=NR ｘ )R ｙ 、-(CH ２ ) ｓ -O-C(=O)-C[[ID=६४]] １－４ alkyl-NR ｘ R ｙ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｎ -O-C(=O)-R ｚ 、-(CH ２ ) ｓ -NR ｘ -(CH ２ ) ｓ -SO ２ -R ｙ 、-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ 、-(CH​​​​​​​​​​​​​​５－１０ aryl, wherein said C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ An alkynyl group is one or more R ｂ groups, and the carbocyclyl and heterocyclyl groups may be substituted with one or more (e.g., 1, 2, or 3) R ｂ optionally substituted with a group; ｂ are each independently a halogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(5- to 10-membered heteroaryl), -(CH ２ ) ｓ -(4- to 7-membered saturated heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , Halo C １－６ Alkyl, haloC １－６ Alkoxy, hydroxy, hydroxy C １－６ Alkyl, ═O, ═S, nitro, Si(Rx) ４ , -(CH ２ ) ｓ -CN, -S(O) ｑ -R ｘ , -C(=O)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ , -(CR ｘ Rｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ - (CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ , -(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ , -(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ , -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ group and —P(═O)(R ｘ ) ２ wherein said C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ３－８Cycloalkenyl, heterocyclyl, phenyl and heteroaryl can be one or more R ｘ optionally substituted with a group; ｘ , R ｙ and R ｚ are each independently a halogen, hydrogen, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(4- to 7-membered saturated heterocyclyl), hydroxy C optionally substituted with one or more halo １－６ Alkyl, —C(═O)OC １－６ Alkyl, hydroxy, C １－６ Alkoxy, HaloC １－６ Alkyl, -(CH ２ ) ｎ -O-C １－６ Alkyl, —C(═O)—(CH ２ ) ｎ -C １－６ Alkoxy, —C(═O)—C １－６ Alkyl, -(CH ２ ) ｓ -CN, C １－６ Alkyl-N(H) ２－ｑ (C １－６ alkyl) ｑ , -N(H) ２－ｑ (C １－６ alkyl) ｑ , -C(=O)-N(H) ２－ｑ (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -NH-SO ２ -N(H) ２－ｑ (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -N(C １－４(alkyl)-SO ２ -N(H) ２－ｑ (C １－６ alkyl) ｑ and -(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-N(H) ２－ｑ (C １－６ alkyl) ｑ and when attached to a nitrogen, carbon, silicon or phosphorus atom, R ｘ and R ｙ may, together with the atoms to which they are attached, form a 3- to 7-membered ring which may contain one or two additional heteroatoms selected from O, N, S, and oxidized forms of N and S; Y and W may each independently be a bond, —(CR ｘ R ｙ ) ｍ -, -C(=CR ｘ )-, -C(=O)-, -NR ｘ , —C(═O)NR ｘ -, -NR ｘ C(=O)-,-(CR ｘ R ｙ ) ｑ -O-, -O-(CR ｘ R ｙ ) ｑ -, -S(O) ２ -NH,NH-S(O) ２ - and -S(O) ｑ - selected from; R １０ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), -(CH ２ ) ｓ -C ３－１２ Carbocyclyl, —C(═O)—(3- to 12-membered heterocyclyl), and —C(═O)—C ３－１２ carbocyclyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C２－６ Alkynyl, heterocyclyl, and carbocyclyl groups can be one or more R ｂ group; s independently represents an integer of 0 to 4; n independently represents an integer of 1 to 4; q independently represents an integer of 0 to 2; m independently represents an integer of 1 to 2; L １ ~L ３ and L ３ and X is bonded to L, or an isomer thereof, or a salt thereof.

[0186] The embodiments of each group in X in the above formula (A) are as follows.

[0187] In one embodiment, R １ and L that is not used for bonding with L １ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl)q, -(CH ２ ) ｓ -(3- to 7-membered heterocyclyl), -(CH ２ ) ｓ -C ３－７ Carbocyclyl, —C(═O)—(3- to 7-membered heterocyclyl), and —C(═O)—C ３－７ carbocyclyl, or R １ and L that is not used for bonding with L １ can form, together with the carbon atoms to which they are attached, a 3- to 6-membered saturated carbocyclyl group or a 4- to 6-membered heterocyclyl group, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl and carbocyclyl groups may be formed by one or more R ｂ group, and the R ｂ are each independently a halogen, C １－４ Alkyl, C ３－４ Alkynyl, -(CH ２ ) ｑ -C ３－６ Cycloalkyl, -(CH２ ) ｑ -phenyl, -(CH ２ ) ｑ -(5- to 6-membered heteroaryl), -(CH ２ ) ｑ -O-C １－４ Alkyl, haloC １－４ Alkyl, haloC １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, ═O, —S(O) ｑ -C １－４ Alkyl, —C(═O)C １－４ Alkyl, -(CH ２ ) ｑ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｑ -NR ｘ C(=O)C １－４ Alkyl, -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｑ -C １－４ Alkyl, -(CH ２ ) ｑ -NR ｘ - (CH ２ ) ｑ -SO ２ -C １－４ Alkyl, and -(CH ２ ) ｑ -SO ２ NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ R ｘ and R ｙ are each independently a halogen, hydrogen, or C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙmay, together with the atom to which they are attached, form a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N.

[0188] In one embodiment, R １ and L that is not used for bonding with L １ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C(═O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 7-membered heterocyclyl), -(CH ２ ) ｓ -C ３－７ Carbocyclyl, —C(═O)—(3- to 7-membered heterocyclyl), and —C(═O)—C ３－７ carbocyclyl, wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, heterocyclyl, and carbocyclyl groups can be one or more R ｂ may be substituted with a group, R ｂ are each independently fluorine, methyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—C １－２ Alkyl, fluoromethyl, fluoromethoxy, hydroxy, ═O, —S(O) ２ -C １－４ Alkyl, —C(═O)C １－４ Alkyl, —C(═O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl, and —NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ R ｘ and R ｙ are each independently chlorine, fluorine, hydrogen, C １－４ Alkyl, and C １－４alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ may, together with the atom to which they are attached, form a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N.

[0189] In one embodiment, R １ and L that is not used for bonding with L １ are each independently hydrogen or C １－６ alkyl (preferably methyl), wherein said C １－６ Alkyl is one or more R ｂ It may be substituted with a group.

[0190] In one embodiment, R １ and L that is not used for bonding with L １ are each independently hydrogen or C １－６ alkyl (preferably methyl), wherein said C １－６ Alkyl is one or more —O—C １－２ It may be substituted with alkyl (preferably methoxy).

[0191] In one embodiment, R １ and L that is not used for bonding with L １ One of the groups is hydrogen and the other is one or more —O—C １－２ C optionally substituted with alkyl (preferably methoxy) １－６ It is alkyl (preferably methyl).

[0192] In one embodiment, R ２ａ and R ２ｂ are each independently hydrogen, C １－３ Alkyl, C ２－３ Alkenyl and C ２－３ alkynyl, or R ２ａ and R ２ｂ together with the carbon atom to which they are attached can form a 3- to 4-membered saturated carbocyclyl group.

[0193] In one embodiment, R ２ａ and R ２ｂis hydrogen.

[0194] In one embodiment, R ３ is one or more R ａ C optionally substituted with a group １－４ It is alkyl (preferably methyl).

[0195] In one embodiment, R ３ is C optionally substituted with one or more halogens (preferably fluorine); １－４ It is alkyl (preferably methyl).

[0196] In one embodiment, R ３ is methyl optionally substituted with one or more fluorines.

[0197] In one embodiment, R ４ is hydrogen.

[0198] In one embodiment, R ５ａ and R ５ｂ are each independently hydrogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, -Y-C ３－６ carbocyclyl, -W-(3- to 6-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN and -C(=O)R ｘ or R ５ａ and R ５ｂ can form, together with the carbon atom to which they are attached, a 3- to 5-membered carbocyclyl group or a 5- to 6-membered heterocyclyl group, wherein said C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ An alkynyl group is one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, C １－４ Alkyl, C３－４ Alkynyl, —C ３－６ Cycloalkyl, —O—C １－４ Alkyl, Fluoro C １－４ Alkyl, haloC １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, —C(═O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl, and —NR ｘ R ｙ is selected from the group

[0199] In one embodiment, R ５ａ and R ５ｂ are each independently hydrogen or methyl, or R ５ａ and R ５ｂ together with the carbon atom to which they are attached can form a cyclopropyl group.

[0200] In one embodiment, R ５ａ and R ５ｂ are each independently １－４ It is alkyl (preferably methyl).

[0201] In one embodiment, R ６ is hydrogen, halogen, C １－４ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, -(CR ｘ R ｙ )-C ３－７ Carbocyclyl, -(CR ｘ R ｙ )-(3- to 7-membered heterocyclyl), -(CR ｘ R ｙ )-O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN, -S(O) ２ -(CH2) ｓ -R ｚ , -C(=O)R ｘ , -(CH ２ )ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ , -(CH ２ ) ｎ -C ５－１０ Aryl, -(CH ２ ) ｎ -(5- to 10-membered heteroaryl), an optionally fused 5- to 7-membered carbocyclyl group, an optionally fused 5- to 7-membered heterocyclyl group, and (E represents the point of attachment), and L ３ and L ３ ' together with the carbon atom to which they are attached can form a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group which can be connected with a linker, wherein said C １－４ Alkyl, C ２－５ Alkenyl and C ２－５ Alkynyl groups, carbocyclyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and (E represents the point of attachment) is one or more R ｂ may be substituted with a group, and the R ｂ are each independently a halogen, C １－４ Alkyl, C ３－４ Alkynyl, -(CH ２ ) ｑ -C ３－６ Cycloalkyl, -(CH ２ ) ｑ -phenyl, -(CH ２ ) ｑ -(5- to 6-membered heteroaryl), -(CH ２ ) ｑ -O-C １－４ Alkyl, haloC １－４ Alkyl, haloC １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, ═O, —S(O) ｑ -C １－４ Alkyl, —C(═O)C １－４ Alkyl, -(CH ２ ) ｑ -C(=O)NR ｘ Rｙ , -(CH ２ ) ｑ -NR ｘ C(=O)C １－４ Alkyl, -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｑ -C １－４ Alkyl, -(CH ２ ) ｑ -NR ｘ - (CH ２ ) ｑ -SO ２ -C １－４ Alkyl, and -(CH ２ ) ｑ -SO ２ NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ CR ｘ R ｙ is CH ２ or CF ２ and other R ｘ , R ｙ and R ｚ are each independently hydrogen, C １－４ Alkyl, C ３－４ Alkynyl, Fluoro C １－４ Alkyl, and C １－４ alkoxy; R ｂ R as a substituent of ｘ The group is halogen, hydrogen, C １－４ Alkyl, and C １－４ Alkoxy is selected from:

[0202] In one embodiment, R ６ is -(CR ｘ R ｙ ) -H, -(CR ｘ R ｙ )-F, -(CR ｘ R ｙ ) - C １－２ Alkyl, -(CR ｘ R ｙ) —O-phenyl, —S(O) ２ -CH ２ -R ｚ , -C(=O)C １－４ Alkyl, —C(═O)-phenyl, —C(═O)-(5-6 membered heteroaryl), —CH ２ -phenyl, -CH ２ -(5-6 membered heteroaryl), and (E represents the point of attachment), and L ３ and L ３ ' together with the carbon atom to which they are attached can form a 3- to 6-membered carbocyclyl group or a 4- to 6-membered heterocyclyl group which can be connected with a linker, wherein said C １－２ Alkyl, C １－４ Alkyl, phenyl, heteroaryl and (E represents a point of attachment) is one or more C １－３ an alkyl group, fluorine, chlorine, or —O—C １－３ may be substituted with an alkyl group, ｘ R ｙ is CH ２ or CF ２ and other R ｘ , R ｙ and R ｚ are each independently hydrogen, C １－４ Alkyl, C ３－４ Alkynyl, Fluoro C １－４ Alkyl, and C １－４ Alkoxy is selected from:

[0203] In one embodiment, R ６ is -CH ２ -phenyl, or (E represents a point of attachment), which can be one or more R ｂ It may be substituted with a group.

[0204] In one embodiment, R ６ is -CH ２ -phenyl, or (E represents a bonding point), which may be substituted with one or more halogen atoms (preferably fluorine atoms).

[0205] In one embodiment, R ７ is hydrogen, halogen, C １－３ Alkyl, C ２－３ Alkenyl, C ２－３ Alkynyl and —C ３－４ carbocyclyl, wherein said C １－３ Alkyl, C ２－３ Alkenyl, C ２－３ Alkynyl and C ３－４ Carbocyclyl is a group consisting of one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, —O—C １－４ Alkyl, Fluoro C １－４ Alkoxy, hydroxy, and —NR ｘ R ｙ R is selected from the group ｘ and R ｙ are each independently hydrogen, and C １－４ alkyl, and when attached to a nitrogen, R ｘ and R ｙ may, together with the atoms to which they are attached, form a 4- to 6-membered ring which may contain one additional heteroatom selected from O and N.

[0206] In one embodiment, R ７ is hydrogen or fluorine.

[0207] In one embodiment, R ７ is hydrogen.

[0208] In one embodiment, R ８ is hydrogen.

[0209] In one embodiment, R ９ is hydrogen, halogen, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, -Y-C ３－６ carbocyclyl, -W-(4- to 6-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ Rｙ ) ｎ -OR ｚ , ═O, -(CH ２ ) ｓ -CN, -C(=O)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ -NR ｘ R ｙ , -(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ , -(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ , -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ , and -Y-C ５－１０ aryl, wherein said C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, carbocyclyl and heterocyclyl groups are each formed by one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, C １－４ Alkyl, C ３－４ Alkynyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, —O—C １－４ Alkyl, Fluoro C １－４ Alkyl, Fluoro C １－４Alkoxy, hydroxy, hydroxy C １－４ Alkyl, ═O, —C(═O)C １－４ Alkyl, —C(═O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl, and —NR ｘ R ｙ groups, wherein the cycloalkyl, phenyl, and heteroaryl groups are selected from one or more R ｘ group, and the R ｘ , R ｙ and R ｚ are each independently chlorine, fluorine, hydrogen, C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ may, together with the atom to which they are attached, form a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N.

[0210] In one embodiment, R ９ is hydrogen, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, —CH ２ -C ３－６ Carbocyclyl, -CH ２ -(4- to 6-membered heterocyclyl), -CH ２ -O-R ｚ -C(=O)R ｘ , and -CH ２ -NR ｘ R ｙ wherein said C is selected from １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, carbocyclyl and heterocyclyl groups are each formed by one or more R ｂ may be substituted with a group, and the R ｂ are each independently fluorine, C １－４ Alkyl, C ３－４ Alkynyl, phenyl, 5- to 6-membered heteroaryl, —O—C １－４ Alkyl, Fluoro C１－４ Alkyl, Fluoro C １－４ Alkoxy, hydroxy, and —NR ｘ R ｙ groups, wherein the phenyl and heteroaryl groups are selected from one or more R ｘ may be substituted with a group, and the R ｘ , R ｙ and R ｚ are each independently chlorine, fluorine, hydrogen, C １－４ Alkyl, and C １－４ alkoxy, when attached to a nitrogen or carbon, R ｘ and R ｙ may, together with the atom to which they are attached, form a 3- to 7-membered ring which may contain one additional heteroatom selected from O and N.

[0211] In one embodiment, R ９ is hydrogen.

[0212] In one embodiment, R １０ is hydrogen or methyl.

[0213] In one embodiment, R ｂ are each independently a halogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(4- to 7-membered saturated heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , —O—(CR ｘ R ｙ ) ｎ -OR ｚ , Halo C １－６ Alkyl, haloC １－６ Alkoxy, hydroxy C１－６ Alkyl, ═O, ═S, nitro, Si(Rx) ４ , -(CH ２ ) ｓ -CN, -S(O) ｑ -R ｘ , -C(=O)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ - (CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ , -(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ , -(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ , -(CH ２ )ｓ -NH-SO ２ -NR ｘ R ｙ , -(CH ２ ) ｓ -SO ２ NR ｘ R ｙ group and —P(═O)(R ｘ ) ２ wherein said C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl and heterocyclyl groups can be one or more R ｘ It may be substituted with a group.

[0214] In one embodiment, R ｘ , R ｙ and R ｚ are each independently a halogen, hydrogen, or C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(4- to 7-membered saturated heterocyclyl), hydroxy C optionally substituted with one or more halo １－６ Alkyl, —C(═O)OC １－６ Alkyl, hydroxy, C １－６ Alkoxy, HaloC １－６ Alkyl, -(CH ２ ) ｎ -O-C １－６ Alkyl, —C(═O)—(CH ２ ) ｎ -C １－６ Alkoxy, —C(═O)—C １－６ Alkyl, -(CH ２ ) ｓ -CN, C １－６ Alkyl-N(H)２－ｑ (C １－６ alkyl) ｑ , -N(H) ２－ｑ (C １－６ alkyl) ｑ , -C(=O)-N(H) ２－ｑ (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -NH-SO ２ -N(H) ２－ｑ (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -N(C １－４ (alkyl)-SO ２ -N(H) ２－ｑ (C １－６ alkyl) ｑ and -(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-N(H) ２－ｑ (C １－６ alkyl) ｑ and when attached to a nitrogen, carbon, silicon or phosphorus atom, R ｘ and R ｙ may, together with the atoms to which they are attached, form a 3- to 7-membered ring which may contain one or two additional heteroatoms selected from O, N, S, and oxidized forms of N and S.

[0215] In one embodiment, Y and W are each independently a bond, —(CR ｘ R ｙ ) ｍ -, -C(=CR ｘ )-, -C(=O)-, -NR ｘ , —C(═O)NR ｘ -, -NR ｘ C(=O)-,-(CR ｘ R ｙ ) ｑ -O-, -O-(CR ｘ R ｙ ) ｑ -, -S(O) ２ -NH,NH-S(O) ２ - or -S(O) ｑ - is.

[0216] In one embodiment of X in the above formula (A), A is N or CR ８ (preferably N), B is N, CR ９ , or C.L. ２ (Preferably CR ９ , or C.L. ２ ), Q is N, and R １ and L that is not used for bonding with L １ are each independently hydrogen or C １－６ alkyl (preferably methyl), wherein said C １－６ Alkyl is one or more —O—C １－２ optionally substituted with alkyl (preferably methoxy); R ２ａ and R ２ｂ is hydrogen, R ３ is C １－４ alkyl (preferably methyl), R ４ is hydrogen, R ５ａ and R ５ｂ are each independently １－４ alkyl (preferably methyl), R ６ is -CH ２ -phenyl, or (E represents a bonding point), which may be substituted with one or more halogen atoms (preferably fluorine atoms), R ７ is hydrogen, R ９ is hydrogen, and L １ ~L ３ and L ３ ', X is bonded to L.

[0217] L １ ~L ３ and L ３ Examples of the case where X is bonded to L in any one of the above formulae 1 and 2 include the following.

[0218] In one embodiment, compounds of formula (A) include the following compounds:

[0219] In one embodiment, the compounds of the present disclosure are compounds excluding compounds of the following formula: [where, X A represents N or CH, L is a linker, X is as defined above and is bonded to L at L1, R 1a H, -SO2C 1-4 Alkyl, -COC 1-4 Alkyl, or C 1-4 alkyl, and R 2b -SR aa , -SOR aa , -SO2R aa , -SO2NH2, or -SO2NR ab R ac where R aa is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl, wherein 1-6 Alkyl is cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 2-6 Alkoxy, -CO2H, -CO2C 1-4 Alkyl, -SO2C1-4Alkyl, C 3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 9- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, and (phenyl)(C 1-4and optionally substituted with one or two groups independently selected from the group consisting of: alkyl)amino-, 3-7 Cycloalkyl, phenyl, (phenyl)(C 1-4 alkyl)amino-, 5- to 6-membered heteroaryl, 9- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is selected from the group consisting of halogen, —CF3, hydroxyl, amino, (C 1-4 alkyl)amino-, (C 1-4 alkyl)( 　 C 1-4 Alkyl)amino-, C 1-4 Alkyl, Phenyl C 1-4 Alkyl-, hydroxy C 1-4 Alkyl, and C 1-4 alkoxy, wherein C is optionally substituted with 1 to 3 groups each independently selected from the group consisting of: 3-7 The cycloalkyl or 4- to 7-membered heterocycloalkyl is selected from the group consisting of halogen, —CF3, hydroxyl, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)(C 1-4 Alkyl)amino, C 1-4 Alkyl, Phenyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, oxo, and C 1-4 and optionally substituted with 1 to 3 groups each independently selected from the group consisting of alkoxy, wherein said aryl or heteroaryl is selected from the group consisting of halogen, —CF3, hydroxyl, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)(C 1-4 Alkyl)amino, C 1-4 Alkyl, Phenyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, and C 1-4 optionally substituted with 1 to 3 groups each independently selected from the group consisting of alkoxy; R ab is C 1-6 alkyl or 4- to 7-membered heterocycloalkyl, wherein 1-6 Alkyl is hydroxyl, C 1-6Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, -CO2H, -CO2C 1-4 Alkyl, (C 1-4 alkyl)amino, (C 1-4 Alkyl)(C 1-4 and optionally substituted with one or two groups each independently selected from the group consisting of alkyl), amino, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein said 5- to 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl is selected from the group consisting of halogen, C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, and C 1-4 and wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with 1 to 3 groups each independently selected from the group consisting of hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxycarbonyl, Hydroxy C 1-4 Alkyl, oxo, and C 1-4 optionally substituted with 1 to 3 groups each independently selected from the group consisting of alkoxy; R ac is H, C 1-4 Alkoxy or C 1-6 alkyl, or R ab and R ac together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl group, optionally containing one or two additional ring heteroatoms each independently selected from nitrogen and oxygen, wherein said 3- to 7-membered heterocycloalkyl is 1-4 Alkyl, hydroxy, -COH, and -COC 1-4 optionally substituted with 1 to 3 groups each independently selected from the group consisting of alkyl; Z A is a phenyl or aryl C 1-4 alkyl-, where phenyl or arylC 1-4 The aryl portion of the alkyl-group is R 4a , R 5a , R 6a , and R 7awhere R 4a is H, halogen, cyano, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, phenoxy, phenyl C 1-4 Alkoxy, Hydroxyl, Hydroxy C 1-4 alkyl-, or aminocarbonyl, wherein the phenoxy or phenyl C 1-4 The phenyl portion of the alkoxy is halogen, -CF3, C 1-4 Alkyl, and C 1-4 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkoxy; R 5a , R 6a , and R 7a Each of these is H, hydroxyl, halogen, -CF3, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, and C 1-4 alkoxy; or Z A is R 8a , R 9a , and R 10a phenyl or pyridyl substituted with R 8a and R 9a are located on adjacent atoms and together with the atoms to which they are attached form a five-membered ring containing one, two, or three heteroatoms each independently selected from N, O, and S, and the five-membered ring is 11a where R 10a or R 11a One of the groups is H, halogen, cyano, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, phenoxy, phenyl C 1-4 Alkoxy, Hydroxyl, Hydroxy C 1-4 alkyl-, or aminocarbonyl, wherein the phenoxy or phenyl C 1-4 The phenyl portion of the alkoxy is halogen, -CF3, C 1-4 Alkyl, and C 1-4optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkoxy; R 10a or R 11a The other is H, hydroxyl, halogen, -CF3, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, or C 1-4 Alkoxy; or Z A is the expression: (In the formula, indicates the attachment point, and R 12a is H, methyl, or hydroxymethyl, and R 13a is methyl, trifluoromethyl, or hydroxymethyl, and R 14a is H, OH, or C 1-3 alkyl, or R 12a and R 13a together with the atoms to which they are attached, R 15a and R 16a wherein the six-membered ring optionally contains one nitrogen atom, and wherein R 15a and R 16a is H, halogen, cyano, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, phenoxy, phenyl C 1-4 Alkoxy, Hydroxyl, Hydroxy C 1-4 alkyl-, and aminocarbonyl, wherein the phenoxy or phenyl C 1-4 The phenyl portion of the alkoxy is halogen, -CF3, C 1-4 Alkyl, and C 1-4 and each independently represents a group consisting of alkoxy.

[0220] X in the present disclosure may have a substituent represented by any of the following:

[0221] R in Tables A and B ｂAlkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl and is one or more R ｂ In addition, L in Tables A and B means that X is bonded to the linker L at that point (in Tables A and B, L １ , L ２ , L ３ , L ３ It exists in the ' column. １ , L １ , R ２ａ and R ２ｂ , R ３ , R ４ , R ５ａ , R ５ｂ , R ６ , R ７ , A, B, Q, R ｂ , R ｘ , R ｙ , R ｚ , L ３ , L ３ ') = (R １（ＡＸ） , L １（ＢＸ） , R ２（ＣＸ） , R ３（ＤＸ） , R ４（ＥＸ） , R ５ａ（ＦＸ） , R ５ｂ（ＧＸ） , R ６（ＨＸ） , R ７（ＩＸ） , A （ＪＸ） , B （ＫＸ） , Q （ＬＸ） , R ｂ （ＭＸ） , R ｘ （ＮＸ） , R ｙ （ＯＸ） , R ｚ （ＰＸ） , L ３（ＱＸ） , L ３ ' （ＲＸ） ) and represents any combination of substituents. Here, each independently represents an integer of 1 to 11, BX represents an integer of 1 to 12, CX represents 1, DX represents an integer of 1 to 4, EX represents 1, FX represents an integer of 1 to 3, GX represents an integer of 1 to 3, HX represents an integer of 1 to 11, IX represents an integer of 1 to 2, JX represents an integer of 1 to 2, KX represents an integer of 1 to 10, LX represents an integer of 1 to 2, MX represents an integer of 1 to 16, NX represents an integer of 1 to 7, OX represents an integer of 1 to 7, PX represents an integer of 1 to 6, QX represents an integer of 1 to 4, and RX represents an integer of 1 to 4, for example, R １（ＡＸ） is R in Table A above１ where the substituent is R ｂ When not substituted with a group, MX is 1 and R ｘ If no exists, NX is 1 and R ｙ is not present, OX is 1, and R Ｚ If there is no ３ , L ３ When "Q" is not present, QX and RX are 1, indicating that each substituent is absent. Here, there is only one linker L per compound.

[0222] In one aspect, there is provided a process for producing the compounds of the present disclosure, the process comprising: (a) reacting a compound of formula (III) (In the formula, A, B, R ５ａ , R ５ｂ , R ６ , R ７ is as defined in the present disclosure) with a compound of formula (IV): (In the formula R ４ is as defined in this disclosure, and L Ａ and L Ｂ each represents a leaving group), followed by reaction with a compound of formula (V): (In the formula R １ , R ２ａ , R ２ｂ , R ３ is as defined in this disclosure, and L １ is L that is not used to bond with L １ and P １ represents hydrogen or a protecting group), followed by the following reaction with a compound of formula P １carrying out a deprotection reaction suitable for removing the protecting group to produce X of the present disclosure; and / or (b) (i) reacting Z of the present disclosure with L of the present disclosure to produce Z-L, and reacting said Z-L with said X to produce a compound of formula (I), (ii) reacting X of the present disclosure with L of the present disclosure to produce X-L, and reacting said X-L with said Z to produce a compound of formula (I); and / or (iii) reacting Z of the present disclosure with La, which is part of L of the present disclosure, to produce Z-La, and reacting X of the present disclosure with Lb, which is the remaining part of said L, to produce X-Lb, and reacting said Z-La with said X-Lb to produce a compound of formula (I). In cases other than when Q=N, a person skilled in the art can prepare the compounds of the present disclosure using an appropriate synthetic method based on the common general technical knowledge in the field (see Argiriadi, Maria A. et al., WO2016198908 A1; Smith, Aaron C. et al., J. Org. Chem. (2016), 81(9); 3509-3519; Thompson, Wayne J. et al., US5756508 A).

[0223] In one aspect, the compounds of the present disclosure have the formula: or an isomer thereof, or a salt thereof, wherein R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ａ , R ５ｂ , A, B, R ６ , R ７ is as defined above, and X １ , X ２ , X ３ represents a halogen atom or a leaving group, PG １ represents a suitable protecting group such as a tert-butoxycarbonyl (Boc) group, and PG ２ represents a suitable protecting group such as a tert-butyldiphenylsilyl (TBDPS) group, and PG ３represents a suitable protecting group such as a benzyl group; RG represents a reactive functional group such as a halogen atom or a leaving group, a hydroxyl group, an amino group, a carboxyl group, an amide group, or a sulfonamide group; L, La, and Lb represent linkers; and Z represents a ligand moiety that specifically binds to an intracellular protein.

[0224] The compounds of the present disclosure will be further described below. Depending on the type of substituent, the compounds of the present disclosure may exist as stereoisomers such as tautomers and geometric isomers, and optical isomers, and these are also included in the present disclosure. That is, when the compounds of the present disclosure have one or more asymmetric carbon atoms, diastereomers and optical isomers exist, and mixtures and isolated forms of these diastereomers and optical isomers are also included in the compounds of the present disclosure.

[0225] The present disclosure is also intended to encompass various hydrates, solvates and crystalline polymorphs.

[0226] Additionally, compounds of the present disclosure may contain isotopes, e.g., ２ H (or D), ３ H (or T), １１ C. １３ C. １４ C. １３ N. １５ N. １５ O. ３５ S. １８ F. １２５ I, etc.), and these compounds are also included in the compounds of the present disclosure.

[0227] Furthermore, the scope of the present disclosure also includes prodrugs of the compounds of the present disclosure. In the present disclosure, a prodrug refers to a derivative that is hydrolyzed by acid or enzymatically in vivo to give a compound represented by the above formula A and its related structural formulas. For example, when the compound represented by the above formula A and its related structural formulas has a functional group such as a hydroxyl group, an amino group, or a carboxyl group or other substituent, a prodrug can be produced by modifying these groups according to conventional methods. For more information on prodrug technology, see, for example, C.G. Wermuth, "The Practice of Medicinal Chemistry," 4 thEd., Academic Press, (2015), Chapter 28.

[0228] For example, in the case of a compound having a carboxyl group, the carboxyl group may be replaced by an alkoxycarbonyl group, an alkylthiocarbonyl group, or an alkylaminocarbonyl group.

[0229] Furthermore, for example, in the case of a compound having an amino group, examples include a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, a compound in which the amino group is substituted with an alkoxycarbonylamino group, a compound in which the amino group is substituted with an alkanoyloxymethylamino group, or a compound in which the amino group is hydroxylamine.

[0230] Further, for example, in the case of a compound having a hydroxyl group, examples include a compound in which the hydroxyl group is substituted with the above-mentioned alkanoyl group to form an alkanoyloxy group, a compound which is a phosphate ester, or a compound which is an alkanoyloxymethyloxy group.

[0231] The alkyl moiety of the group used for making these prodrugs includes the above-mentioned alkyl groups, and the alkyl group may be substituted with, for example, an alkoxy group, etc. Preferred examples include the following:

[0232] For example, examples of compounds in which a carboxyl group is an alkoxycarbonyl group include alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, and alkoxycarbonyl substituted with an alkoxy group such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, or pivaloyloxymethoxycarbonyl.

[0233] Z in the above formula (A) is a ligand moiety that specifically binds to an intracellular protein and has inhibitory or binding activity to the intracellular protein. The intracellular protein represented by Z in the above formula (A) can be a kinase or a non-kinase. The abbreviations for kinase and non-kinase used in this disclosure are shown below.

[0234] Serine / threonine kinases, receptor tyrosine kinases, and non-receptor tyrosine kinases that may be covered by the present disclosure include the Akt / PKB family (AKT1, AKT2, AKT3), PDK1, PKA, PKC, PKG, ROCK (ROCK1, ROCK2), RSK family (RSK1, RSK2, RSK3, RSK4), SGK family (SGK1, SGK2, SGK3), AMPK, CaMK family (CaMK1, CaMK2, CaMK4), Chk (ChK1, ChK2), DAPK family (DAPK1, DAP K2, DAPK3), MK2 (MAPKAP2, MAPKAP), MLCK (MYLK1, MYLK2, MYLK3, MYLK4), MNK, PI family (PIM1, PIM2), PKD, CK1, TTBK (TTBK1), VRK family (VRK1), CDK family (CDK1-9, CDK11-14, CDK16, CDK19), CK2, CLK family (CLK1, CLK2, CLK3, CLK4), ERK family (ERK1, ERK2, ERK5, ERK7, ERK8), GSK3, JNK / c-Jun, p38 MAPK, DYRK family (DYRK1, DYRK2, DYRK3), HIPK, ASK family (ASK1, ASK2, ASK3), MEK family (MEK1, MEK2), PAK family (PAK1, PAK2, PAK3, PAK4, PAK5, PAK6), MST family (MST1, MST2, MST4), HPK1, BMP family and other activin receptors (BMPR1A, BMPR1B, BMPR 2, ALK1, ALK2, ALK3, ALK4, ALK5), LRRK2, RAF family (A-RAF, B-RAF, RAF1), RIP family (RIP1, RIP2, RIP3), TAK1, TGF-β receptor, IRAK family (IRAK1, IRAK2, IRAK3, IRAK4), MLK family (MLK1, MLK2, MLK3, MLK4), LIMK family (LIMK1, LIMK2), Aurora Kinase, CaMKK, IKK (IKK-1, IKK-2), Mps1, PLK family (PKK1, PLK2, PLK3, PLK4, PLK5), ATM, DNA-PK, mTOR (mTORC1, mTORC2), ILK, NEK family (NEK2, 3, 6,7, 11), TNNI3K, Wee1, TBK1, MST1R, epidermal growth factor receptor family (EGFR, RBB1, ERBB2, ERBB3, ERBB4), insulin receptor family (INSR, IGF-1R, INSRR), platelet-derived growth factor receptor family (PDGFRα, PDGFRβ, CSF1R, FLT1, FLT3, FLT4, KIT), vascular endothelial growth factor receptor family (VEGFR1, VEGF2, VEGF3, VEGFR4, soluble VEGFR1, soluble VEGFR2, soluble VEG FR3), fibroblast growth factor receptor family (FGFR1, FGFR2, FGFR3, FGFR4), CCK family, nerve growth factor receptor family (MET or c-MET, RON), hepatocyte growth factor receptor family, Eph receptor family (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6), AXL receptor family (AXL, MER, TYRO3), TIE Receptor family (TIE, TEK), RYK receptor family (RYK), DDR receptor family (DDR1, DDR2), RET receptor family, ROS receptor family (ROS1), LTK receptor family (LTK, ALK), ROR receptor family (ROR1, ROR2), MuSK receptor family (MUSK), LRM receptor family (LMTK2, LMTK3), TRKA, TRKB, PTK7, NTRK1, NTRA2, NTRK3, RYK, TYRP3, STYK1, ABL family (ABL1, ARG), ACK family (ACK1, TNK1), CSK family (CSK, MATK), FAK family (FAK, PYK2), FES family (FES, FER), FRK family (FRK, BRK, SRMS), JAK family (JAK1, JAK2, JAK3, TYRK2), SRC family (SRC, YES1, FYN, FGR, LYN, LCK, HCK, BLK), TEC family (TEC, BMX, BTK, ITK, TXK), SYK family (SYK, ZAP70). Examples of ligand structures for representative kinases are shown in Table 1.

[0235] Serine / threonine kinases that may be covered by the present disclosure include Akt / PKB (AKT1, AKT2, AKT3), PDK1, PKA, PKC, PKG, ROCK (ROCK1, ROCK2), RSK (RSK1, RSK2, RSK3, RSK4), SGK (SGK1, SGK2, SGK3), AMPK, CaMK (CaMK1, CaMK2, CaMK4), Chk (ChK1, ChK2), DAPK (DAPK1, DAPK2, DAPK3), MK2 (MAPK1, DAPK2, DAPK3), and PK3 (MAPK4). PKAP2, MAPKAP), MLCK (MYLK1, MYLK2, MYLK3, MYLK4), MNK, PIM (PIM1, PIM2), PKD, CK1, TTBK (TTBK1), VRK (VRK1), CDK (CDK1) -9, CDK11-14, CDK16, CDK19), CK2, CLK (CLK1, CLK2, CLK3, CLK4), ERK (ERK1, ERK2, ERK5, ERK7, ERK8), GSK3, JNK / c-Jun, p38 MAPK, DYRK (DYRK1, DYRK2, DYRK3), HIPK, ASK (ASK1), MEK (MEK1, MEK2), PAK (PAK1, PAK2, PAK3, PAK4, PAK5, PAK6), MST (MST1, MST2, MST4), HPK1, BMP and other activin receptors (BMPR1A, BMPR1B, BMPR2, ALK1, ALK2, ALK3, ALK4, ALK5), LRRK2, RAF (A-RAF, B-RAF, RAF1), RIP (RIP1, RIP2, RIP3), TAK1, TGF-b receptor body, IRAK (IRAK1, IRAK2, IRAK3, IRAK4), MLK (MLK1, MLK2, MLK3, MLK4), LIMK (LIMK1, LIMK2), Aurora Kinase, CaMKK, IKK (IKK-1, IKK-2), Mps1, PLK (PKK1, PLK2, PLK3, PLK4, PLK5), ATM, DNA-PK, mTOR (mTORC1, mTORC2), ILK, NEK (NEK2, 3, 6, 7, 11), TNNI3K, Wee1, TBK1, and MST1R.

[0236] In one embodiment, serine / threonine kinases include, but are not limited to: <AGC Group> Akt / PKB (AKT1, AKT2, AKT3), PDK1, PKA, PKC, PKG, ROCK (ROCK1, ROCK2), RSK (RSK1, RSK2, RSK3, RSK4), SGK (SGK1, SGK2, SGK3) <CAMK Group> AMPK, CaMK (CaMK1, CaMK2, CaMK4), Chk (ChK1, ChK2), DAPK (DAPK1, DAPK2, DAPK3), MK2 (MAPKAP2, MAPKAP), MLCK (MYLK1, MYLK2, MYLK3, MYLK4), MNK, PIM (PIM1, PIM2), PKD <CK1 Group> CK1, TTBK (TTBK1), VRK (VRK1) <CMGC group> CDK (CDK1-9, CDK11-14, CDK16, CDK19), CK2, CLK (CLK1, CLK2, CLK3, CLK4), ERK (ERK1, ERK2, ERK5, ERK7, ERK8), GSK3, JNK / c-Jun, p38 MAPK, DYRK (DYRK1, DYRK2, DYRK3), HIPK <STE group> ASK (ASK1, ASK2, ASK3), MEK (MEK1, MEK2), PAK (PAK1, PAK2, PAK3, PAK4, PAK5, PAK6), MST (MST1, MST2, MST4), HPK1 <TKL Group> BMP and other activin receptors (BMPR1A, BMPR1B, BMPR2, ALK1, ALK2, ALK3, ALK4, ALK5), LRRK2, RAF (A-RAF, B-RAF, RAF1), RIP (RIP1, RIP2, RIP3), TAK1, TGF-β receptor, IRAK (IRAK1, IRAK2, IRAK3, IRAK4), MLK (MLK1, MLK2, MLK3, MLK4), LIMK (LIMK1, LIMK2) <Other serine-threonine kinases> Aurora Kinase, CaMKK, IKK (IKK-1, IKK-2), Mps1, PLK, ATM, DNA-PK, mTOR, ILK, NEK (NEK2, 3, 6, 7, 11), TNNI3K, Wee1, TBK1, MST1R

[0237] Receptor tyrosine kinases that may be covered by the present disclosure include the epidermal growth factor receptor family (EGFR, RBB1, ERBB2, ERBB3, ERBB4), the insulin receptor family (INSR, IGF-1R, INSRR), the platelet-derived growth factor receptor family (PDGFRα, PDGFRβ, CSF1R, FLT1, FLT3, FLT4, KIT), the vascular endothelial growth factor receptor family (VEGF R1, VEGF2, VEGF3, VEGFR4, soluble VEGFR1, soluble VEGFR2, soluble VEGFR3), fibroblast growth factor receptor family (FGFR1, FGFR2, FGFR3, FGFR4), CCK family, nerve growth factor receptor family (MET or c-MET, RON), hepatocyte growth factor receptor family, Eph receptor family (EPHA1, EPHA2, EPH A3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6), AXL receptor family (AXL, MER, TYRO3), TIE receptor family (TIE, TEK), RYK receptor family (RYK), DDR receptor family (DDR1, DDR2), RET receptor family, ROS receptor family These include, but are not limited to, RI (ROS1), LTK receptor family (LTK, ALK), ROR receptor family (ROR1, ROR2), MuSK receptor family (MUSK), LRM receptor family (LMTK2, LMTK3), and other receptor tyrosine kinases (TRKA, TRKB, PTK7, NTRK1, NTRA2, NTRK3, RYK, TYRP3, STYK1).

[0238] Non-receptor tyrosine kinases that may be covered by the present disclosure include, but are not limited to, the ABL family (ABL1, ARG), the ACK family (ACK1, TNK1), the CSK family (CSK, MATK), the FAK family (FAK, PYK2), the FES family (FES, FER), the FRK family (FRK, BRK, SRMS), the JAK family (JAK1, JAK2, JAK3, TYRK2), the SRC family (SRC, YES1, FYN, FGR, LYN, LCK, HCK, BLK), the TEC family (TEC, BMX, BTK, ITK, TXK), and the SYK family (SYK, ZAP70).

[0239] In one embodiment, protein kinases include, but are not limited to, CDK2, CDK4, CDK6, CDK8, CDK9, CDK12, TRK, BTK, FAK, epidermal growth factor receptor family, TGF-β receptor, ABL1, p38 MAPK, JAK2, c-MET, ALK, Wee1, Akt, MEK (MEK1, MEK2), Mps1, Aurora Kinase, SGK3, TBK1, FLT3, LRRK2, RIP1, RIP2, and HPK1.

[0240] In one embodiment, protein kinases include, but are not limited to, FAK, ROCK (ROCK1, ROCK2), TGF-b receptor, platelet-derived growth factor receptor family, fibroblast growth factor receptor family, vascular endothelial growth factor receptor family, epidermal growth factor receptor family, SYK, PIM2, and ALK5.

[0241] Non-kinases that may be of interest to the present disclosure include muscarinic acetylcholine receptors, adenosine receptors, adrenergic receptors, GABA receptors, angiotensin receptors, cannabinoid receptors, cholecystokinin receptors, dopamine receptors, orexin receptors, glucagon receptors, histamine receptors, olfactory receptors, opioid receptors, rhodopsin receptors, secretin receptors, serotonin receptors, somatostatin receptors, gastrin receptors, P2Y receptors, chemokine receptors, potassium channels, sodium channels, calcium channels, chloride channels, cation channels, and the like. IL-2 receptor, IL-3 receptor, IL-4 receptor, IL-5 receptor, IL-6 receptor, IL-7 receptor, IL-9 receptor, IL-11 receptor, IL-12 receptor, IL-13 receptor, IL-15 receptor, granulocyte-macrophage colony-stimulating factor receptor, human granulocyte-colony-stimulating factor receptor, erythropoietin receptor, thrombopoietin receptor, leukemia inhibitory factor receptor, oncostatin M receptor, ciliary neurotrophic factor receptor, growth hormone receptor, leptin receptor, interferon receptor, IL-10 receptor, tumor necrosis factor receptor, Fas receptor Gand receptor, CD40L receptor, inhibin receptor, IL-8 receptor, IL-16 receptor, eotaxin receptor, RANTES receptor, IL-1 receptor, epidermal growth factor, insulin-like growth factor, transforming growth factor, basic fibroblast growth factor, nerve growth factor, brain-derived neurotrophic factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, platelet-derived growth factor, erythropoietin, thrombopoietin, hepatocyte growth factor, ligand-binding ion channel, voltage-gated ion channel, phosphorylation-gated ion channel Nel, thermosensor ion channel, force-sensor ion channel, ion pump, ABC transporter, secondary active transporter, thyroid hormone receptor, retinoic acid receptor, peroxisome proliferator-activated receptor, Rev-ErbA, RAR-related orphan receptor, liver X receptor, farnesoid X receptor, vitamin D receptor, pregnane X receptor, constitutive adrenoceptor, hepatocyte nuclear factor 4, retinoid X receptor, TXL / PNR, avian ovalbumin upstream promoter transcription factor, V-erbA-related protein, estrogen receptor, estrogen-related receptor,Glucocorticoid receptor, mineralocorticoid receptor, progesterone receptor, androgen receptor, nerve growth factor IB, nuclear receptor-related 1 protein, neural-derived orphan receptor 1, steroidogenic factor 1, liver receptor homolog 1, germ cell nuclear factor, DAX1, SHP, PPARγ, CD45, DUSP, HEPTP, LMPTPA, LMPTPB, PP1a, P P1b, PP2A, PP1B, PTPb, PTPMRG1, PTPMEG2, SHP1, SHP2, TCPTP, VHR, YopH, ADAM10, collagenase, MMP-2, MMP-8, MMP-9, MMP-12, MMP-13, caspase (1-12), cathepsin (B, C, F, H, K, L, O, S, V, W, X), HTRA1, histone acetyltransferase These include, but are not limited to, transferases, histone deacetylases, bromodomain proteins, lysine methyltransferases (DOT1L, EZH2), lysine demethylases, methylated lysine-binding proteins, signal transducers and activators of transcription, BAF, CDC20, MYC, PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, PDE11, ubiquitin, ubiquitin-like proteins, DUB, BCL2, BCL6, BRCA1, BRCA2, FANCA, FANCD2, FANCE, Her3, and heat shock proteins, amyloid beta, alpha synuclein, tau protein, huntingtin protein, TPD-43, intracellular retinoic acid-binding protein, TACC3, and parkin.

[0242] Examples of the structures of non-kinase protein ligands are shown in Table 2.

[0243] In one embodiment, non-kinases include, but are not limited to, the following: <G protein-coupled receptors (GPCRs)> muscarinic acetylcholine receptors, adenosine receptors, adrenergic receptors, GABA receptors, angiotensin receptors, cannabinoid receptors, cholecystokinin receptors, dopamine receptors, orexin receptors, glucagon receptors, histamine receptors, olfactory receptors, opioid receptors, rhodopsin receptors, secretin receptors, serotonin receptors, somatostatin receptors, gastrin receptors, P2Y receptors, chemokine receptors <Ion channels> potassium channels, sodium channels, calcium channels, chloride channels, cation channels <Cytokine receptors> IL-2 receptor, IL-3 receptor, IL-4 receptor, IL-5 receptor, IL-6 receptor, IL-7 receptor, IL-9 receptor, IL-11 receptor, IL-12 receptor, IL-13 receptor, IL-15 receptor, granulocyte-macrophage colony-stimulating factor receptor, human granulocyte-colony-stimulating factor receptor, erythropoietin receptor, thrombopoietin receptor, leukemia inhibitory factor receptor, oncostatin M receptor, ciliary neurotrophic factor receptor, growth hormone receptor, leptin receptor, interferon receptor, IL-10 receptor, tumor necrosis factor receptor, Fas ligand receptor, CD40L receptor, inhibin receptor, IL-8 receptor, IL-16 receptor, eotaxin receptor, RANTES receptor, IL-1 receptor <Growth factors and their receptors> Epidermal growth factor, insulin-like growth factor, transforming growth factor, basic fibroblast growth factor, nerve growth factor, brain-derived neurotrophic factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, platelet-derived growth factor, erythropoietin, thrombopoietin, hepatocyte growth factor <Transporters> Ligand-binding ion channels, voltage-gated ion channels, phosphorylation-gated ion channels, temperature-sensor ion channels, force-sensor ion channels, ion pumps, ABC transporters, secondary active transporters <Nuclear receptors and their ligands>Thyroid hormone receptor, retinoic acid receptor, peroxisome proliferator-activated receptor, Rev-ErbA, RAR-related orphan receptor, liver X receptor, farnesoid X receptor, vitamin D receptor, pregnane X receptor, constitutive adrstane receptor, hepatocyte nuclear factor 4, retinoid X receptor, TXL / PNR, avian ovalbumin upstream promoter transcription factor, V-erbA-related protein, estrogen receptor, estrogen-related receptor, glucocorticoid receptor, mineralocorticoid receptor, progesterone receptor, androgen receptor, nerve growth factor IB, nuclear receptor-related 1 protein, neural-derived orphan receptor 1, steroidogenic factor 1, liver receptor homolog 1, germ cell nuclear factor, DAX1, SHP, PPARγ <Phosphatase> CD45, DUSP, HEPTP, LMPTPA, LMPTPB, PP1a, PP1b, PP2A, PP1B, PTPb, PTPMRG1, PTPMEG2, SHP1, SHP2, TCPTP, VHR, YopH <Proteases> ADAM10, collagenase, MMP-2, MMP-8, MMP-9, MMP-12, MMP-13, caspase (1-12), cathepsin (B, C, F, H, K, L, O, S, V, W, X), HTRA1 <Epigenic proteins and enzymes> Histone acetyltransferase, histone deacetylase, bromodomain protein, lysine methyltransferase (DOT1L, EZH2), lysine demethylase, methylated lysine-binding protein, signal transducer and activator of transcription, BAF, CDC20, MYC <phosphodiesterase> PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, PDE11 <ubiquitin-related proteins, central nervous system-related proteins, and oncogene-related proteins> Ubiquitin, ubiquitin-like protein, DUB, BCL2, BRCA1, BRCA2, FANCA, FANCD2, FANCE, Her3, heat shock protein, amyloid beta, α-synuclein, tau protein, huntingtin protein, TPD-43, intracellular retinoic acid binding protein, TACC3, parkin

[0244] In one embodiment, non-kinases include, but are not limited to, estrogen receptor, androgen receptor, histone acetyltransferase, bromodomain protein, lysine methyltransferase, phosphodiesterase, BCL2, BCL6, signal transducer and activator of transcription, alpha-synuclein, tau protein, huntingtin protein, intracellular retinoic acid binding protein, TACC3, CDC20, and MYC.

[0245] In one embodiment, the non-kinase is a chemokine receptor, a sodium channel, an epidermal growth factor, an insulin-like growth factor, a transforming growth factor, a basic fibroblast growth factor, a nerve growth factor, a brain-derived neurotrophic factor, a vascular endothelial growth factor, a granulocyte colony-stimulating factor, a granulocyte-macrophage colony-stimulating factor, a platelet-derived growth factor, a hepatocyte growth factor, an IL-2 receptor, an IL-3 receptor, an IL-4 receptor, an IL-5 receptor, an IL-6 receptor, an IL-7 receptor, an IL-9 receptor, an IL-11 receptor, an IL-12 receptor, an IL-13 receptor, an IL-15 receptor, a granulocyte-macrophage colony-stimulating factor receptor, a human granulocyte colony-stimulating factor receptor, a leukemia inhibitory factor receptor, an interferon receptor, an IL-10 receptor, a tumor necrosis factor receptor , Fas ligand receptor, CD40L receptor, IL-8 receptor, RANTES receptor, IL-1 receptor, estrogen receptor, androgen receptor, thyroid hormone receptor, caspases, histone acetyltransferases, histone deacetylases, bromodomain proteins, lysine methyltransferases, lysine demethylases, methylated lysine-binding proteins, PDE3, PDE4, PDE5, PDE11, ubiquitin, ubiquitin-like proteins, DUB, BCL2, BCL6, BRCA1, BRCA2, FANCA, FANCD2, FANCE, Her3, and heat shock proteins, PPARγ, signal transducer and activator of transcription, intracellular retinoic acid-binding protein, BAF, CDC20, MYC, TACC3.

[0246] In one embodiment, proteins include, but are not limited to, chemokine receptors, vitamin D receptors, phosphodiesterases, and heat shock proteins, signal transducers and activators of transcription.

[0247] The embodiments of Z in the above formula (A) are as follows.

[0248] In one embodiment, the intracellular protein in Z may be a serine / threonine kinase, a receptor tyrosine kinase, or a non-receptor tyrosine kinase.

[0249] One embodiment of the intracellular protein in Z is a serine / threonine kinase, which may be selected from the group consisting of the AGC group, the CAMK group, the CK1 group, the CMGC group, the STE group, the TKL group, and other serine / threonine kinases. Here, the serine / threonine kinase may be the AGC group, and the AGC group may be ROCK2. Examples of ligand moieties that specifically bind to ROCK2 include: Examples include:

[0250] One embodiment of the intracellular protein in Z is a receptor tyrosine kinase, which may be selected from the group consisting of the epidermal growth factor receptor family, insulin receptor family, platelet-derived growth factor receptor family, vascular endothelial growth factor receptor family, fibroblast growth factor receptor family, CCK family, nerve growth factor receptor family, hepatocyte growth factor receptor family, Eph receptor family, AXL receptor family, TIE receptor family, RYK receptor family, DDR receptor family, RET receptor family, ROS receptor family, LTK receptor family, ROR receptor family, MuSK receptor family, LMR receptor family, and other receptor tyrosine kinases. Here, the receptor tyrosine kinase may be the LTK receptor family, and the LTK receptor family may be ALK. Examples of ligand moieties that specifically bind to ALK include: Examples include:

[0251] One embodiment of the intracellular protein in Z is a non-receptor tyrosine kinase, which may be selected from the group consisting of the ABL family, the ACK family, the CSK family, the FAK family, the FES family, the FRK family, the JAK family, the SRC family, the TEC family, and the SYK family. Here, the non-receptor tyrosine kinase may be the FAK family, and the FAK family may be FAK. Examples of the ligand moiety that specifically binds to FAK include: Examples include:

[0252] The linker (L) is represented by the formula (L1): -B-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 wherein each B independently represents the following structural formula: a group represented by *-O-*, *-NR 06 -* (where R 06 is a hydrogen atom or C １－６ It is an alkyl group.) *-CO ２ -*, *-CO-*, *-SO ２ -*, optionally substituted C １－６ Alkylene group, optionally substituted C ２－６ Alkenylene group, optionally substituted C ２－６ Alkynylene group, optionally substituted C ３－１０ Cycloalkylene group, optionally substituted C ６－１４ represents an arylene group or a bond, and L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are each independently represented by the following structural formula: (wherein m represents an integer of 1 to 4, n represents an integer of 1 to 4, and each A independently represents N, CHCO, or CHCHO) 1 ~L 7Three or more of these cannot have this structure.), bond, oxygen atom, sulfur atom, C １－６ Alkylene group, C ３－１０ Cycloalkylene group, carbonyl group, C １－６ an imino group optionally substituted with an alkyl group, an ethynylene group, C １－６ a vinylene group optionally substituted with an alkyl group, C ３－１０ a cycloalkenylene group, a phenylene group, a thiazolyldiyl group, an optionally substituted C １－６ a non-aromatic heterocyclic group optionally substituted with an alkyl group or a halogen atom, an optionally substituted C １－６ a piperazinediyl group optionally substituted by an alkyl group, an optionally substituted C １－６ a piperidinediyl group which may be substituted with an alkyl group or a fluorine atom, a pyrrolidinediyl group which may be substituted with a fluorine atom, an optionally substituted C １－６ A morpholinediyl group optionally substituted with an alkyl group, an azetidinediyl group optionally substituted with a fluorine atom, a group of the formula -SO2-, -CH2CH2O-, -OCH2CH2-, -COCH2-, -CH2CO-, -CO2-, -OCO-, and -COCHR 101 NR 102 -, formula -OCH2CHR 103 NR 104 -, formula -NR 105 CHR 106 CO-, formula-NR 107 CO-, formula-CONR 108 -, formula -SO2NR 109 -, formula -NR 110 SO2-, or formula -NR 111 CHR 112 CH2O− (R in the above formula 101 , R 103 , R 106 , and R 112 are each independently a hydrogen atom, C １－６R represents an alkyl group, a 3-guanidinopropyl group, a carbamoylmethyl group, a carboxymethyl group, a mercaptomethyl group, a 2-carbamoylethyl group, a 2-carboxyethyl group, an imidazol-4-ylmethyl group, a 4-aminobutyl group, a 2-methylthioethyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, an indol-3-ylmethyl group, a 4-hydroxyphenylmethyl group, or a pyridylmethyl group; 102 , R 104 , R 105 , R 107 , R 108 , R 109 , R 110 , and R 111 are each independently a hydrogen atom or C １－６ represents an alkyl group. ) or together represent one bond. ) where * indicates the point of attachment.

[0253] B has the following structural formula: a group represented by *-O-*, *-NR 06 -* (where R 06 is a hydrogen atom or a C1-6 alkyl group.), *-CO-*, an optionally substituted C1-6 alkylene group, an optionally substituted C ６－１４ It is an arylene group, an optionally substituted C2-6 alkynylene group, or a bond.

[0254] The linker (L) has the structural formula: (where * indicates a bond to X or Z), *-(CH2CH2O)n(CH2)m(NRCO)s(CH2)t-* (where n is an integer of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or C １－６ It represents an alkyl group.) or a bond, where and indicates a point of attachment; m, n, o, p, q, r, s, t, and u are each independently 0, 1, 2, 3, 4, 5, or 6, and even when the number is 0, the N-O and O-O bonds are absent; each R in each occurrence is independently hydrogen, methyl, and ethyl; X is H or F; and W Ｌ１ and W Ｌ１ are independently a 4- to 8-membered ring having 0-4 heteroatoms, a 4- to 8-membered ring optionally substituted with RQ (each RQ is independently H, halo, OH, CN, CF3), an optionally substituted straight or branched C １－６ Alkyl, optionally substituted straight or branched C １－６ Alkoxy, or two RQ groups together with the atoms to which they are attached, may form a 4-8 membered ring having 0-4 heteroatoms, and Y Ｌ１ are independently a bond, an optionally substituted straight-chain or branched C, optionally with one or more C replaced by O, １－６ Alkyl or optionally substituted straight or branched chain C １－６ It is an alkoxy.

[0255] (Medicines, treatments, etc.) General explanation

[0256] In one embodiment, the compounds of the present disclosure can be administered orally or parenterally, either directly or in the form of a formulation, medicament, or pharmaceutical composition using an appropriate dosage form. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These formulations can be manufactured by known methods using additives commonly used as pharmaceutical additives.

[0257] Depending on the purpose, these additives may include excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0258] In one embodiment, the compound of the present disclosure is a compound having target protein modulating activity, and has inhibitory activity or binding activity against a target protein.

[0259] The administration timing of the compounds of the present disclosure and the therapeutic agents thereof is not limited, and they may be administered to the subject simultaneously or at different times. The compounds of the present disclosure and the therapeutic agents may also be combined. The dosage of the therapeutic agents may be appropriately selected based on the clinically used dose. The compounding ratio of the compounds of the present disclosure and the therapeutic agents may be appropriately selected depending on the subject, administration route, target, disease, disorder, symptom, combination, etc.

[0260] In one embodiment of the present disclosure, when using a pharmaceutical composition, the compounds of the present disclosure can be administered in combination at the same time or at different times. Such pharmaceutical compositions are also within the scope of the present disclosure.

[0261] Such medicines, formulations, and pharmaceutical compositions can be manufactured using any technique known in the art by mixing the compounds of the present disclosure and / or additional drugs (e.g., antibacterial agents, antiviral agents (e.g., ribavirin, amantadine, etc.), sedatives (e.g., ketamine, midazolam, etc.), etc.) together or separately, as a combination drug or as separate drugs, with any appropriate ingredients, and can be formulated into appropriate preparations, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices, using any technique known in the art. When the compound of the present disclosure and / or the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.) are prepared as separate drugs, they may be provided as a kit of two drugs, or one component may be provided as a single drug along with instructions (such as a package insert) instructing that the other component (which is the additional drug in the case of the compound of the present disclosure, and the compound of the present disclosure in the case of the additional drug (e.g., an antibacterial agent, an antiviral agent (e.g., ribavirin, amantadine, etc.), a sedative (e.g., ketamine, midazolam, etc.), etc.)) be administered in combination at the same time or at different times.

[0262] When the compounds of the present disclosure are used as active ingredients in medicines, they are not intended for use only in humans, but can also be used in other animals other than humans (cats, dogs, cows, horses, bats, foxes, mongooses, raccoons, etc.).

[0263] (Method for Producing Compounds of the Present Disclosure) Hereinafter, methods for producing compounds of the present disclosure will be described with reference to examples, but the present disclosure is not limited to these.

[0264] The compounds of the present disclosure can be produced, for example, by the production methods described below, but are not limited thereto. These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry. In the production methods described below, the compounds used as raw materials may be used in the form of salts thereof, as long as they do not interfere with the reaction.

[0265] The compound represented by formula (A) of the present invention may have isomers depending on the type of substituent, for example. In this specification, the chemical structure of only one form of the isomer may be described, but the present invention also includes all structurally occurring isomers (geometric isomers, stereoisomers, tautomers, etc.), and also includes all isomers alone or mixtures thereof. In addition, in the present invention, "hydrogen atom" includes １ H and ２ H(D) and any one or more compounds represented by formula (A): １ H ２ Deuterium-converted derivatives converted to H(D) are also encompassed in the compounds represented by formula (A).

[0266] The compounds of the present invention represented by formula (A) and their pharmaceutically acceptable salts, crystalline polymorphs, prodrugs, solvates, and isotope-containing derivatives can be produced, for example, by the following methods. In the production methods shown below, if the defined groups change under the conditions of the method or are inappropriate for carrying out the method, they can be easily produced by methods commonly used in organic synthetic chemistry, such as those described in [Organic Reactions, John Wiley & Sons, Inc., 1942-2021; Organic Syntheses, Organic Syntheses, Inc., 1921-2021; TW Greene, Greene's Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, Inc., 2006] or methods similar thereto. In addition, the order of reaction steps such as substituent introduction and bond formation can also be changed as necessary.

[0267] The meanings of the abbreviations and symbols used in the following explanations, reference examples, examples, etc. are as follows.

[0268] Compounds of formula (A), or pharmaceutically acceptable salts, crystalline polymorphs, prodrugs, solvates, and isotopic derivatives thereof, can be prepared by the following general approaches (Schemes 1-3), together with synthetic methods known in the art of organic chemistry, or modification and derivatization methods known to those skilled in the art.

[0269]

[0270] As shown in Scheme 1, compound (3) can be produced by subjecting a ligand Z (compound (1)) that specifically binds to an intracellular protein or a reactive derivative thereof, and a linker L, compound (2) or a reactive derivative thereof, to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or a coupling reaction using a transition metal catalyst, etc., and a compound represented by formula A (compound (A)) can be produced by subjecting compound (3) or a reactive derivative thereof and X (compound (4)) represented by formula (I) or a reactive derivative thereof, to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or a coupling reaction using a transition metal catalyst, etc.

[0271] Alternatively, as shown in Scheme 2, compound (5) can be produced by subjecting compound (4) or a reactive derivative thereof and compound (2) or a reactive derivative thereof to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or a coupling reaction using a transition metal catalyst, and compound (A) can be produced by subjecting compound (5) or a reactive derivative thereof and compound (1) or a reactive derivative thereof to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or a coupling reaction using a transition metal catalyst, and the like.

[0272] Alternatively, as shown in Scheme 3, compound (3a) can be produced by subjecting compound (1) or a reactive derivative thereof and linker compound (2a) or a reactive derivative thereof to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, transition metal-catalyzed coupling reaction, or the like; compound (5b) can be produced by subjecting compound (4) or a reactive derivative thereof and linker compound (2b) or a reactive derivative thereof to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, transition metal-catalyzed coupling reaction, or the like; and compound (A) can be produced by subjecting compound (3a) and compound (5b) or reactive derivatives thereof to an alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, transition metal-catalyzed coupling reaction, or the like.

[0273] Compound (4a), which is one of the reactive derivatives of (X) constituting a part of formula (A), can be produced, for example, according to Scheme 4.

[0274] The symbols in the following schemes have the same meanings as in the above formula (A) and formula (I). X1, X2, and X3 represent a halogen atom or a leaving group, PG1 represents a suitable protecting group such as a tert-butoxycarbonyl (Boc) group, PG2 represents a suitable protecting group such as a tert-butyldiphenylsilyl (TBDPS) group, PG3 represents a suitable protecting group such as a benzyl group, and RG represents a halogen atom or a leaving group or a reactive functional group such as a hydroxyl group, amino group, carboxyl group, amide group, or sulfonamide group.

[0275] When X1 is a halogen, compound (7) can usually be produced by reacting compound (6) with a haloacetic acid halide such as chloroacetyl chloride in a solvent such as THF or acetonitrile in the presence of a suitable base such as TEA.

[0276] Compound (9) can usually be produced by reacting compounds (7) and (8), for example, in acetonitrile solvent, optionally in the presence of a suitable base such as potassium carbonate and a suitable additive such as potassium iodide.

[0277] When RG is chlorine, compound (4a) can be produced, for example, by reacting compound (9) with methanesulfonyl chloride or the like in a solvent such as THF or DCM in the presence of a suitable base such as TEA.

[0278] Compound (4b), which is one of the reactive derivatives of (X) constituting a part of formula (A), can be produced, for example, according to Scheme 5.

[0279] Compound (11) can usually be produced by reacting compound (10) with a halogenating agent such as N-bromosuccinimide in a solvent such as DMF.

[0280] Compound (12) can be produced in a stepwise manner, for example, by reacting compound (11) with tert-butyllithium or the like in a halogen-metal exchange reaction to obtain an anion species, which is then reacted with a suitable electrophile such as DMF to introduce a formyl group, followed by treatment with a reducing agent such as sodium borohydride. Alternatively, compound (11) can be produced in a stepwise manner by treating it with, for example, palladium acetate and a transition metal catalyst such as 1,1'-ferrocenebis(diphenylphosphine) in an alcohol solvent such as methanol under a carbon monoxide atmosphere to introduce an ester group, followed by treatment with a reducing agent such as lithium borohydride or lithium triethylborohydride.

[0281] Compound (13) can be prepared by reacting compound (12) with a suitable protecting reagent such as tert-butylchlorodiphenylsilane in the presence of a suitable base such as TEA in a solvent such as THF or DCM.

[0282] When X1 is a halogen, compound (14) can be obtained by reacting compound (13) with a haloacetic acid halide such as chloroacetyl chloride in a solvent such as THF or acetonitrile in the presence of a suitable base such as TEA.

[0283] Compound (16) can usually be produced by reacting compounds (14) and (15) and then deprotecting the reacted compounds. For example, compounds (14) and (15) may be reacted in an acetonitrile solvent in the presence of a suitable base such as potassium carbonate and a suitable additive such as potassium iodide. When PG2 is a TBDPS group, compounds (14) and (15) may be reacted in a THF solvent with a suitable deprotecting agent such as TBAF.

[0284] When RG is chlorine, compound (4b) can be produced, for example, by reacting compound (16) with methanesulfonyl chloride or the like in a solvent such as THF or DCM in the presence of a suitable base such as TEA.

[0285] Compound (4c), which is one of the reactive derivatives of (X) constituting a part of formula (A), can be produced, for example, according to Scheme 6.

[0286] Compound (18) can be produced by reacting compound (17) with a compound represented by PG3-O-C6H4-CH2-M in a solvent such as THF or DMF in the presence of an organotransition metal catalyst such as a divalent or zerovalent palladium salt or complex, where PG3-O-C6H4-CH2-M represents, for example, benzyloxybenzyl zinc halide or benzyloxybenzylboronic acid ester.

[0287] Compound (19) can usually be obtained by a deprotection reaction of compound (18). For example, when PG1 is Boc, compound (19) can be produced by treating with an acid such as hydrochloric acid or TFA.

[0288] When X1 is a halogen, compound (20) can be obtained by reacting compound (18) with a haloacetic acid halide such as chloroacetyl chloride in a solvent such as THF or acetonitrile in the presence of a suitable base such as TEA.

[0289] Compound (4c) can usually be produced by reacting compounds (15) and (20) and then deprotecting the resulting compound. For example, compounds (15) and (20) may be reacted in an acetonitrile solvent in the presence of a suitable base such as potassium carbonate and a suitable additive such as potassium iodide. When PG3 is a benzyl group, the reaction may be carried out in a solvent such as methanol in the presence of a catalyst such as palladium carbon under a hydrogen atmosphere.

[0290] When compound (4a), which is one of the reactive derivatives of (X), is used, the compound of formula (Aa) can be produced, for example, according to Scheme 7.

[0291] Compound (2), which is the linker L constituting a part of formula (A-a), La (compound (2a) and Lb (compound (2b)), which are parts of the linker, and compound (1), which is the ligand Z that specifically binds to an intracellular protein, can be commercially available products as they are, or can be produced by a method known per se or a method similar thereto.

[0292] Compound (21) can be produced by reacting compound (3) or a reactive derivative thereof, which is composed of a ligand Z that specifically binds to an intracellular protein and a linker L, with compound (4a) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or coupling reaction using a transition metal catalyst.

[0293] Compound (21) can also be produced via compound (22) composed of compound (4a) and compound (2), which is the linker L. For example, compound (22) can be produced by reacting compound (2) or a reactive derivative thereof with compound (4a) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, and compound (21) can be produced by subjecting compound (22) or a reactive derivative thereof and compound (1) or a reactive derivative thereof to alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, etc.

[0294] Compound (21) can also be produced via compound (23) composed of compound (4a) and Lb (compound (2b)), which is a part of the linker. For example, compound (23) can be produced by reacting compound (2b) or a reactive derivative thereof with compound (4a) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, and compound (21) can be produced by reacting compound (3a), composed of compound (1) and La (compound (2a)), which is a part of the linker, with compound (23) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction.

[0295] Compound (Aa) can be produced by a deprotection reaction of compound (21). For example, when PG1 is Boc, it can be produced by treating with an acid such as hydrochloric acid or TFA.

[0296] When compound (4b), which is one of the reactive derivatives of (X), is used, the compound of formula (Ab) can be produced, for example, according to Scheme 8.

[0297] Compound (2), which is the linker L constituting a part of formula (A-b), La (compound (2a) and Lb (compound (2b)), which are parts of the linker, and compound (1), which is the ligand Z that specifically binds to an intracellular protein, can be commercially available products as they are, or can be produced by a method known per se or a method similar thereto.

[0298] Compound (24) can be produced by reacting compound (3) or a reactive derivative thereof, which is composed of a ligand Z that specifically binds to an intracellular protein and a linker L, with compound (4b) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or coupling reaction using a transition metal catalyst.

[0299] Compound (24) can also be produced via compound (25) composed of compound (4b) and compound (2), which is the linker L. For example, compound (25) can be produced by reacting compound (2) or a reactive derivative thereof with compound (4b) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, and compound (24) can be produced by subjecting compound (25) or a reactive derivative thereof and compound (1) or a reactive derivative thereof to alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, etc.

[0300] Compound (24) can also be produced via compound (26) composed of compound (4b) and Lb (compound (2b)), which is a part of the linker. For example, compound (26) can be produced by reacting compound (2b) or a reactive derivative thereof with compound (4b) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, and compound (24) can be produced by reacting compound (3a), composed of compound (1) and La (compound (2a)), which is a part of the linker, with compound (26) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction.

[0301] Compound (Ab) can be produced by deprotection reaction of compound (24). For example, when PG1 is Boc, it can be produced by treating with an acid such as hydrochloric acid or TFA.

[0302] When compound (4c), which is one of the reactive derivatives of (X), is used, the compound of formula (Ac) can be produced, for example, according to Scheme 9.

[0303] Compound (2), which is the linker L constituting a part of formula (Ac), and parts of linkers La (compound (2a) and Lb (compound (2b)), and compound (1), which is the ligand Z that specifically binds to an intracellular protein, can be commercially available products as they are, or can be produced by a method known per se or a method similar thereto.

[0304] Compound (27) can be produced by reacting compound (3) or a reactive derivative thereof, which is composed of a ligand Z that specifically binds to an intracellular protein and a linker L, with compound (4c) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or coupling reaction using a transition metal catalyst.

[0305] Compound (27) can also be produced via compound (28) composed of compound (4c) and compound (2) as the linker L. For example, compound (28) can be produced by reacting compound (2) or a reactive derivative thereof with compound (4b) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, and compound (27) can be produced by subjecting compound (28) or a reactive derivative thereof and compound (1) or a reactive derivative thereof to alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, etc.

[0306] Compound (27) can also be produced via compound (29) composed of compound (4c) and Lb (compound (2b)), which is a part of the linker. For example, compound (29) can be produced by reacting compound (2b) or a reactive derivative thereof with compound (4c) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction, and compound (27) can be produced by reacting compound (3a), composed of compound (1) and La (compound (2a)), which is a part of the linker, with compound (29) under conditions such as alkylation reaction, Mitsunobu reaction, reductive amination reaction, amidation reaction, or transition metal-catalyzed coupling reaction.

[0307] Compound (Ac) can be produced by a deprotection reaction of compound (27). For example, when PG1 is Boc, it can be produced by treating with an acid such as hydrochloric acid or TFA.

[0308] An embodiment of the combination of Z, L and X groups in formula (A) is as follows: The intracellular protein in Z may be a serine / threonine kinase, a receptor tyrosine kinase, or a non-receptor tyrosine kinase, or may be an AGC group, an LTK receptor family, or an FAK family, or may be ROCK2, ALK, or FAK. (Examples of ligand moieties that specifically bind to such intracellular proteins include, for example, and the like); L is selected from the following: wherein each group has the same meaning as defined above; in the group X, A is N or CR ８ (preferably N), B is N, CR ９ , or C.L. ２ (Preferably CR ９ , or C.L. ２ ), Q is N, and R １ and L that is not used for bonding with L １ are each independently hydrogen or C １－６ alkyl (preferably methyl), wherein said C１－６ Alkyl is one or more —O—C １－２ optionally substituted with alkyl (preferably methoxy); R ２ａ and R ２ｂ is hydrogen, R ３ is C １－４ alkyl (preferably methyl), R ４ is hydrogen, R ５ａ and R ５ｂ are each independently １－４ alkyl (preferably methyl), R ６ is -CH ２ -phenyl, or (E represents a bonding point), which may be substituted with one or more halogen atoms (preferably fluorine atoms), R ７ is hydrogen, R ９ is hydrogen, and L １ ~L ３ and L ３ ', X is bonded to L. (L １ ~L ３ and L ３ Examples of the case where X is bonded to L in any one of the above formulae 1 and 2 include the following.

[0309] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims.

[0310] The compound was identified by hydrogen nuclear magnetic resonance spectroscopy ( 1 1 H NMR) and mass spectroscopy (MS). 1 H NMR was measured at 400 MHz or 500 MHz, and exchangeable hydrogens may not be clearly observed depending on the compound and measurement conditions. MS was measured by LC / MS. The HPLC or UPLC analytical methods shown in Table 3 were used to measure the retention times of the compounds.

[0311]

[0312] Reference Example 1 tert-Butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (Step A) Methyl ((benzyloxy)carbonyl)-L-seryl-D-alaninate: Methyl ((benzyloxy)carbonyl)-L-seryl-D-alaninate. To a solution of methyl D-alaninate (75 g, 0.54 mol) in DCM (1.8 L) was added ((benzyloxy)carbonyl)-L-serine (0.13 kg, 0.54 mol) at room temperature, followed by the addition of EDC-HCl (0.13 kg, 1.1 mol). The reaction mixture was cooled to 0°C, and then DIPEA (0.25 L, 1.3 mol) was added, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous sodium carbonate and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with 2 M hydrochloric acid and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.12 kg). MS (m / z): 325.19 [M+H] + .

[0313] (Step B) Methyl L-seryl-D-alaninate: Palladium-carbon (5.0 g) was added to a methanol solution (0.40 L) of methyl ((benzyloxy)carbonyl)-L-seryl-D-alaninate (40 g, 0.12 mol) at room temperature, and the mixture was stirred under a hydrogen atmosphere (30 psi) for 18 hours. The reaction mixture was filtered through Celite, and the Celite was washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (23 g). MS (m / z): 191.27 [M+H] + .

[0314] (Step C) (3S,6R)-3-(Hydroxymethyl)-6-methylpiperazine-2,5-dione: (3S,6R)-3-(Hydroxymethyl)-6-methylpiperazine-2,5-dione. A solution of methyl L-seryl-D-alaninate (68 g, 0.36 mol) in methanol (1.5 L) was heated under reflux for 18 hours. After cooling, the reaction mixture was evaporated under reduced pressure to give the title compound (64 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.29 (d, J = 7.2 Hz, 3H), 3.51-3.54 (m, 1H), 3.68-3.79 (m, 3H), 5.12 (brs, 1H), 7.15 (s, 1H), 8.09 (s, 1H).

[0315] (Step D) ((2R,5R)-5-Methylpiperazin-2-yl)methanol dihydrochloride: ((2R,5R)-5-Methylpiperazin-2-yl)methanol dihydrochloride. To a THF solution (0.45 L) of (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (42 g, 0.27 mol), borane-THF complex (1 M THF solution, 0.23 L, 0.23 mol) was added at room temperature, and the reaction mixture was stirred at 70°C for 18 hours. After cooling the reaction mixture to 0°C, methanol (0.45 L) and 5 M hydrochloric acid (0.10 L) were added, and the mixture was stirred at 70°C for 2 hours. The precipitated solid was collected by filtration, washed with THF, and dried under reduced pressure to give the title compound (41 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.30 (d, J = 6.4 Hz, 3H), 3.05-3.09 (m, 2H), 3.42-3.71 (m, 6H), 5.57-5.68 (m, 1H), 9.30-10.35 (m, 2H).

[0316] (Step E) tert-Butyl (6R,8aR)-6-methyl-3-oxotetrahydro-3H-oxazolo[3,4-a]piperazine-7(1H)-carboxylate: To a methanol solution (0.50 L) of tert-Butyl (6R,8aR)-6-methyl-3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate ((2R,5R)-5-methylpiperazin-2-yl)methanol dihydrochloride (50 g, 0.25 mol) was added TEA (0.11 L, 0.75 mol) under ice cooling, and then a methanol solution (50 mL) of di-tert-butyl dicarbonate (0.14 L, 0.60 mol) was added dropwise. After stirring at 0°C for 1 hour and at 50°C for 18 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (62 g). MS (m / z): 201.13 [M-56+H] + .

[0317] (Step F) tert-Butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate: tert-Butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate. To a solution (0.30 L) of ethanol containing tert-butyl (6R,8aR)-6-methyl-3-oxotetrahydro-3H-oxazolo[3,4-a]piperazine-7(1H)-carboxylate (31 g, 0.12 mol), an aqueous solution (0.30 L) of sodium hydroxide (28 g) was added at room temperature. The mixture was stirred at 100°C for 18 hours, after which 1M hydrochloric acid (0.25 L) was added and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (23 g). 1H NMR (400 MHz, DMSO-d6) δ 1.13 (d, J = 6.4 Hz, 3H), 1.38 (s, 9H), 2.32-2.38 (m, 2H), 2.72-2.77 (m, 1H), 2.88 (dd, J = 12.4, 4.4 Hz, 1H), 3.06 (dd, J = 13.6, 4.4 Hz, 1H), 3.27-3.32 (m, 1H), 3.38-3.44 (m, 1H), 3.56-3.59 (m, 1H), 3.92-3.95 (m, 1H), 4.47 (brs, 1H); MS (m / z): 231.20 [M+H] + .

[0318] Reference Example 2 tert-Butyl (2R,5R)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (Step A) 1-Benzyl 4-(tert-butyl) (2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate: 1-Benzyl 4-(tert-butyl) (2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (Compound of Reference Example 1, 40 g, 0.17 mol) was added to a THF solution (0.40 L) of 1 M aqueous sodium hydroxide solution (0.20 L), and then carbobenzoxychloride (25 mL, 0.17 mol) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 6 hours, then diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to obtain the title compound (48 g). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.19 (m, 1H), 1.39 (s, 9H), 1.98 (s, 1H), 3.04-3.13 (m, 2H), 3.32-3.44 (m, 2H), 3.65-3.84 (m, 2H), 4.00-4.08 (m, 3H), 4.79-4.86 (m, 1H), 5.04-5.16 (m, 2H), 7.30-7.38 (m, 5H); MS (m / z): 265.14 [M-Boc+H] + .

[0319] (Step B) 1-Benzyl 4-(tert-butyl) (2R,5R)-2-(methoxymethyl)-5-methylpiperazine-1,4-dicarboxylate: 1-Benzyl 4-(tert-butyl) (2R,5R)-2-(methoxymethyl)-5-methylpiperazine-1,4-dicarboxylate. To a DCM solution (0.10 L) of 1-benzyl 4-(tert-butyl) (2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (8.0 g, 22 mmol), proton sponge (24 g, 0.11 mol) was added, and then trimethyloxonium tetrafluoroborate (17 g, 0.11 mmol) was added dropwise at 0° C. After stirring at room temperature for 4 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with DCM. The organic layer was washed with 1 M hydrochloric acid, then with saturated aqueous sodium bicarbonate, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to yield the title compound (5.8 g). 1 H NMR (400 MHz, CDCl3) δ 1.23-1.28 (m, 1H), 1.46 (s, 9H), 2.04 (s, 1H), 3.14-3.55 (m, 7H), 3.74-3.84 (m, 1H), 3.92-3.94 (m, 1H), 4.10-4.18 (m, 1H), 4.20-4.70 (m, 2H), 5.00-5.30 (m, 2H), 7.26-7.36 (m, 5H); MS (m / z): 379.24 [M+H]+ .

[0320] (Step C) tert-Butyl (2R,5R)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate: Tert-Butyl(2R,5R)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate. Palladium carbon (13 g) was added to a methanol solution (0.30 L) of 1-benzyl 4-(tert-butyl)(2R,5R)-2-(methoxymethyl)-5-methylpiperazine-1,4-dicarboxylate (30 g, 79 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure to give the title compound (15 g). 1 H NMR (400 MHz, CDCl3) δ 1.25 (d, J = 6.8 Hz, 3H), 1.46 (s, 9H), 2.50 (dd, J = 12.8, 3.2 Hz, 1H), 3.06-3.12 (m, 2H), 3.20-3.30 (m, 2H), 3.34-3.39 (m, 3H), 3.60-3.72 (m, 2H), 4.14-4.18 (m, 1H), one proton missing; GC-MS (m / z): 244.2 [M] + .

[0321] Reference Example 3 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (Step A) 5-Bromo-2-iodopyridine-3-amine: 5-Bromo-2-iodopyridine-3-amine. N-iodosuccinimide (0.29 kg, 1.3 mol) was added to a solution of 5-bromopyridin-3-amine (0.25 kg, 1.4 mol) in acetic acid (5.0 L), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and then an aqueous solution of sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to obtain the title compound (0.27 kg). MS (m / z): 300.83 [M(Br 81 )+H] + .

[0322] (Step B) 5-Bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine: 5-Bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine. To a THF solution (2.6 L) of 5-bromo-2-iodopyridin-3-amine (0.17 kg, 0.57 mol), potassium tert-butoxide (77 g, 0.68 mol) was added at 0°C, and the mixture was stirred for 30 minutes. Next, 3-bromo-2-methyl-1-propene (92 g, 0.68 mol) was added, and the mixture was stirred at 0°C for 1 hour and at room temperature for an additional 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude product. This was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (0.12 kg). MS (m / z): 353.06 [M+H] + .

[0323] (Step C) 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine: 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. Palladium acetate (4.5 g, 20 mmol) was added to a DMSO / water mixture (0.70 L:0.15 L) containing 5-bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine (60 g, 0.20 mol), sodium formate (16 g, 0.24 mol), tetrabutylammonium chloride (67 g, 0.24 mol), and TEA (84 mL, 0.60 mol) at room temperature. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was then diluted with ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (13 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.20 (s, 6H), 3.29-3.32 (m, 2H), 6.05 (s, 1H), 6.87 (d, J = 2 Hz, 1H), 7.70 (d, J = 2 Hz, 1H); MS (m / z): 227.22 [M+H] + .

[0324] (Step D) tert-Butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate: tert-butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. To a THF solution (0.50 L) of 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (25 g, 0.11 mol), potassium tert-butoxide (15 g, 0.13 mol) and di-tert-butyl dicarbonate (27 g, 0.12 mol) were added and stirred at room temperature for 18 hours. Ice water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (29 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.32 (s, 6H), 1.51 (s, 9H), 3.72 (s, 2H), 7.57 (brs, 1H), 8.15 (s, 1H); MS (m / z): 327.36 [M+H] + .

[0325] (Step E) tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate: tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate tert-butyl To a solution of 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (28 g, 86 mmol) in NMP / THF (0.18 L:0.18 L), lithium bromide (30 g, 0.34 mol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (1.2 g, 1.7 mmol) were added at room temperature and stirred for 10 minutes. Next, 4-fluorobenzylzinc bromide (0.5 M THF solution, 0.70 L, 0.35 mol) was added and the mixture was stirred for 18 hours. A 5% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (30 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.25 (s, 6H), 1.45 (s, 9H), 3.68 (s, 2H), 3.92 (s, 2H), 7.13 (t, J = 8.8 Hz, 2H), 7.27-7.30 (m, 2H), 7.74 (brs, 1H), 8.04 (s, 1H); MS (m / z): 357.21 [M+H] + .

[0326] (Step F) 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine: To a solution of 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (0.48 g, 1.3 mmol) in 1,4-dioxane (5.0 mL) was added 4 M hydrogen chloride / 1,4-dioxane solution (5.0 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was separated. Aqueous sodium carbonate solution was added until the pH of the aqueous layer became alkaline, followed by extraction with DCM. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.30 g). MS (m / z): 257.22 [M+H] + .

[0327] Reference Example 4 (6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)methanol (Step A) 5-Bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine: 5-Bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. To a DMF solution (0.60 L) of 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (Compound of Reference Example 3, 59 g, 0.23 mol), N-bromosuccinimide (41 g, 0.23 mol) was added under ice cooling, and the mixture was stirred at 0°C for 2 hours and at room temperature for an additional 16 hours. Ice water was added to the reaction mixture, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (37 g) as a crude product. 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 6H), 3.37 (s, 2H), 3.65 (s, 1H), 3.94 (s, 2H), 6.51 (s, 1H), 6.97-7.01 (m, 2H), 7.14-7.18 (m, 2H); MS (m / z): 335.2 [M+H] + .

[0328] (Step B) 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carbaldehyde: 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carbaldehyde To a THF solution (0.15 L) of 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (15 g, 44 mmol), methyllithium (1.6 M diethyl ether solution, 42 mL, 67 mmol) was added at −78° C., and the mixture was stirred for 30 minutes. Subsequently, tert-butyllithium (1.7 M pentane solution, 66 mL, 0.11 mol) was added, and the mixture was further stirred for 30 minutes. Then, DMF (15 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (15 g). 1 H NMR (400 MHz, CDCl3) δ 1.38 (s, 6H), 3.48 (s, 2H), 4.26-4.39 (m, 3H), 6.40 (s, 1H), 6.94-6.98 (m, 2H), 7.14-7.18 (m, 2H), 10.00 (s, 1H). MS (m / z); 285.14 [M+H] + .

[0329] (Step C) (6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)methanol: (6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)methanol To a solution of 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carbaldehyde (29 g, 0.10 mol) in methanol (0.30 L) was added sodium borohydride (4.5 g, 0.12 mol) at 0°C. The reaction solution was stirred at room temperature for 2 hours, followed by addition of ice water and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (17 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.20 (s, 6H), 3.20-3.21 (m, 2H), 3.92 (s, 2H), 4.46 (d, J = 5.2 Hz, 2H), 4.89-4.92 (m, 1H), 5.60 (brs, 1H), 6.45 (s, 1H), 7.08-7.13 (m, 2H), 7.21-7.25 (m, 2H); MS (m / z): 287.29 [M+H] + .

[0330] Reference Example 5 (R)-4-(1-aminoethyl)-N-(pyridin-4-yl)benzamide dihydrochloride (Step A) Methyl (R)-4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoate: Methyl (R)-4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoate To a solution of methyl (R)-4-(1-aminoethyl)benzoate (5.0 g, 28 mmol) in DCM (0.10 L) were added TEA (8.3 mL, 70 mmol) and di-tert-butyl dicarbonate (7.3 g, 33 mmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.7 g). 1 H NMR (400 MHz, CDCl3) δ 1.42-1.58 (m, 13H), 3.91 (s, 3H), 4.83 (brs, 1H), 7.35-7.37 (m, 2H), 7.99-8.02 (m, 2H); MS (m / z): 224.25 [M-56+H] + .

[0331] (Step B) (R)-4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoic acid: To a THF / water mixed solution (35 mL:40 mL) of (R)-4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoate (7.7 g, 27 mmol) in methyl (R)-4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoate (7.7 g, 27 mmol), lithium hydroxide monohydrate (5.6 g, 0.14 mol) was added at room temperature, and the mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and then a saturated aqueous citric acid solution was added to the residue, and the precipitated solid was filtered. The solid was washed with water and dried under reduced pressure to obtain the title compound (6.7 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.42-1.59 (m, 13H), 4.86 (brs, 2H), 7.40 (d, J = 8 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H); MS (m / z): 266.36 [M+H] 　+ .

[0332] (Step C) tert-butyl (R)-(1-(4-(pyridin-4-ylcarbamoyl)phenyl)ethyl)carbamate: tert-butyl (R)-(1-(4-(pyridin-4-ylcarbamoyl)phenyl)ethyl)carbamate. To a solution of (R)-4-(1-((tert-butoxycarbonyl)amino)ethylbenzoic acid (6.7 g, 25 mmol) in DMF (67 mL) was added pyridin-4-amine (2.6 g, 28 mmol) and HATU (11 g, 28 mmol) at room temperature, followed by the addition of DIPEA (11 mL, 60 mmol). The reaction mixture was stirred for 18 hours, then diluted with water, and the precipitate was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (7.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.24-1.37 (m, 12H), 4.66-4.68 (m, 1H), 7.44-7.51 (m, 3H), 7.77 (d, J = 6.4 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 8.47 (d, J = 6.0 Hz, 2H), 10.52 (s, 1H); MS (m / z): 342.29 [M+H] + .

[0333] (Step D) (R)-4-(1-aminoethyl)-N-(pyridin-4-yl)benzamide dihydrochloride: (R)-4-(1-aminoethyl)-N-(pyridin-4-yl) benzamide dihydrochloride tert-butyl (R)-(1-(4-(pyridin-4-ylcarbamoyl)phenyl)ethyl)carbamate (7.5 g, 22 mmol) in 1,4-dioxane (38 mL) was added 4 M hydrogen chloride / 1,4-dioxane solution (75 mL) and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with diethyl ether. The solid was collected by filtration and dried under reduced pressure to give the title compound (6.1 g). 1H NMR (400 MHz, DMSO-d6) δ 1.55 (d, J = 6.8 Hz, 3H), 4.51-4.54 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H), 8.43 (d, J = 7.2 Hz, 2H), 8.72-8.77 (m, 5H), 11.85 (s, 1H), 15.29 (brs, 1H); MS (m / z): 242.30 [M+H] + .

[0334] Reference Example 6 (R)-2-amino-3-(3-fluorophenyl)-N-(4-(pyridin-4-yl)phenyl)propanamide dihydrochloride (Step A) 4-(pyridin-4-yl)aniline: 4-(pyridin-4-yl)aniline. To a DMF / water mixture (0.8 L:0.4 L) of 4-bromopyridine (20 g, 91 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (18 g, 93 mmol), sodium carbonate (51 g, 0.46 mol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (3.7 g, 4.8 mmol) were added at room temperature. The reaction mixture was stirred at 130°C for 16 hours, after which the reaction solution was diluted with water, and the precipitated solid was collected by filtration. The resulting solid was washed with water and then petroleum ether and dried under reduced pressure to give the title compound (14 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.88 (brs, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.48-7.50 (m, 4H), 8.57-8.58 (m, 2H); MS (m / z): 171.15 [M+H] + .

[0335] (Step B) tert-butyl (R)-(3-(3-fluorophenyl)-1-oxo-1-((4-(pyridin-4-yl)phenyl)amino)propan-2-yl)carbamate: tert-butyl (R)-(3-(3-fluorophenyl)-1-oxo-1-((4-(pyridin-4-yl)phenyl)amino)propan-2-yl)carbamate. To a DMF solution (0.25 L) of 4-(pyridin-4-yl)aniline (14 g, 78 mmol), DIPEA (25 mL, 0.18 mol), HATU (29 g, 77 mmol), and (R)-2-((tert-butoxycarbonyl)amino)-3-(3-fluorophenyl)propionic acid (20 g, 71 mmol) were added under ice cooling. After stirring at room temperature for 16 hours, ice water was added to the reaction mixture, and the precipitate was collected by filtration. The resulting solid was dissolved in a methanol / DCM mixed solvent (10:90) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate) to give the title compound (16 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H), 3.10-3.25 (m, 2H), 4.46-4.48 (m, 1H), 5.05 (brs, 1H), 6.95-7.00 (m, 2H), 7.04-7.06 (m, MS (m / z): 436.45 [M+H] + .

[0336] (Step C) (R)-2-amino-3-(3-fluorophenyl)-N-(4-(pyridin-4-yl)phenyl)propanamide dihydrochloride: (R)-2-amino-3-(3-fluorophenyl)-N-(4-(pyridin-4-yl)phenyl)propenamide dihydrochloride tert-butyl (R)-(3-(3-fluorophenyl)-1-oxo-1-((4-(pyridin-4-yl)phenyl)amino)propan-2-yl)carbamate (16 g, 38 mmol) in DCM (0.20 L) was added with 4 M hydrogen chloride / 1,4-dioxane solution (30 mL) under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give the title compound (13 g). 1 H NMR (500 MHz, DMSO-d6) δ 3.12-3.17 (m, 1H), 3.27-3.32 (m, 1H), 4.39 (brs, 1H), 7.11 (dt, J1 = 2.4 8.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.84 (d. (m / z): 336.18 [M+H] + .

[0337] Reference Example 7 (S)-3-amino-N-(isoquinolin-6-yl)-2-phenylpropanamide dihydrochloride (Step A) tert-butyl (S)-(3-(isoquinolin-6-ylamino)-3-oxo-2-phenylpropyl)carbamate: tert-butyl (S)-(3-(isoquinolin-6-ylamino)-3-oxo-2-phenylpropyl)carbamate. To a DMF solution (0.10 L) of (S)-3-((tert-butoxycarbonyl)amino)-2-phenylpropionic acid (10 g, 39 mmol), DIPEA (17 mL, 98 mmol) and HATU (16 g, 43 mmol) were added under ice cooling, followed by the addition of isoquinolin-6-amine (6.2 g, 43 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (13 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.35 (s, 9H), 2.69-2.73 (m, 1H), 3.52-3.57 (m, 1H), 4.07-4.11 (m, 1H), 7.02-7.05 (m, 1H), 7.25-7.42 (m, 5H), 7.67-7.71 (m, 2H), 8.02-8.04 (m, 1H), 8.39-8.40 (m, 2H), 9.15 (s, 1H), 10.59 (s, 1H).

[0338] (Step B) (S)-3-amino-N-(isoquinolin-6-yl)-2-phenylpropanamide dihydrochloride: To a DCM solution (0.15 L) of (S)-3-amino-N-(isoquinolin-6-yl)-2-phenylpropanamide dihydrochloride tert-butyl (S)-(3-(isoquinolin-6-ylamino)-3-oxo-2-phenylpropyl)carbamate (13 g, 33 mmol), 4 M hydrogen chloride in 1,4-dioxane (27 mL) was added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (8.5 g). 1H NMR (400 MHz, DMSO-d6) δ 3.08-3.12 (m, 1H), 3.62-3.65 (m, 1H), 4.35-4.39 (m, 1H), 7.32-7.35 (m, 1H), 7.39-7.42 (m, 2H), 7.49-7.51 (m, 2H), 8.06 (dd, J = 9.2, 2.0 Hz, 1H), 8.15 (brs, 3H), 8.28 (d, J = 6.4 Hz, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.54 (d, J = 6.4 Hz, 1H), 8.68-8.69 (m, 1H), 11.52 (s, 1H); MS (m / z): 292.13 [M+H] + .

[0339] Reference Example 8 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetic acid: 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetic acid (Step A) tert-butyl 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetate: Tert-butyl 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetate. To a DCM solution (100 mL) of ceritinib (10 g, 19 mmol), TEA (6.6 mL, 47 mmol) and tert-butyl 2-bromoacetate (5.5 g, 28 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (12 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.16 (d, J = 6.4 Hz, 6H), 1.22 (d, J = 6.0 Hz, 6H), 1.43 (s, 9H), 1.64 (d, J = 5.2 Hz, 4H), 2.11 (s, 3H), 2.27-2.33 (m, 2H), 2.56-2.61 (m, 1H), 2.94 (d, J = 11.2 Hz, 2H), 3.13 (s, 2H), 3.44 (t, J = 6.8 Hz, 1H), 4.58 (t, J = 6.0 Hz, 1H), 6.85 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.60-7.64 (m, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 8.05 (s, 1H), 8.25 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 9.46 (s, 1H); MS (m / z): 672.74 [M+H] + .

[0340] (Step B) 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetic acid: 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetic acid tert-butyl 2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)acetate (12 g, 17 mmol) was added TFA (110 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (10 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.16 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.0 Hz, 6H), 1.70 (d, J = 12.4 Hz, 2H), 1.87 (d, J = 13.2 Hz, 2H), 2.12 (s, 3H), 2.64 (t, J = 10.0 Hz, 2H), 2.73-2.75 (m, 1H), 3.21 (s, 3H), 3.23-3.27 (m, 4H), 4.56 (t, J = 6.4 Hz, 1H), 6.87 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.51 MS (m / z): 616.50 [M+H] + .

[0341] Reference example 9 N ２ -(4-aminophenyl)-N ４-(3-(methylsulfonyl)benzyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine: N 2 -(4-aminophenyl)-N 4 -(3-(methylsulfonyl)benzyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Step A) tert-butyl (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate: Tert-butyl (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate Zinc bromide (3.2 g, 14 mmol) was added to a mixed solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.2 g, 5.8 mmol) in tert-butyl alcohol / DCE (10 mL:10 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Next, tert-butyl (4-aminophenyl)carbamate (1.0 g, 4.8 mmol) and TEA (1.5 mL, 11 mmol) were added at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give the title compound (1.2 g). 1 H NMR (400 MHz, CDCl3) δ 1.52 (s, 9H), 6.48 (brs, 1H), 7.37-7.39 (m, 3H), 7.47-7.50 (m, 2H), 8.54 (brs, 1H); MS (m / z): 389.23 [M+H] + .

[0342] (Step B) tert-butyl (4-((4-((3-(methylsulfonyl)benzyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate: Tert-butyl (4-((4-((3-(methylsulfonyl)benzyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate DIPEA (1.1 mL, 6.4 mmol) and 3-methylsulfonylbenzylamine (0.60 g, 3.2 mmol) were added to a solution of tert-butyl (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate (0.50 g, 1.3 mmol) in a tert-butyl alcohol / DCE mixture (10 mL:10 mL) at room temperature, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with a mixed solution of tert-butyl alcohol / DCE (10 mL:10 mL) to give the title compound (0.45 g). MS (m / z): 538.41 [M+H] + .

[0343] (Process C) N ２ -(4-aminophenyl)-N ４ -(3-(methylsulfonyl)benzyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine: N 2 -(4-aminophenyl)-N 4 To a 1,4-dioxane solution (5.0 mL) of 4-((4-((3-(methylsulfonyl)benzyl)amino)-5-(trifluoromethyl)pyrimidine-2,4-diamine tert-butyl (4-((4-((3-(methylsulfonyl)benzyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate (0.45 g, 0.84 mmol), 4M hydrogen chloride / dioxane solution (30 mL) was added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.19 g). MS (m / z): 438.32 [M+H] + .

[0344] Reference Example 10 (R)-4-(1-((2-(2-methoxyethoxy)ethyl)amino)ethyl)-N-(pyridin-4-yl)benzamide To a solution (5.0 mL) of (R)-4-(1-aminoethyl)-N-(pyridin-4-yl)benzamide dihydrochloride (Compound of Reference Example 5, 0.26 g, 0.83 mmol) in acetonitrile, potassium carbonate (0.23 g, 1.7 mmol), potassium iodide (catalytic amount), and then 1-bromo-2-(2-methoxyethoxy)ethane (0.15 g, 0.83 mmol) were added at room temperature. The reaction solution was stirred at 50°C for 24 hours and then diluted with ethyl acetate. The suspension was filtered to remove inorganic salts, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC preparative chromatography (column: X-Bridge, eluent: 10 mM aqueous ammonium bicarbonate solution / acetonitrile, gradient mode) to obtain the title compound (0.035 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.27 (d, J = 6.8 Hz, 3H), 2.12 (brs, 1H), 2.40-2.45 (m, 1H), 2.53-2.54 (m, 1H), 3.23 (s, 3H), 3.41-3.44 (m, 4H), 3.46-3.49 (m, 2H), 3.78-3.81 (m, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 4.8, 1.6 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 8.47 (d, J = 6.0 Hz, 2H), 10.52 (s, 1H); MS (m / z): 344.3 [M+H] + .

[0345] Reference Example 11 (R)-4-(1-((3-(2-methoxyethoxy)propyl)amino)ethyl)-N-(pyridin-4-yl)benzamide (R)-4-(1-aminoethyl)-N-(pyridin-4-yl)benzamide dihydrochloride (compound of Reference Example 5) was reacted in the same manner as in Reference Example 10 using 1-bromo-3-(2-methoxyethoxy)propane instead of 1-bromo-2-(2-methoxyethoxy)ethane to obtain the title compound (0.025 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.25 (d, J = 6.8 Hz, 3H), 1.57-1.63 (m, 2H), 2.27-2.34 (m, 1H), 2.37-2.43 (m, 1H), 3.21 (s, 3H), 3.38-3.48 (m, 7H), 3.73-3.78 (m, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.78 (dd, J = 4.8, 1.2 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 8.47 (d, J = 6.4 Hz, 2H), 10.51 (s, 1H); MS (m / z): 358.38 [M+H] + .

[0346] Reference Example 12 (R)-3-(3-fluorophenyl)-2-((2-(2-methoxyethoxy)ethyl)amino)-N-(4-(pyridin-4-yl)phenyl)propanamide To a solution of (R)-2-amino-3-(3-fluorophenyl)-N-(4-(pyridin-4-yl)phenyl)propanamide dihydrochloride (Compound of Reference Example 6, 1.2 g, 3.0 mmol) in acetonitrile (10 mL) were added 1-bromo-2-(2-methoxyethoxy)ethane (0.60 g, 3.3 mmol), potassium carbonate (1.2 g, 9.0 mmol), and potassium iodide (0.050 g) at room temperature. The reaction solution was stirred at 60°C for 48 hours, and then the solvent was evaporated. The residue was purified by HPLC preparative chromatography (column: Inertsil ODS, eluent: 10 mM aqueous ammonium bicarbonate solution / acetonitrile, gradient mode) to obtain the title compound (0.45 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.21 (brs, 1H), 2.60-2.67 (m, 2H), 2.87-2.89 (m, 1H), 2.95-2.96 (m, 1H), 3.22 (s, 3H), 3.39-3.50 (m, 7H), 7.01 (t, J = 8.8 Hz, 1H), 7.09 (t, J = 10 Hz, 2H), 7.27-7.33 (m, 1H), 7.68-7.80 (m, 6H), 8.6 (d, J = 4.8 Hz, 2H), 10.06 (s, 1H); MS (m / z): 438.34 [M+H] + .

[0347] Reference Example 13 (R)-3-(3-fluorophenyl)-2-((3-(2-methoxyethoxy)propyl)amino)-N-(4-(pyridin-4-yl)phenyl)...

Claims

1. Formula (A) Z-L-X A compound represented by or its isomer, or a salt thereof, Z is the ligand portion that specifically binds to intracellular proteins. L is either a linker or a single bond. X is given by the following formula 【Chemistry 1】 And, A is N or CR ８ And, B is N, CR ９ , or CL ２ And, Q is N or CR １０ And, R １ and L not used for bonding to L １ are each independently hydrogen, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, -C(=O)NH （２－ｑ） (C １－６ alkyl) ｑ , -(CH ２ ) ｓ -(3- to 12-membered heterocyclyl), -(CH ２ ) ｓ -C ３－１２ carbocyclyl, -C(=O)-(3- to 12-membered heterocyclyl), and -C(=O)-C ３－１２ selected from carbocyclyl, or R １ and L that is not used in the combination with L １ These can form a 3- to 10-membered saturated carbocykyl group or a heterocycline group together with the carbon atoms to which they are bonded, where the C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, heterocyclyl, and carbocykyl groups are one or more R ｂ It is also acceptable if it is substituted with the base; R ２ａ and R ２ｂ Each of them is independently of hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -C(=O)NH （２－ｑ） (C １－６ Alkyl) ｑ ,-(CH ２ ) ｓ - (3- to 12-membered heterocyclyl), and - (CH ２ ) ｓ -C ３－１２ Selected from carbocyclyl or R ２ａ and R ２ｂ These can form a 3- to 10-membered saturated carbocykyl group or a heterocycline group together with the carbon atoms to which they are bonded, where the C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, heterocyclyl, and carbocykyl groups are one or more R ｂ It is also acceptable if it is substituted with the base; R ３ C １－４ Alkyl, C ２－４ Alkenyl and -(CH ２ ) ｓ -C ３－８ Selected from cycloalkyl, where C １－４ Alkyl, C ２－４ Alkenyl and C ３－８ Cycloalkyl is one or more R ａ It is also acceptable if it is substituted with the base; R ａ These are halogens, -OH and -O-C １－６ Selected from alkyl groups; R ４ is hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl and -(CH ２ ) ｓ -C ３－８ Selected from cycloalkenyls, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－８ Cycloalkyl and C ３－８ Cycloalkenyl is one or more R ａ It is also acceptable if it is substituted with the base; R ５ａ and R ５ｂ are each independently hydrogen, C １－８ alkyl, C ２－８ alkenyl, C ２－８ alkynyl, -Y-C ３－１２ carbocyclyl, -W-(3- to 12-membered heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ , -O-(CR ｘ R ｙ ) ｎ -OR ｚ , -(CH ２ ) ｓ -CN, -S(O) ｑ -R ｘ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ , -(CR ｘ R ｙ ) ｓ -C(=O)OR ｚ , -(CR ｘ R ｙ ) ｓ -O-C(=O)-R ｚ , -(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)R ｙ , -(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ , -(CH ２ ) ｓ -NR ｘ C(=O)OR ｙ , -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ -(CH ２ ) ｓ -R ｚ , -(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ ,-(CR ｘ R ｙ ) ｓ -C(=N)NR ｚ ,-(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ ,-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ and - (CH ２ ) ｓ -SO ２ NR ｘ R ｙ Selected from the base, or R ５ａ and R ５ｂ These can form a 3-6 membered carbocykyl group or a 4-6 membered heterocycline group together with the carbon atoms to which they are bonded. Here C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ The alkynyl group is one or more R ｂ The group may be substituted with a group, and the carbocyclyl group and heterocyclyl group may be one or more R ｂ It is also acceptable if it is substituted with the base; R ６ is hydrogen, halogen, C １－８ Alkyl, C ２－８ Alkenil, C ２－８ Alkinyl, -Y-C ３－１２ Carbocyclyl, -W- (3-12 member heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ ,-O-(CR ｘ R ｙ ) ｎ -OR ｚ ,=O,=S,Nitro,Si(R) ｘ ) ４ ,-(CH ２ ) ｓ -CN, -S(O) ｑ - (CR ｘ R ｙ ) ｓ -R ｚ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ ,-(CR ｘ R ｙ ) ｓ -C (=O) OR ｚ ,-(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ ,-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ ,-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C (=O) OR ｙ ,-(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ ,-(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ ,-(CR ｘ R ｙ ) ｓ -C(=N)NR ｘ , -S(O)(=NR ｘ ) R ｙ ,-(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ ,-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ ,-(CH ２ ) ｓ -SO ２ NR ｘ R ｙ group, -P(=O)(R ｘ ) ２ , -Y-C ５－１０ aryl, -Y- (5-10 membered ring heteroaryl), optionally condensable 5-10 membered carbocyryl group, optionally condensable 5-10 membered heterocyclyl group and 【Chemistry 2】 (E indicates a connection point.) Selected from, L ３ and L ３ ' together with the carbon atoms to which they are bonded can form a 3-6 membered carbocykyl group or a 4-6 membered heterocycline group connected to a linker, where the C １－８ Alkyl, C ２－８ Alkenil, C ２－８ Alkynyl group, carbocykyl group, heterocyclyl group and 【Transformation 3】 (E indicates a bond point.) is one or more R ｂ It may be substituted with the base; R ７ , R ８ and R ９ These are, independently, hydrogen, halogen, and C. １－８ Alkyl, C ２－８ Alkenil, C ２－８ Alkinyl, -Y-C ３－１２ Carbocyclyl, -W- (3-12 member heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ ,-O-(CR ｘ R ｙ ) ｎ -OR ｚ ,=O,=S,Nitro,Si(R) ｘ ) ４ ,-(CH ２ ) ｓ -CN, -S(O) ｑ - (CR ｘ R ｙ ) ｓ -R ｚ , -C(=O)R ｘ , -C(=S)R ｘ , -C(=N)R ｘ ,-(CR ｘ R ｙ ) ｓ -C (=O) OR ｚ ,-(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ ,-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ ,-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C (=O) OR ｙ ,-(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ ,-(CR ｘ R ｙ ) ｓ -C(=S)NR ｚ ,-(CR ｘ R ｙ ) ｓ -C(=N)NR ｘ , -S(O)(=NR ｘ ) R ｙ ,-(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ ,-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ ,-(CH ２ ) ｓ -SO ２ NR ｘ R ｙ group, -P(=O)(R ｘ ) ２ and -Y-C ５－１０ Selected from aryl, where C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ The alkynyl group is one or more R ｂ The groups may be substituted with R groups, and the carbocyclyl and heterocyclyl groups may be one or more (e.g., one, two, or three) R groups. ｂ It is also acceptable if it is substituted with the base; R ｂ These are halogen and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ - (5-10 membered ring heteroaryl), - (CH ２ ) ｓ - (4-7 member saturated heterocyclyl), - (CR ｘ R ｙ ) ｓ -O-R ｚ ,-O-(CR ｘ R ｙ ) ｎ -OR ｚ Hello C １－６ Alkyl, Halo C １－６ Alkoxy, hydroxy, hydroxy C １－６ Alkyl, =O, =S, Nitro, Si(Rx) ４ ,-(CH ２ ) ｓ -CN, -S(O) ｑ -R ｘ , -C(=O)R ｘ ,-(CR ｘ R ｙ ) ｓ -C (=O) OR ｚ ,-(CR ｘ R ｙ ) ｓ -OC(=O)-R ｚ ,-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ ,-(CH ２ ) ｓ -OC(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C (=O) OR ｙ - (CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ ,-(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｎ -OC(=O)-R ｚ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ ,-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ ,-(CH ２ ) ｓ -SO ２ NR ｘ R ｙ base and -P(=O)(R ｘ ) ２ Selected from, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, heterocyclyl, phenyl, and heteroaryl groups are one or more R ｘ It is also acceptable if it is substituted with the base; R ｘ , R ｙ and R ｚ These are, independently, halogen, hydrogen, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -(CH ２ ) ｓ -C ３－８ Cycloalkyl, -(CH ２ ) ｓ -C ３－８ Cycloalkenyl, -(CH ２ ) ｓ -phenyl, -(CH ２ ) ｓ -(4-7 member saturated heterocycline), hydroxy C which may be substituted with one or more halos １－６ Alkyl, -C(=O)OC １－６ Alkyl, hydroxy, C １－６ Alkoxy, Halo C １－６ Alkyl, -(CH ２ ) ｎ -O-C １－６ Alkyl, -C(=O)-(CH ２ ) ｎ -C １－６ Alkoxy, -C(=O)-C １－６ Alkyl, -(CH ２ ) ｓ -CN, C １－６ Alkyl-N(H) ２－ｑ (C １－６ Alkyl) ｑ , -N(H) ２－ｑ (C １－６ Alkyl) ｑ , -C(=O)-N(H) ２－ｑ (C １－６ Alkyl) ｑ ,-(CH ２ ) ｓ -NH-SO ２ -N(H) ２－ｑ (C １－６ Alkyl) ｑ ,-(CH ２ ) ｓ -N(C) １－４ Alkyl)-SO ２ -N(H) ２－ｑ (C １－６ Alkyl) ｑ and - (CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-N(H) ２－ｑ (C １－６ Alkyl) ｑ If selected from and bonded to a nitrogen, carbon, silicon, or phosphorus atom, R ｘ and R ｙ They may form a 3- to 7-membered ring, which may include one or two additional heteroatoms selected from O, N, S and oxidized N and S, along with the atoms to which they are bonded; Y and W are independent of each other, combined, -(CR ｘ R ｙ ) ｍ -, -C (=CR ｘ )-, -C(=O)-, -NR ｘ , -C(=O)NR ｘ -, -NR ｘ C(=O)-,-(CR ｘ R ｙ ) ｑ -O-, -O-(CR ｘ R ｙ ) ｑ -, -S(O) ２ -NH,NH-S(O) ２ - and -S(O) ｑ - Selected from; R １０ is hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -C(=O)NH （２－ｑ） (C １－６ Alkyl) ｑ ,-(CH ２ ) ｓ - (3-12 member heterocyclyl), - (CH ２ ) ｓ -C ３－１２ Carbocyclyl, -C(=O)-(3-12 member heterocyclyl), and -C(=O)-C ３－１２ Selected from carbocyclyl, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, heterocyclyl, and carbocyrillic groups are one or more R ｂ It is also acceptable if it is substituted with the base; s independently represents an integer between 0 and 4; n independently represents an integer between 1 and 4; q independently represents an integer between 0 and 2; m represents an integer between 1 and 2. L １ ~L ３ and L ３ In any one of the following cases, X is combined with L. A compound, its isomer, or a salt thereof.

2. The compound or isomer thereof, or a salt thereof, according to claim 1, wherein the intracellular protein in Z is serine / threonine kinase, receptor tyrosine kinase, non-receptor tyrosine kinase, or non-kinase.

3. The compound or isomer thereof according to claim 1, or a salt thereof, which has inhibitory activity or binding activity to intracellular proteins in Z.

4. The intracellular protein in Z is a serine / threonine kinase, and the serine / threonine kinase is ROCK2, the compound or isomer thereof according to claim 1, or a salt thereof.

5. The intracellular protein in Z is a receptor tyrosine kinase, and the receptor tyrosine kinase is ALK, the compound or isomer thereof according to claim 1, or a salt thereof.

6. The intracellular protein in Z is a non-receptor tyrosine kinase, and the non-receptor tyrosine kinase is FAK, the compound or isomer thereof according to claim 1, or a salt thereof.

7. The aforementioned X is L １ , L ２ , L ３ or L ３ The compound or isomer thereof according to claim 1, or a salt thereof, connected to L by any of the following:

8. The compound or isomer thereof according to claim 1, or a salt thereof, wherein Q is N.

9. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein Q is CH.

10. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein A is N.

11. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein A is CH.

12. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein B is N.

13. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein B is CH.

14. The aforementioned R １ and L that is not used in the combination with L １ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -C(=O)NH （２－ｑ） (C １－６ Alkyl) ｑ ,-(CH ２ ) ｓ - (3-7 member heterocyclyl), - (CH ２ ) ｓ -C ３－７ Carbocyclyl, -C(=O)-(3-7 member heterocyclyl), and -C(=O)-C ３－７ Selected from carbocyclyl, or R １ and L that is not used in the combination with L １ Together with the carbon atoms to which they are bonded, they can form a 3-6 member saturated carbocykyl group or a 4-6 member heterocycline group, where the C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, heterocyclyl, and carbocykyl groups are one or more R ｂ It may also be substituted with the base, The aforementioned R ｂ These are halogen and C, respectively, independently. １－４ Alkyl, C ３－４ Alkinyl, -(CH ２ ) ｑ -C ３－６ Cycloalkyl, -(CH ２ ) ｑ -phenyl, -(CH ２ ) ｑ - (5-6 membered ring heteroaryl), - (CH ２ ) ｑ -O-C １－４ Alkyl, Halo C １－４ Alkyl, Halo C １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, =O, -S(O) ｑ -C １－４ Alkyl, -C(=O)C １－４ Alkyl, -(CH ２ ) ｑ -C(=O)NR ｘ R ｙ ,-(CH ２ ) ｑ -NR ｘ C(=O)C １－４ Alkyl, -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｑ -C １－４ Alkyl, -(CH ２ ) ｑ -NR ｘ - (CH ２ ) ｑ -SO ２ -C １－４ Alkyl and -(CH ２ ) ｑ -SO ２ NR ｘ R ｙ Selected from the groups, where the cycloalkyl, phenyl, and heteroaryl groups are one or more R ｘ It may also be substituted with the base, R ｘ and R ｙ These are, independently, halogen, hydrogen, and C. １－４ Alkyl and C １－４ If selected from alkoxy and bonded to nitrogen or carbon, R ｘ and R ｙ The compound or isomer thereof according to claim 1, or a salt thereof, which may form a 3- to 7-membered ring together with the atoms to which they are bonded, which may include one additional heteroatom selected from O and N.

15. The aforementioned R １ and L that is not used in the combination with L １ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -C(=O)NH （２－ｑ） (C １－６ Alkyl) ｑ ,-(CH ２ ) ｓ - (3-7 member heterocyclyl), - (CH ２ ) ｓ -C ３－７ Carbocyclyl, -C(=O)-(3-7 member heterocyclyl), and -C(=O)-C ３－７ Selected from carbocyclyl, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, heterocyclyl, and carbocyrillic groups are one or more R ｂ It may be substituted with R ｂ These are independently fluorine, methyl, and C. ３－６ Cycloalkyl, phenyl, 5-6 membered ring heteroaryl, -O-C １－２ Alkyl, fluoromethyl, fluoromethoxy, hydroxy, =O, -S(O) ２ -C １－４ Alkyl, -C(=O)C １－４ Alkyl, -C(=O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl and -NR ｘ R ｙ Selected from the groups, where the cycloalkyl, phenyl, and heteroaryl groups are one or more R ｘ It may also be substituted with the base, R ｘ and R ｙ These are chlorine, fluorine, hydrogen, and C, respectively, independently. １－４ Alkyl and C １－４ If selected from alkoxy and bonded to nitrogen or carbon, R ｘ and R ｙ The compound or isomer thereof according to claim 1, or a salt thereof, which may form a 3- to 7-membered ring together with the atoms to which they are bonded, which may include one additional heteroatom selected from O and N.

16. The aforementioned R ２ａ and R ２ｂ Each of them is independently of hydrogen and C １－３ Alkyl, C ２－３ Alkenyl and C ２－３ Selected from Alkinyl, or R ２ａ and R ２ｂ The compound or isomer thereof according to claim 1, or a salt thereof, which can form a 3-4 membered saturated carbocykyl group together with the carbon atoms to which they are bonded.

17. The aforementioned R ２ａ and R ２ｂ The compound or isomer thereof according to claim 1, or a salt thereof, wherein the compound is hydrogen.

18. The aforementioned R ３ C １－４ It is alkyl, where C １－４ Alkyl is one or more R ａ The compound according to claim 1, or an isomer thereof, or a salt thereof, which may be substituted with a group.

19. The aforementioned R ３ The compound or isomer thereof according to claim 1, or a salt thereof, wherein is methyl, where the methyl may be substituted with one or more fluorines.

20. The aforementioned R ４ The compound or isomer thereof according to claim 1, or a salt thereof, wherein is hydrogen.

21. The aforementioned R ５ａ and R ５ｂ Each of them is independently of hydrogen and C １－８ Alkyl, C ２－８ Alkenil, C ２－８ Alkinyl, -Y-C ３－６ Carbocyclyl, -W- (3-6 member heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ ,-O-(CR ｘ R ｙ ) ｎ -OR ｚ ,-(CH ２ ) ｓ -CN and -C(=O)R ｘ Selected from, or R ５ａ and R ５ｂ These can form a 3- to 5-membered carbocykyl group or a 5- to 6-membered heterocycline group together with the carbon atoms to which they are bonded. Here C １－８ Alkyl, C ２－８ Alkenyl and C ２－８ The alkynyl group is one or more R ｂ The base may be substituted, and the R ｂ These are fluorine and C, respectively, independently. １－４ Alkyl, C ３－４ Alkinyl, -C ３－６ Cycloalkyl, -O-C １－４ Alkyl, fluoroC １－４ Alkyl, Halo C １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, -C(=O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ Alkyl and -NR ｘ R ｙ A compound or isomer thereof according to claim 1, or a salt thereof, selected from the groups.

22. The aforementioned R ５ａ and R ５ｂ Each is independently either hydrogen or methyl, or R ５ａ and R ５ｂ The compound or isomer thereof according to claim 1, or a salt thereof, which can form a cyclopropyl group together with the carbon atoms to which they are bonded.

23. The aforementioned R ６ However, hydrogen, halogen, C １－４ Alkyl, C ２－５ Alkenil, C ２－５ Alkinyl, -(CR ｘ R ｙ )-C ３－７ Carbocyclil, - (CR ｘ R ｙ )-(3-7 member heterocyclyl),-(CR ｘ R ｙ )-O-R ｚ ,-O-(CR ｘ R ｙ ) ｎ -OR ｚ ,-(CH ２ ) ｓ -CN, -S(O) ２ - (CH ２ ) ｓ -R ｚ , -C(=O)R ｘ ,-(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｓ -R ｚ ,-(CH ２ ) ｎ -C ５－１０ Aryl, - (CH ２ ) ｎ - (5-10 member ring heteroaryl), a condensable 5-7 member carbocyclyl group, a condensable 5-7 member heterocyclyl group and 【Chemistry 4】 (E indicates a connection point.) Selected from, L ３ and L ３ ' can form a 3-6 membered carbocykyl group or a 4-6 membered heterocycline group that can be linked to a linker, together with the carbon atoms to which they are bonded, where the C １－４ Alkyl, C ２－５ Alkenyl and C ２－５ Alkynyl group, carbocykyl group, heterocyclyl group, aryl group, heteroaryl group and 【Transformation 5】 (E indicates a bond point.) is one or more R ｂ The base may be substituted, and the R ｂ These are halogen and C, respectively, independently. １－４ Alkyl, C ３－４ Alkinyl, -(CH ２ ) ｑ -C ３－６ Cycloalkyl, -(CH ２ ) ｑ -phenyl, -(CH ２ ) ｑ - (5-6 membered ring heteroaryl), - (CH ２ ) ｑ -O-C １－４ Alkyl, Halo C １－４ Alkyl, Halo C １－４ Alkoxy, hydroxy, hydroxy C １－４ Alkyl, =O, -S(O) ｑ -C １－４ Alkyl, -C(=O)C １－４ Alkyl, -(CH ２ ) ｑ -C(=O)NR ｘ R ｙ ,-(CH ２ ) ｑ -NR ｘ C(=O)C １－４ Alkyl, -(CH ２ ) ｓ -NR ｘ R ｙ , -NR ｘ - (CH ２ ) ｑ -C １－４ Alkyl, -(CH ２ ) ｑ -NR ｘ - (CH ２ ) ｑ -SO ２ -C １－４ Alkyl and -(CH ２ ) ｑ -SO ２ NR ｘ R ｙ Selected from the groups, where the cycloalkyl, phenyl, and heteroaryl groups are one or more R ｘ It may also be substituted with the base, CR ｘ R ｙ CH ２ or CF ２ And other R ｘ , R ｙ and R ｚ These are hydrogen and C, respectively, independently. １－４ Alkyl, C ３－４ Alkinyl, FluoroC １－４ Alkyl and C １－４ Selected from alkoxy, R ｂ R as a substituent ｘ The base is halogen, hydrogen, C １－４ Alkyl and C １－４ A compound according to claim 1, an isomer thereof, or a salt thereof, selected from alkoxys.

24. The aforementioned R ６ However, - (CR ｘ R ｙ )-H,-(CR ｘ R ｙ )-F,-(CR ｘ R ｙ ) - C １－２ Alkyl, -(CR ｘ R ｙ )-O-phenyl,-S(O) ２ -CH ２ -R ｚ , -C(=O)C １－４ Alkyl, -C(=O)-phenyl, -C(=O)-(5-6 membered ring heteroaryl), -CH ２ -phenyl, -CH ２ - (5-6 membered ring heteroaryl), and 【Transformation 6】 (E indicates a connection point.) Selected from, L ３ and L ３ These can form 3-6 membered carbocykyl groups or 4-6 membered heterocyclyl groups that can be linked to a linker, along with the carbon atoms to which they are bonded. Here C １－２ Alkyl, C １－４ Alkyl, phenyl, heteroaryl groups and 【Transformation 7】 (E indicates a bond point.) is one or more C １－３ Alkyl alkyl groups, fluorine, chlorine, or -O-C １－３ The CR may be substituted with an alkyl group. ｘ R ｙ CH ２ or CF ２ And other R ｘ , R ｙ and R ｚ These are hydrogen and C, respectively, independently. １－４ Alkyl, C ３－４ Alkinyl, FluoroC １－４ Alkyl and C １－４ A compound according to claim 1, an isomer thereof, or a salt thereof, selected from alkoxys.

25. said R ７ is selected from hydrogen, halogen, C １－３ alkyl, C ２－３ alkenyl, C ２－３ alkynyl and C ３－４ carbocyclyl, wherein said C １－３ alkyl, C ２－３ alkenyl, C ２－３ alkynyl and C ３－４ carbocyclyl may be substituted with one or more R ｂ groups, and each said R ｂ is each independently selected from fluorine, -O-C １－４ alkyl, fluoro C １－４ alkoxy, hydroxy, and -NR ｘ R ｙ groups, R ｘ and R ｙ These are, independently, hydrogen and C １－４ If selected from alkyl groups and bonded to nitrogen, R ｘ and R ｙ The compound or isomer thereof according to claim 1, or a salt thereof, which may form a 4- to 6-membered ring together with the atoms to which they are bonded, which may include one additional heteroatom selected from O and N.

26. said R ７ is hydrogen or fluorine, the compound according to claim 1, an isomer thereof, or a salt thereof.

27. The aforementioned R ８ The compound or isomer thereof according to claim 1, or a salt thereof, wherein the compound is hydrogen.

28. The aforementioned R ９ is hydrogen, halogen, C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, -Y-C ３－６ Carbocyclyl, -W- (4-6 member heterocyclyl), -(CR ｘ R ｙ ) ｓ -O-R ｚ ,-O-(CR ｘ R ｙ ) ｎ -OR ｚ , = O, - (CH ２ ) ｓ -CN, -C(=O)R ｘ ,-(CR ｘ R ｙ ) ｓ -C(=O)NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ C(=O)R ｙ ,-(CH ２ ) ｓ -NR ｘ R ｙ ,-(CH ２ ) ｓ -OC(=O)-C １－４ Alkyl-NR ｘ R ｙ ,-(CH ２ ) ｓ -NR ｘ - (CH ２ ) ｓ -SO ２ -R ｙ ,-(CH ２ ) ｓ -NH-SO ２ -NR ｘ R ｙ ,-(CH ２ ) ｓ -SO ２ NR ｘ R ｙ , and -Y-C ５－１０ Selected from aryl, where C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkynyl, carbocyclyl and heterocyclyl groups may be substituted with one or more R ｂ groups, and each R ｂ is independently selected from fluorine, C １－４ alkyl, C ３－４ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-C １－４ alkyl, fluoro C １－４ alkyl, fluoro C １－４ alkoxy, hydroxy, hydroxy C １－４ alkyl, =O, -C(=O)C １－４ alkyl, -C(=O)NR ｘ R ｙ , -NR ｘ C(=O)C １－４ alkyl, and -NR ｘ R ｙ groups, wherein said cycloalkyl, phenyl and heteroaryl groups may be substituted with one or more R ｘ groups, The aforementioned R ｘ , R ｙ and R ｚ These are chlorine, fluorine, hydrogen, and C, respectively, independently. １－４ Alkyl and C １－４ If selected from alkoxy and bonded to nitrogen or carbon, R ｘ and R ｙ The compound according to claim 1, wherein the atoms may form a 3- to 7-membered ring, which may include one additional heteroatom selected from O and N, together with the atoms to which they are bonded.

29. The aforementioned R ９ is hydrogen, C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, -CH ２ -C ３－６ Carbocyclyl, -CH ２ - (4-6 member heterocyclyl), -CH ２ -O-R ｚ -C(=O)R ｘ , and -CH ２ -NR ｘ R ｙ Selected from, where C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, carbocykrill, and heterocyclyl groups are one or more R ｂ The base may be substituted, and the R ｂ These are fluorine and C, respectively, independently. １－４ Alkyl, C ３－４ Alkynyl, phenyl, 5-6 membered ring heteroaryl, -O-C １－４ Alkyl, fluoroC １－４ Alkyl, fluoroC １－４ Alkoxy, hydroxy, and -NR ｘ R ｙ Selected from the groups, where the phenyl and heteroaryl groups are one or more R ｘ It may also be substituted with the base, The aforementioned R ｘ , R ｙ and R ｚ These are chlorine, fluorine, hydrogen, and C, respectively, independently. １－４ Alkyl and C １－４ If selected from alkoxy and bonded to nitrogen or carbon, R ｘ and R ｙ The compound according to claim 1, wherein the atoms may form a 3- to 7-membered ring, which may include one additional heteroatom selected from O and N, together with the atoms to which they are bonded.

30. The aforementioned R １０ The compound according to claim 1, wherein the compound is hydrogen or methyl.

31. The compound according to claim 1, represented by the following structure: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】

32. A pharmaceutical composition comprising a compound or an isomer thereof, or a salt thereof, as described in any one of claims 1 to 31.

33. A target protein regulator comprising the compound or isomer thereof, or a salt thereof, according to any one of claims 1 to 31.

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