Proline amide derivative

Abstract

The present invention addresses the problem of providing: a novel compound that induces degradation of the target protein P13Kα; and a pharmaceutical containing this compound. The present invention relates to a compound represented by formula (I) (the symbols in the formula are as defined in the Description) or a salt thereof, and a pharmaceutical containing this compound.

Description

Prolineamide derivatives

[0001] This invention relates to a novel compound that induces the degradation of the target protein PI3Kα, and to pharmaceuticals and other products containing said compound.

[0002] PI3K (phosphatidylinositol-3 kinase) is a family of lipid kinases consisting of three classes, of which class I PI3K has four isoforms in its catalytic subunit: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. PI3Kα, encoded by the PIK3CA gene, is recruited to the cell membrane in response to a signal from receptor tyrosine kinase. There, it phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid present in the cell membrane, to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a crucial role as a second messenger in intracellular signal transduction, recruiting kinases such as AKT and PDK1 to the cell membrane, thereby activating the downstream PI3K / AKT / mTOR signaling pathway and promoting diverse functions such as cell proliferation, metabolism, and angiogenesis (Non-Patent Literature 1).

[0003] Mutations in PIK3CA are frequently observed in various cancer types, including breast cancer (Non-Patent Literature 2, 3), and mutations in glutamic acid at positions 542 and 545 and histidine at position 1047, in particular, are known as driver mutations that enhance PIK3CA kinase activity (Non-Patent Literature 4), leading to the development of various PI3Kα inhibitors (Non-Patent Literature 5).

[0004] On the other hand, in recent years, the usefulness of heterobifunctional molecules, in which a portion that binds to a target protein and a portion that recruits endogenous effector molecules are linked via a linker, has been reported. Heterobifunctional molecules exert the desired effect by causing changes in the target protein by physically bringing the target protein and endogenous effector molecules into close proximity (Non-Patent Literature 6).

[0005] One technique that utilizes such heterobifunctional molecules is Targeted Protein Degradation (TPD). TPD is a technique that induces the degradation of target proteins. It uses a heterobifunctional molecule in which a binder portion that binds to the target protein and a binder portion that binds to an E3 ligase are linked by a linker. This induces the formation of a complex between the target protein and the E3 ligase within the cell, thereby inducing ubiquitination and degradation of the target protein and exhibiting potent physiological activity. More than 600 types of E3 ligases have been identified, but only a limited number are used in TPD, particularly cereblon (CRBN) and von Hippel-Lindau (VHL) (Non-Patent Document 7). In particular, the binder portion that binds to CRBN (also called "CRBN ligand") is widely used in TPD, and its diverse structures and usefulness have been reported (Patent Documents 1-9, Non-Patent Document 8).

[0006] International Publication No. 2017 / 197051, International Publication No. 2018 / 237026, International Publication No. 2019 / 060693, International Publication No. 2019 / 060742, International Publication No. 2019 / 099868, International Publication No. 2019 / 199816, International Publication No. 2020 / 210630, International Publication No. 2022 / 081927, International Publication No. 2022 / 081928

[0007] Cell, 170, 605-635 (2017)Science, 304, 554 (2004)Nature, Cancer, 2, 587-597 (2021)Breast Cancer Res Treat., Nov;112(2):217-27 (2008)Nat Rev Drug Discov., Oct;20(10):741-769 (2021)J. Med. Chem., 65: 8091-8112 (2022)Chem. Soc. Rev., 51: 7066-7114 (2022)Expert Opinion on Therapeutic Patents, 32: 2: 171-190 (2022)

[0008] An object of the present invention is to provide a novel compound that induces degradation of the target protein PI3Kα. Another object of the present invention is to provide a novel compound having cereblon (CRBN) E3 ligase binding activity (hereinafter sometimes referred to as "CRBN binding activity") and target protein PI3Kα binding activity. A further object of the present invention is to provide a novel compound that induces degradation of the target protein PI3Kα by binding to CRBN and PI3Kα. Another object of the present invention is to provide a medicament containing the novel compound.

[0009] As a result of intensive studies, the present inventors found that a compound represented by the following formula (I) or a salt thereof induces degradation of the target protein PI3Kα, and thereby found that it can exert a desired therapeutic effect on diseases associated with PI3Kα. Furthermore, the present inventors found that the compound represented by formula (I) or a salt thereof has both CRBN binding activity and PI3Kα binding activity, and completed the present invention.

[0010] That is, the present invention relates to the following. [1] Formula (I):

[0011]

[0012] [In formula (I), E is represented by the following formula:

[0013]

[0014] (In formulas (a) to (d), R ａ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy, and R ｂ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy, and R ｃ１ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C１－３ It is a haloalkoxy, and R ｃ２ C is a hydrogen atom. １－３ Alkyl, 3- to 7-membered aliphatic hydrocarbon ring group, or 4- to 7-membered aliphatic heterocyclic group, R ｄ１ is a hydrogen atom, halogen, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ It is a haloalkoxy, and R ｄ２ C is a hydrogen atom. １－３ Alkyl, 3- to 7-membered aliphatic hydrocarbon ring group, or 4- to 7-membered aliphatic heterocyclic group, X ａ , X ｂ , X ｃ , X ｄ , Y ａ , Y ｂ , Y ｃ , and Y ｄ Each is independently a carbon atom or a nitrogen atom, and * indicates the bonding position with L. ) is a group selected from the group consisting of the following, where L is a group of formulas (II):

[0015]

[0016] {In formula (II), Q １ These are G １ A divalent 6-membered aromatic hydrocarbon ring group, a 5- to 6-membered aromatic heterocyclic group, a 4- to 7-membered aliphatic hydrocarbon ring group, a 4- to 7-membered aliphatic heterocyclic group, or a bicyclic group combining these, which may be further substituted with one to three identical or different substituents selected from the group, G １ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ It consists of alkoxy, Q ２ These are G ２ A divalent, 4- to 7-membered aliphatic hydrocarbon ring group, a 4- to 7-membered aliphatic heterocyclic ring group, or a bicyclic group combining the same, which may be further substituted with 1 to 3 identical or different substituents selected from the group, G ２ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ Composed of alkoxy, L １This is a single bond, methylene, -C(O)-, a divalent six-membered aromatic hydrocarbon ring group, or the following formula:

[0017]

[0018] (In the formula, *1 is Q) １ This is the bonding position with L, and *2 is L ２ This is the bonding position with R, and Ｌ (is a hydrogen atom, a fluorine atom, or a hydroxyl group.) is a divalent group selected from the group consisting of L ２ This is a single bond, methylene, -C(O)-, a divalent aromatic hydrocarbon ring group, or the following formula:

[0019]

[0020] (In the formula, *2 is L １ This is the bonding position with Q, and *3 is Q ２ This is the bonding position with R, and Ｌ The above is equivalent to the above.) A divalent group selected from the group consisting of, where * is the bond position with E, and the wavy line is the bond position with T. However, Q １ and L １ , L １ and L ２ , and L ２ and Q ２ These do not form bonds with each other's nitrogen atoms.} is a group represented by}, and T is the target protein PI3Kα binding motif. ] A compound represented by ] (hereinafter sometimes abbreviated as "the compound of the present invention") or a salt thereof. [2] T is of formula (III):

[0021]

[0022] [In formula (III), R １ and R ２ These are, independently, a hydrogen atom, a halogen, and C. １－６ Alkyl, or C １－３ It is either a haloalkyl or R １ and R ２ These atoms bond to each other, and together with the carbon atoms they bond to, form a 5- to 7-membered aliphatic hydrocarbon ring, Q ３ G３ A divalent aromatic heterocyclic group which may be further substituted with one or two identical or different substituents selected from the group, G ３ The group consists of halogens, di(C) １－３ Alkyl)amino, morpholinyl, and the following formula:

[0023]

[0024] (In the formula, R ３ , R ４ , and R ５ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R ３ , R ４ , and R ５ Two of them bond to each other, and together with the carbon atoms they bond to, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, and ● is Q ３ The compound or salt thereof described in [1], which consists of a group indicated by ) and the wavy line indicates the bond position with L. [3] E is of the following formula:

[0025]

[0026] [In equations (a1) to (d1), R ａ , R ｂ , R ｃ１ , R ｄ１ , X ａ , Y ａ , Y ｃ , Y ｄ , and * are synonymous with [1]. A compound or salt thereof described in [1] or [2], which is any group selected from the group consisting of ]. [4] E is of the following formula:

[0027]

[0028] A compound or salt thereof described in any one of [1] to [3], which is any group selected from the group consisting of [In the formula, * is synonymous with [1].] [4-2] E is of the following formula:

[0029]

[0030] [wherein * has the same definition as in [1]. ] The compound or a salt thereof according to any one of [1] to [3], which is any group selected from the group consisting of: [4-3] E is represented by the following formula:

[0031]

[0032] [wherein * has the same definition as in [1]. ] The compound or a salt thereof according to any one of [1] to [3], which is a group represented by: [4-4] E is represented by the following formula:

[0033]

[0034] [wherein * has the same definition as in [1]. ] The compound or a salt thereof according to any one of [1] to [3], which is a group represented by: [4-5] E is represented by the following formula:

[0035]

[0036] [wherein * has the same definition as in [1]. ] The compound or a salt thereof according to any one of [1] to [3], which is a group represented by: [4-6] E is represented by the following formula:

[0037]

[0038] [wherein * has the same definition as in [1]. ] The compound or a salt thereof according to any one of [1] to [3], which is a group represented by: [5] T is represented by the following formula:

[0039]

[0040] [wherein, X １ is a nitrogen atom or a carbon atom, and R ６ , R ７ , and R ８ are each independently a hydrogen atom, C １－４ alkyl, or C １－４ haloalkyl, or two of R ６ , R ７ , and R ８ are bonded to each other and together with the carbon atom to which they are bonded form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocyclic ring, and R ９ , R１０ , and R １１ are each independently a hydrogen atom, C １－４ alkyl, or C １－４ haloalkyl, or two of R ９ , R １０ , and R １１ are bonded to each other, and together with the carbon atom to which they are bonded form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocyclic ring; R １２ , R １３ , and R １４ are each independently a hydrogen atom, C １－４ alkyl, or C １－４ haloalkyl, or two of R １２ , R １３ , and R １４ are bonded to each other, and together with the carbon atom to which they are bonded form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocyclic ring; and the wavy line indicates the position of bonding to L. The compound or a salt thereof according to any one of [1] to [4-6], which is a group represented by ]. [6] T is represented by the following formula:

[0041]

[0042] [wherein the wavy line has the same definition as in [5]]. The compound or a salt thereof according to [5], which is a group represented by . [6-2] T is represented by the following formula:

[0043]

[0044] [wherein the wavy line has the same definition as in [5]]. The compound or a salt thereof according to [5], which is a group represented by . [6-3] T is represented by the following formula:

[0045]

[0046] [wherein the wavy line has the same definition as in [5]]. The compound or a salt thereof according to [5], which is a group represented by . [6-4] T is represented by the following formula:

[0047]

[0048] [In the formula, the dashed line is synonymous with [5].] The compound or salt thereof described in [5], which is the group represented by [6-5] T is given by the following formula:

[0049]

[0050] [In the formula, the dashed line is synonymous with [5].] The compound or salt thereof described in [5], which is the group represented by [7] L is of the following formula:

[0051]

[0052] [In the formula, m and n are each independently integers from 1 to 3, and m + n is an integer from 2 to 5, X ２ and X ３ Each is independently either a nitrogen atom or a carbon atom, and R １５ L is a hydrogen atom, a fluorine atom, or a hydroxyl atom. １ , L ２ , *, and the dashed line are synonymous with [1]. A compound or salt thereof described in any one of [1] to [6-5], which is a group indicated by ]. [8] A compound or salt thereof described in [7], wherein m is 2 and n is 2. [9] *1-L １ -L ２ -*3 is expressed by the following formula:

[0053]

[0054] [In the formula, *1 and *3 are synonymous with [1].] A compound or salt thereof that is represented by any one of [1] to [8]. [9-2] *1-L １ -L ２ -*3 is expressed by the following formula:

[0055]

[0056] [In the formula, *1 and *3 are synonymous with [1].] A compound or salt thereof, which is a group represented by [1] or [8], as described in any one of [1] to [8]. [9-3] *1-L １ -L ２ -*3 is expressed by the following formula:

[0057]

[0058] [In the formula, *1 and *3 are synonymous with [1].] A compound or salt thereof, which is a group represented by [1] or [8], as described in any one of [1] to [8]. [9-4] *1-L １ -L ２ -*3 is expressed by the following formula:

[0059]

[0060] [In the formula, *1 and *3 are synonymous with [1].] A compound or salt thereof, which is a group represented by any one of [1] to [8].

[10] L is of the following formula:

[0061]

[0062] [In the formula, * and the dashed line are synonymous with [1].] A compound or salt thereof described in any one of [1] to [9-4], which is a group represented by [10-2] L is given by the following formula:

[0063]

[0064] [In the formula, * and the dashed line are synonymous with [1].] A compound or salt thereof described in any one of [1] to [9-4], which is a group represented by [10-3] L is given by the following formula:

[0065]

[0066] [In the formula, * and the dashed line are synonymous with [1].] A compound or salt thereof described in any one of [1] to [9-4], which is a group represented by [10-4]. [10-4] L is given by the following formula:

[0067]

[0068] [In the formula, * and the dashed line are synonymous with [1].] A compound or salt thereof described in any one of [1] to [9-4], which is a group represented by

[11] E is of the following formula:

[0069]

[0070] (In the formula, * is synonymous with [1].) The base is represented by the following formula, where T is:

[0071]

[0072] (In the formula, X １ R is a nitrogen atom or a carbon atom. ９ , R １０ , and R １１ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R ９ , R １０ , and R １１ Two of them bond to each other, and together with the carbon atoms to which they bond, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, R １２ , R １３ , and R １４ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R １２ , R １３ , and R １４ Two of these groups bond to each other, and together with the carbon atoms they bond to, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, and the dashed lines indicate the bonding positions with L. ) These groups are represented by the formula below, and L is given by the formula below:

[0073]

[0074] [In the formula, m and n are each independently integers from 1 to 3, and m + n is an integer from 2 to 5, X ２ and X ３ Each is independently either a nitrogen atom or a carbon atom, and R １５ is a hydrogen atom, a fluorine atom, or a hydroxyl atom, *1-L １ -L ２ -*3 is expressed by the following formula:

[0075]

[0076] (In the formula, *1 and *3 are the same as in [1].) The compound or salt thereof described in [1], where * is the bond position with E and the wavy line is the bond position with T. [11-2] E is of the following formula:

[0077]

[0078] (In the formula, * is synonymous with [1].) The base is represented by the following formula, where T is:

[0079]

[0080] (In the formula, the dashed line is equivalent to [1].) The base is shown by, and L is given by the following formula:

[0081]

[0082] (In the formula, * and the dashed line are synonymous with [1].) The compound or salt thereof described in [1], which is represented by the group shown in [1].

[12] (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1-(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1-(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-(4-{1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}benzyl)-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)pyrrolidine-1,2-dicarboxamide, and (2S,3R)-N 1 Any one compound selected from the group consisting of -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)pyrrolidine-1,2-dicarboxamide or a salt thereof. [12-2] (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1-(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -{5-[6-(diethylamino)pyrazine-2-yl]-4-methyl-1,3-thiazole-2-yl}-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrroridine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrorol[3,4-b]pyridine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3S)-3-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-4-yl}methyl)piperazine-1-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-1-yl}methyl)benzyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3S)-3-{[5-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-1-yl}methyl)pyridine-2-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[2-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-4-yl}methyl)-2,3-dihydro-1H-isoindole5-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-({1-[(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)methyl]piperidine-4-yl}methyl)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, and (2S,3R)-3-({1-[(4-{4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1 -A compound selected from the group consisting of {4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide or a salt thereof. [12-3] (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, and (2S,3R)-N 1Any one compound selected from the group consisting of -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarboxamide or a salt thereof. [12-4] (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, and (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -A compound selected from the group consisting of (4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide or a salt thereof. [12-5] (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, and (2S,3R)-N 1Any one compound selected from the group consisting of -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide or a salt thereof. [12-6] (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, and (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -A compound selected from the group consisting of {4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide or a salt thereof. [12-7] (2S,3R)-N 1-(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide 4-methylbenzene sulfonate. [12-8] (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide-4-methylbenzenesulfonate. [12-9] (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide 2-naphthalene sulfonate. [12-10] (2S,3R)-N 1-(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide-2-naphthalene sulfonate. [12-11] (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide 4-methylbenzene sulfonate. [12-12] (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide-4-methylbenzenesulfonate. [12-13] (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide 2-naphthalene sulfonate. [12-14] (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide-2-naphthalene sulfonate.

[13] A pharmaceutical product containing any one of the compounds described in [1] to [12-14] or a pharmaceutically acceptable salt thereof as an active ingredient.

[14] A pharmaceutical composition for inhibiting or degrading phosphatidylinositol 3-kinase alpha (PI3Kα), comprising any one of the compounds described in [1] to [12-14] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[15] The pharmaceutical product according to

[13] for treating cancer.

[16] The pharmaceutical product according to

[15] , wherein the cancer is breast cancer.

[17] A method for treating cancer, comprising the step of administering a therapeutically effective amount of any one of [1] to [12-14] or a pharmaceutically acceptable salt thereof to a subject in need of treatment for cancer.

[18] The method according to

[17] , wherein the cancer is breast cancer.

[19] A compound according to any one of [1] to [12-14] or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[20] A compound according to

[19] or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer.

[21] Use of a compound according to any one of [1] to [12-14] or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of cancer.

[22] The use according to

[21] , wherein the cancer is breast cancer. For example, if the item numbers are indicated as a range, such as "[1] to [9-4]" above, and there are items with sub-numbers such as [6-4] or [9-3] within that range, then the items with those sub-numbers are also included in that range.

[0083] The compound represented by formula (I) of the present invention or a salt thereof (a pharmaceutically acceptable salt) induces the degradation of the target protein PI3Kα and can therefore be used for the therapeutic purposes of diseases related to PI3Kα. Furthermore, the compound represented by formula (I) of the present invention or a salt thereof can induce the degradation of PI3Kα by binding to CRBN and PI3Kα.

[0084] <1. Definitions> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In the event of any conflict between the meaning of a term as defined herein and the meaning commonly understood by those skilled in the art, the meaning as defined herein shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in carrying out or testing the present invention. All references (including patent and non-patent documents) cited herein are incorporated herein by reference in their entirety. The materials, methods and examples disclosed herein are illustrative and not intended to limit the scope of the invention.

[0085] In this specification, "halogen" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0086] In this specification, "alkyl" means a linear or branched alkyl group. In this specification, "C １－６ "Alkyl" means an alkyl group having 1 to 6 carbon atoms, and "C １－４ "Alkyl" means an alkyl group having 1 to 4 carbon atoms, and "C １－３ "Alkyl" refers to an alkyl group having one to three carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl. In this specification, "tert" is synonymous with "tertiary" or "t-" and has the same meaning.

[0087] In this specification, "haloalkyl" means an alkyl group substituted with one or more halogens, preferably an alkyl group substituted with 1 to 7 halogens, more preferably an alkyl group substituted with 1 to 5 halogens, even more preferably an alkyl group substituted with 1 to 3 halogens, and may also mean an alkyl group substituted with 1 halogen. "Halogen" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom. １－６ "Haloalkyl" refers to a C atom substituted with one or more halogens. １－６ It means alkyl. １－４ "Haloalkyl" refers to a C atom substituted with one or more halogens. １－４ It means alkyl. １－３ "Haloalkyl" refers to a C atom substituted with one or more halogens. １－３ This refers to alkyl groups. Examples of "haloalkyl" include trifluoromethyl, difluoromethyl, monofluoromethyl, pentafluoroethyl, tetrafluoroethyl, monofluoroethyl, trifluoroethyl, and trichloromethyl, but are not limited to these.

[0088] In this specification, "aliphatic hydrocarbon ring" means a monocyclic or bicyclic hydrocarbon ring that does not possess aromaticity. Examples of such rings include saturated or unsaturated rings, with saturated rings being exemplified as a preferred embodiment. A monocyclic ring is exemplified as a preferred embodiment of the aliphatic hydrocarbon ring. The notation "four- to seven-membered aliphatic hydrocarbon ring" means an aliphatic hydrocarbon ring consisting of four to seven ring-forming atoms. Examples of "aliphatic hydrocarbon rings" include, but are not limited to, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene, and cycloheptene.

[0089] In this specification, "aliphatic heterocycle" means a monocyclic or bicyclic ring that does not have an aromatic character and contains one or more heteroatoms selected from atoms other than carbon, such as nitrogen, oxygen, and sulfur, as ring constituent atoms. Examples of such rings include saturated and unsaturated rings, with saturated rings being exemplified as a preferred embodiment. A monocyclic ring is exemplified as a preferred embodiment of the aliphatic heterocycle. The notation "4- to 7-membered aliphatic heterocycle" means an aliphatic heterocycle consisting of 4 to 7 ring constituent atoms. Examples of "aliphatic heterocycles" include, but are not limited to, azetidine, pyrrolidine, pyrroline, piperidine, piperazine, dihydroazepine, azepine, tetrahydrofuran, tetrahydropyran, pyran, morpholine, tetrahydrothiophene, and thian.

[0090] In this specification, "aromatic hydrocarbon ring" means a monocyclic or bicyclic hydrocarbon ring having aromatic properties. A monocyclic aromatic hydrocarbon ring is exemplified as a preferred embodiment. The notation "six-membered aromatic hydrocarbon ring" means an aromatic hydrocarbon ring consisting of six ring-constituting carbon atoms, i.e., a benzene ring.

[0091] In this specification, “aromatic heterocycle” means an aromatic monocyclic or bicyclic heterocycle having one or more heteroatoms selected from atoms other than carbon, such as nitrogen, oxygen, and sulfur, as ring constituent atoms. Monocyclic rings are exemplified as a preferred embodiment of aromatic heterocycles. “Five- to six-membered aromatic heterocycle” means an aromatic heterocycle consisting of five to six ring constituent atoms. Examples of “five- to six-membered aromatic heterocycles” include, but are not limited to, pyrrole, pyrazole, imidazole, triazole, furan, thiophene, oxazole, thiazole, pyridine, pyrimidine, pyridazine, or pyrazine.

[0092] As used herein, the terms "aliphatic hydrocarbon ring group", "aliphatic heterocyclic group", "aromatic hydrocarbon ring group", or "aromatic heterocyclic group" refer to monovalent groups obtained by removing one hydrogen atom respectively from the aforementioned "aliphatic hydrocarbon ring", "aliphatic heterocyclic ring", "aromatic hydrocarbon ring", or "aromatic heterocyclic ring". In addition, divalent "aliphatic hydrocarbon ring group", "aliphatic heterocyclic group", "aromatic hydrocarbon ring group", or "aromatic heterocyclic group" refer to groups obtained by removing two hydrogen atoms respectively from the aforementioned "aliphatic hydrocarbon ring", "aliphatic heterocyclic ring", "aromatic hydrocarbon ring", or "aromatic heterocyclic ring".

[0093] As used herein, unless otherwise specified, as will be apparent to those skilled in the art, the symbol:

[0094]

[0095] means that the bond is on the opposite side of the paper plane (α-configuration), and the symbol:

[0096]

[0097] means that the bond is on the near side of the paper plane (β-configuration), and the symbol:

[0098]

[0099] means a mixture of the α-configuration and the β-configuration.

[0100] (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-1-yl)-1-hydroxycyclohexyl]acetyl}piperidin-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}pyrrolidine-1,2-dicarboxamide is (2S,3R)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-1-hydroxycyclohexyl)acetyl]piperidin-4-yl}methyl)-N1 -This refers to the same compound as {4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide.

[0101] (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide is (2S,3R)-N 1 This refers to the same compound as -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)pyrrolidine-1,2-dicarboxamide.

[0102] (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide is (2S,3R)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1means the same compound as -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridin-4-yl}-1,3-thiazol-2-yl)pyrrolidine-1,2-dicarboxamide.

[0103] (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-1-yl)-1-hydroxycyclohexyl]acetyl}piperidin-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridin-4-yl}-1,3-thiazol-2-yl)pyrrolidine-1,2-dicarboxamide is (2S,3R)-3-(4-{1-[(cis-4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-1-hydroxycyclohexyl)acetyl]piperidin-4-yl}benzyl)-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridin-4-yl}-1,3-thiazol-2-yl)pyrrolidine-1,2-dicarboxamide means the same compound.

[0104] (2S,3R)-N 1 -[5-(2-tert-butylpyrimidin-4-yl)-4-methyl-1,3-thiazol-2-yl]-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidin-1-yl)-1-hydroxycyclohexyl]acetyl}piperidin-4-yl)methyl]pyrrolidine-1,2-dicarboxamide is (2S,3R)-N 1This refers to the same compound as -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)pyrrolidine-1,2-dicarboxamide.

[0105] (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarboxamide is (2S,3R)-N 1 This refers to the same compound as -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-({1-[(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)pyrrolidine-1,2-dicarboxamide.

[0106] In this specification, "pharmaceutically acceptable" means that it does not have significant toxicity and can be used as a medicine. Therefore, in this specification, "pharmaceutically acceptable salt" means a salt that does not have significant toxicity and can be used as a medicine.

[0107] In this specification, "prevention" includes preventing the onset of disease, delaying the onset of disease, and preventing the development of a pathological condition.

[0108] In this specification, “treatment” includes the cure of a disease, the improvement of the pathology of a disease (e.g., one or more symptoms), and the suppression of the progression of a disease (or its severity).

[0109] In this specification, “effective dose” or “therapeutic dose” means an amount that is effective in treating, preventing progression of, or alleviating the existing symptoms of the subject being treated. The determination of the effective dose can be carried out appropriately in accordance with conventional methods, taking into account the desired therapeutic effect and side effects.

[0110] In this specification, “subject” means a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of active ingredients necessary to prevent and / or treat (or improve) a disease or the pathological condition of a disease is administered. Examples of such “subjects” include humans and non-human animals, and in particular mammals (e.g., humans, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, etc.).

[0111] <2. Target protein PI3Kα degradation inducer> In one embodiment of the present invention, Formula (I):

[0112]

[0113] [In equation (I), E is given by the following equation:

[0114]

[0115] (In equations (a) to (d), R ａ is a hydrogen atom, halogen, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ It is a haloalkoxy, and R ｂ is a hydrogen atom, halogen, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ It is a haloalkoxy, and R ｃ１ is a hydrogen atom, halogen, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ It is a haloalkoxy, and R ｃ２ C is a hydrogen atom. １－３ Alkyl, 3- to 7-membered aliphatic hydrocarbon ring group, or 4- to 7-membered aliphatic heterocyclic group, R ｄ１ is a hydrogen atom, halogen, C１－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ It is a haloalkoxy, and R ｄ２ C is a hydrogen atom. １－３ Alkyl, 3- to 7-membered aliphatic hydrocarbon ring group, or 4- to 7-membered aliphatic heterocyclic group, X ａ , X ｂ , X ｃ , X ｄ , Y ａ , Y ｂ , Y ｃ , and Y ｄ Each is independently a carbon atom or a nitrogen atom, and * indicates the bonding position with L. ) is a group selected from the group consisting of ), where L is a group of formula (II):

[0116]

[0117] {In formula (II), Q １ These are G １ A divalent 6-membered aromatic hydrocarbon ring group, a 5- to 6-membered aromatic heterocyclic group, a 4- to 7-membered aliphatic hydrocarbon ring group, a 4- to 7-membered aliphatic heterocyclic group, or a bicyclic group combining these, which may be further substituted with one to three identical or different substituents selected from the group, G １ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ It consists of alkoxy, Q ２ These are G ２ A divalent, 4- to 7-membered aliphatic hydrocarbon ring group, a 4- to 7-membered aliphatic heterocyclic ring group, or a bicyclic group combining the same, which may be further substituted with 1 to 3 identical or different substituents selected from the group, G ２ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ Composed of alkoxy, L １ This is a single bond, methylene, -C(O)-, a divalent six-membered aromatic hydrocarbon ring group, or the following formula:

[0118]

[0119] (In the formula, *1 is Q) １This is the bonding position with L, and *2 is L ２ This is the bonding position with R, and Ｌ (is a hydrogen atom, a fluorine atom, or a hydroxyl group.) is a divalent group selected from the group consisting of L ２ This is a single bond, methylene, -C(O)-, a divalent aromatic hydrocarbon ring group, or the following formula:

[0120]

[0121] (In the formula, *2 is L １ This is the bonding position with Q, and *3 is Q ２ This is the bonding position with R, and Ｌ The above is equivalent to the above.) A divalent group selected from the group consisting of, where * is the bond position with E, and the wavy line is the bond position with T. However, Q １ and L １ , L １ and L ２ , and L ２ and Q ２ The nitrogen atoms do not form bonds with each other. The group is represented by}, and T is the target protein PI3Kα binding motif. A compound or salt thereof represented by ] is provided.

[0122] In one embodiment of the present invention, E in formula (I) is given by the following formula:

[0123]

[0124] An example is given of one group selected from the group consisting of the following.

[0125] In the above equations (a) to (d), R ａ Examples include hydrogen atoms, halogens, and C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ Haloalkoxys are given as an example. ｂ Examples include hydrogen atoms, halogens, and C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ Haloalkoxys are given as an example.ｃ１ Examples include a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy. R ｃ２ Examples include a hydrogen atom, C １－３ alkyl, a 3- to 7-membered aliphatic hydrocarbon cyclic group, or a 4- to 7-membered aliphatic heterocyclic group. R ｄ１ Examples include a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy. R ｄ２ Examples include a hydrogen atom, C １－３ alkyl, a 3- to 7-membered aliphatic hydrocarbon cyclic group, or a 4- to 7-membered aliphatic heterocyclic group. X ａ , X ｂ , X ｃ , X ｄ , Y ａ , Y ｂ , Y ｃ , and Y ｄ are each independently exemplified by a carbon atom or a nitrogen atom. * is the bonding position to L.

[0126] As another embodiment of E, the following formula:

[0127]

[0128] (wherein each symbol in formulas (a1) to (d1) has the same definition as each symbol in formulas (a) to (d) above.) Any one group selected from the group consisting of is exemplified.

[0129] As another embodiment of E, the following formula:

[0130]

[0131] (wherein * has the same definition as * in formulas (a) to (d) above.) Any one group selected from the group consisting of is exemplified.

[0132] As another embodiment of E, the following formula:

[0133]

[0134] (In the formulas, * is equivalent to * in formulas (a) to (d) above.) This is an example.

[0135] In one embodiment of the present invention, L in formula (I) is:

[0136]

[0137] The group shown is an example.

[0138] In formula (II), Q １ As for each, G １ Examples include divalent six-membered aromatic hydrocarbon ring groups, five- to six-membered aromatic heterocyclic groups, four- to seven-membered aliphatic hydrocarbon ring groups, four- to seven-membered aliphatic heterocyclic groups, or bicyclic groups combining these, which may be further substituted with one to three identical or different substituents selected from the group. １ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ It consists of alkoxy. Q ２ As for each, G ２ Examples include divalent 4- to 7-membered aliphatic hydrocarbon ring groups, 4- to 7-membered aliphatic heterocyclic groups, or bicyclic groups combining these, which may be further substituted with one to three identical or different substituents selected from the group. ２ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ It consists of alkoxy compounds. １ Examples include a single bond, methylene, -C(O)-, a divalent six-membered aromatic hydrocarbon ring group, or the following formula:

[0139]

[0140] (In the formula, *1 is Q) １ This is the bonding position with L, and *2 is L ２ This is the bonding position with R, and Ｌ (The group consists of a hydrogen atom, a fluorine atom, or a hydroxyl atom.) Examples include any one divalent group selected from the group consisting of these. ２ Examples include single bonds, methylene groups, -C(O)- groups, divalent aromatic hydrocarbon ring groups, or the following formula:

[0141]

[0142] (In the formula, *2 is L １ This is the bonding position with Q, and *3 is Q ２ This is the bonding position with R, and Ｌ Q is a hydrogen atom, a fluorine atom, or a hydroxyl group.) Examples include any one divalent group selected from the group consisting of the above. * indicates the bond position with E. The wavy line indicates the bond position with T. However, in formula (II) above, Q １ and L １ , L １ and L ２ , and L ２ and Q ２ These nitrogen atoms do not form bonds with each other.

[0143] Another form of L is given by the following formula:

[0144]

[0145] The group shown is an example.

[0146] In the above equation, m and n are each independently integers from 1 to 3, and m + n is an integer from 2 to 5. In another embodiment, m is 2, and in yet another embodiment, n is 2. ２ and X ３ Examples of these are, independently, nitrogen atoms or carbon atoms. １５ Examples include hydrogen atoms, fluorine atoms, or hydroxyl atoms. *1-L １ -L ２ -3 is expressed by the following formula:

[0147]

[0148] A group represented by (wherein *1 and *3 are as defined above) is preferred, and the following formula:

[0149]

[0150] The group represented by (wherein *1 and *3 are as defined above) is more preferred.

[0151] Another form of L is the following formula:

[0152]

[0153] The base shown by (wherein * and the dashed line have the same meaning as above) is an example.

[0154] In one embodiment of the present invention, T in formula (I) is a target protein PI3Kα-binding motif. The PI3Kα-binding motif means a site containing a substructure that binds to PI3Kα, and is not particularly limited as long as it contains a substructure that binds to PI3Kα.

[0155] In one embodiment of the present invention, T is defined by formula (III):

[0156]

[0157] The group shown is an example.

[0158] In formula (III), R １ and R ２ In terms of each, they are: hydrogen atom, halogen, and C １－６ Alkyl, or C １－３ Haloalkyls are given as examples. Alternatively, R １ and R ２ They can also bond with each other, and together with the carbon atoms they bond to, form a 5- to 7-membered aliphatic hydrocarbon ring. Q ３ As for G ３ Examples include divalent aromatic heterocyclic groups which may be further substituted with one or two identical or different substituents selected from the group. ３ The group consists of halogens, di(C) １－３ Alkyl)amino, morpholinyl, and the following formula:

[0159]

[0160] (In the formula, R ３ , R ４ , and R ５ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R ３ , R ４ , and R ５Two of them bond to each other, and together with the carbon atoms they bond to, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, and ● is Q ３ It consists of groups indicated by ( ). The wavy line indicates the bond position with L.

[0161] Another form of T is given by the following formula:

[0162]

[0163] The group shown is an example.

[0164] In the above formula, X １ Examples include nitrogen atoms or carbon atoms. ６ , R ７ , and R ８ As for each, independently, hydrogen atom, C １－４ Alkyl, or C １－４ Haloalkyls are given as examples. Alternatively, R ６ , R ７ , and R ８ Two of these can bond with each other, together with the carbon atoms they bond to, to form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle. ９ , R １０ , and R １１ As for each, independently, hydrogen atom, C １－４ Alkyl, or C １－４ Haloalkyls are given as examples. Alternatively, R ９ , R １０ , and R １１ Two of these can bond with each other, together with the carbon atoms they bond to, to form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle. １２ , R １３ , and R １４ As for each, independently, hydrogen atom, C １－４ Alkyl, or C １－４ Haloalkyls are given as examples. Alternatively, R １２ , R １３ , and R １４Two of these can bond with each other, together with the carbon atoms they bond to, to form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle. The dashed lines indicate the bond positions with L.

[0165] Another form of T is given by the following formula:

[0166]

[0167] (In the formula, R ９ , R １０ , R １１ , R １２ , R １３ , R １４ The , and the dashed line are equivalent to those described above.) The bases shown are examples.

[0168] Another form of T is the following formula:

[0169]

[0170] The base shown by (wherein the formula, the dashed line has the same meaning as above) is an example.

[0171] Another form of T is the following formula:

[0172]

[0173] The base shown by (wherein the formula, the dashed line has the same meaning as above) is an example.

[0174] Another form of T is the following formula:

[0175]

[0176] (In the formula, R ９ , R １０ The , and the dashed line are equivalent to those described above.) The bases shown are examples.

[0177] In yet another aspect of the present invention, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1-(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -{5-[6-(diethylamino)pyrazine-2-yl]-4-methyl-1,3-thiazole-2-yl}-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrroridine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrorol[3,4-b]pyridine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3S)-3-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-4-yl}methyl)piperazine-1-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-1-yl}methyl)benzyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3S)-3-{[5-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-1-yl}methyl)pyridine-2-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[2-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-4-yl}methyl)-2,3-dihydro-1H-isoindole5-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-({1-[(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)methyl]piperidine-4-yl}methyl)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, and (2S,3R)-3-({1-[(4-{4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1 A compound or salt thereof selected from the group consisting of -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide is provided. All of these compounds are included in the compound or salt thereof represented by formula (I) above.

[0178] <3. Salts, Isomers, Prodrugs, etc.> In the present invention, the term "salt of a compound" is not particularly limited as long as it can form a salt with the compound of the present invention. When the "salt of a compound" is used as a pharmaceutical, it is preferable that it be a "pharmaceutically acceptable salt". If the compound of the present invention has an acidic group, it can be reacted with a base to form a basic salt (also referred to as a "base addition salt"), and if it has a basic group, it can be reacted with an acid to form an acidic salt (also referred to as an "acid addition salt"). Therefore, in one embodiment of the present invention, the salt of the compound represented by formula (I) is a basic salt, and in another embodiment of the present invention, the salt of the compound represented by formula (I) is an acidic salt.

[0179] In the present invention, suitable examples of "basic salts" include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, and picoline salt; or amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, and aspartate salt.

[0180] In the present invention, "acidic salts" can preferably include hydrohalides such as hydrofluoric acid, hydrochloride, hydrobromide, and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates such as benzenesulfonates, 4-methylbenzenesulfonates, and 2-naphthalenesulfonates; organic salts such as acetates, malates, fumarates, succinates, citrates, ascorbic acid, tartrates, oxalates, and maleates; or amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates. 4-methylbenzenesulfonic acid is sometimes called p-toluenesulfonic acid. Also, 2-naphthalenesulfonic acid is sometimes called β-naphthalenesulfonic acid.

[0181] The compounds or salts thereof of the present invention may absorb water molecules and become hydrates when left in the atmosphere or recrystallized, and such hydrates are also included in the present invention. Furthermore, the compounds or salts thereof of the present invention may absorb certain solvents and become solvates when left in a solvent or recrystallized, and such solvates are also included in the present invention. Moreover, the compounds or salts thereof of the present invention can exist as amorphous or crystalline.

[0182] Furthermore, the compounds of the present invention or their salts may be labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Examples of isotopes that can be incorporated into the compounds of the present invention or their salts include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and so on, specifically, each ２ H, ３ H, １１ C, １３ C, １４ C, １３ N, １５ N, １５ O, １７ O, １８ O, １８ Examples include, but are not limited to, F. Radioactive or non-radioactive labeled compounds may be useful in determining or measuring the efficacy of the compounds of the present invention by characterizing, for example, the site or mode of action, or the binding affinity to pharmacologically important sites of action. Such isotope-labeled compounds can be prepared by conventional techniques generally known to those skilled in the art.

[0183] The compounds of the present invention, their salts, or their solvates may exist as various isomers depending on the type and combination of substituents, including cis or trans geometric isomers, tautomers, rotational isomers, d-isomers, l-isomers, and other optical isomers (including enantiomers and diastereomers). Unless otherwise specified, the compounds of the present invention include all of these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any proportion. These mixtures of isomers can be separated by known separation methods.

[0184] Furthermore, the present invention also encompasses prodrugs of the compounds of the present invention. A prodrug is a compound having a group that can be converted to an amino group, hydroxyl group, carboxyl group, etc., by hydrolysis or under physiological conditions. Examples of groups that form such prodrugs include those described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc. More specifically, the prodrugs include: (1) If the compound of the present invention contains an amino group, the amino group is acylated, alkylated, or phosphorylated (for example, compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated); (2) If the compound of the present invention contains a hydroxyl group, the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated); (3) If a carboxyl group is present in the compound of the present invention, examples of compounds in which the carboxyl group is esterified or amidized include compounds in which the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidized, or methylamidized.

[0185] <4. Compositions and Pharmaceutical Uses> In one aspect of the present invention, a composition for inhibiting the target protein PI3Kα, a composition for inducing the degradation of PI3Kα, or a pharmaceutical composition thereof (hereinafter sometimes referred to as "the composition of the present invention"), or a pharmaceutical containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is provided. In another aspect of the present invention, a method for treating a disease related to PI3Kα is provided, characterized by administering an effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring treatment of the disease. Furthermore, in yet another aspect of the present invention, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of a disease related to PI3Kα. In addition, in yet another aspect of the present invention, a method for using the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of a disease related to PI3Kα is provided.

[0186] In the present invention, "composition for inducing the degradation of PI3Kα" means a composition intended to induce the degradation of PI3Kα. "Composition for inducing the degradation of PI3Kα" includes not only compositions whose sole purpose is to induce the degradation of PI3Kα, but also compositions whose purpose includes the degradation of PI3Kα as one of its objectives. Typically, "composition for inducing the degradation of PI3Kα" refers to compositions in which the degradation of PI3Kα is listed as one of its uses in the accompanying documents, packaging, promotional materials, etc., but also includes compositions that substantially and substantively include the degradation of PI3Kα as one of their uses even without such explicit mention. In one embodiment of the present invention, it is preferable to degrade PI3Kα selectively using isoforms.

[0187] In the present invention, "pharmaceutical" means a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Since the compound of the present invention has PI3Kα-degrading activity, it can be used as a composition for the treatment and / or prevention of diseases related to PI3Kα, more specifically, diseases in which PI3Kα is involved in the development or progression. Such diseases include, but are not limited to, breast cancer. Therefore, in one embodiment of the present invention, the pharmaceutical of the present invention is a pharmaceutical for the treatment of breast cancer. When the pharmaceutical of the present invention contains a pharmaceutically acceptable carrier, the pharmaceutical may be referred to as "the pharmaceutical composition of the present invention."

[0188] The route of administration of such pharmaceutical compositions to humans or other animals may be oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in the form of injections for intra-articular, intravenous, intramuscular, etc., suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc. However, considering that the molecular weight of the compounds of the present invention is not extremely large, oral administration is preferred from the viewpoint of reducing the burden of taking medication. Furthermore, intravenous administration is preferred from the viewpoint of bioavailability.

[0189] Examples of solid compositions for oral administration include tablets, powders, granules, etc. Such solid compositions contain, in addition to the compound of the present invention, at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, etc. Such solid compositions may also contain inert additives, such as lubricants like magnesium stearate, disintegrants like sodium carboxymethyl starch, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may, if necessary, be coated with sugar or a gastric-soluble or enteric-soluble film.

[0190] Examples of liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, elixirs, etc. Such liquid compositions may contain commonly used inert diluents, such as purified water or ethanol. In addition to inert diluents, such liquid compositions may also contain auxiliary agents such as solubilizers and wetting agents, sweeteners, flavoring agents, fragrances, and preservatives.

[0191] Examples of injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of solvents for injectable preparations include aqueous solvents such as distilled water for injection and physiological saline, and non-aqueous solvents such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such injectable preparation compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and / or solubilizers. These injectable preparation compositions can be sterilized, for example, by filtration through a bacterial retention filter, by the addition of a bactericide, or by irradiation. Alternatively, these injectable preparation compositions can be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0192] Examples of topical preparations include ointments, plasters, creams, gels, poultices, sprays, lotions, eye drops, and eye ointments. These topical preparations may contain commonly used ointment bases, lotion bases, aqueous or non-aqueous solvents, suspending agents, emulsifiers, etc. For example, examples of ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

[0193] Transmucosal preparations, such as inhalants and nasal preparations, can be used in solid, liquid, or semi-solid form and can be manufactured according to conventionally known methods. Transmucosal preparations may contain, for example, known excipients, and may also contain pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., as appropriate. These transmucosal preparations can be administered using a suitable inhalation or blowing device. For example, the compound of the present invention can be administered alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier, as a solution or suspension, using a known device such as a metered inhalation device or a sprayer. Dry powder inhalers may be for single or multiple doses and can use dry powder or powder-containing capsules. A suitable excipient can also be used with dry powder inhalers. For example, it may be in the form of a pressurized aerosol spray using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

[0194] The composition (pharmaceutical composition) of the present invention may contain other active ingredients, or may be used in combination with another composition containing other active ingredients. This combination may involve simultaneous administration, separate and consecutive administration, or administration at desired time intervals. The simultaneous administration formulation may be a combination formulation or formulated separately.

[0195] The amount of the compound of the present invention used to fill the composition or the amount administered to the subject is not particularly limited as long as it is an effective amount to achieve the objective, and can be appropriately selected according to the purpose of use, the age, weight, symptoms, health condition, disease progression of the subject, etc. The frequency of administration of the composition of the present invention is not particularly limited and can be appropriately selected according to the purpose, for example, the daily dose may be administered once a day or divided into multiple doses.

[0196] <5. Combined Use> The compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing the degradation of PI3Kα, a pharmaceutical composition, or a pharmaceutical containing the compound or a pharmaceutically acceptable salt thereof may be used in combination with other antitumor agents. Examples of other antitumor agents include alkylating agents, antimetabolites, antitumor antibiotics, microtubule inhibitors, topoisomerase inhibitors, BRMs (biological response regulators), hormones, vitamins, antitumor antibodies, molecular targeted drugs, and other antitumor agents.

[0197] More specifically, examples of alkylating agents include alkylating agents such as nitrogen mustard, nitrogen mustard-N-oxide, and chlorambutyl; aziridine alkylating agents such as carbocone and thiotepa; epoxide alkylating agents such as dibromomannitol and dibromodulcitol; nitrosourea alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozosin, chlorozotosin, and ranimustine; busulfan; improsulfan tosylate; and dacarbazine.

[0198] Examples of various antimetabolites include purine antimetabolites such as 6-mercaptopurine, 6-thioguanine, and thioinosine; pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, proxuridine, cytarabine, enocitabine, and capecitabine; folic acid antimetabolites such as methotrexate, trimethrexate, and pemetrexed; and activated folic acid preparations such as levofolinate.

[0199] Examples of antitumor antibiotics include anthracycline antibiotics such as daunorubicin, acralubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, epirubicin, and amrubicin; mitomycin C; bleomycin; peplomycin; chromomycin A3; and actinomycin D.

[0200] Examples of microtubule inhibitors include vinca alkaloids such as vindesine, vincristine, vinblastine, and vinorelbine; taxanes such as paclitaxel, docetaxel, and cabazitaxel; and eribulin.

[0201] Examples of topoisomerase inhibitors include epipodophyllotoxins such as etoposide and teniposide, and camptothecin derivatives such as irinotecan.

[0202] Examples of BRMs include tumor necrosis factor or indomethacin.

[0203] Examples of hormonal agents include hydrocortisone, cortisone acetate, fludrocortisone, fludrocortisone acetate, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, metenolone, phosphestrol, ethinylestradiol, chlormadinone, glucocorticoids, medroxyprogesterone, bicalutamide, enzalutamide, apalutamide, darolutamide, flutamide, anastrozole, exemestane, letrozole, abiraterone, goserelin, leuprorelin, toremifene, degarelux, mitotane, and tamoxifen.

[0204] Examples of vitamins include vitamin C and vitamin A.

[0205] Examples of antitumor antibodies and molecularly targeted drugs include antitumor antibodies (including their variants) such as trastuzumab, rituximab, cetuximab, pertuzumab, nimotuzumab, pembrolizumab, camrelizumab, denosumab, bevacizumab, infliximab, and ramucirumab; kinase inhibitors such as imatinib, gefitinib, erlotinib, sunitinib, lapatinib, eganerisib, sorafenib, dasatinib, nilotinib, vemurafenib, osimertinib, apatinib, and cabozantinib; PARP inhibitors such as olaparib, rucaparib, veliparib, and niraparib; and molecularly targeted drugs such as OR-449.

[0206] Other antitumor agents include, for example, platinum compounds such as cisplatin, carboplatin, and oxaliplatin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acegraton, schizophyllan, picibanil, procarbazine, pipobromane, neocartinostatin, hydroxyurea, ubenimex, and krestin.

[0207] Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing the degradation of PI3Kα, a pharmaceutical composition, or a pharmaceutical containing the compound or a pharmaceutically acceptable salt thereof may be used in combination with an antibody-drug conjugate (ADC) containing the above-mentioned antitumor agent as a payload, or a target protein degradation inducer that uses the above-mentioned antitumor agent as a target protein ligand, etc.

[0208] The compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing the degradation of PI3Kα, a pharmaceutical composition, or a pharmaceutical containing the compound or a pharmaceutically acceptable salt thereof may be administered simultaneously with or separately at intervals from the above-mentioned concomitant agents, and may be provided as a combination or kit formulation.

[0209] <General Manufacturing Methods> The following describes typical manufacturing methods for the compounds of the present invention or their pharmaceutically acceptable salts. The compounds of the present invention can be manufactured by various manufacturing methods, and the manufacturing methods shown below, as well as the reference examples and examples described later, are examples only, and the present invention should not be interpreted as being limited thereto. Each raw material compound may form a salt, provided that it does not inhibit the reaction, and such salts are the same as those for the pharmaceutically acceptable salts of the compounds described above. Unless otherwise specified, the raw material compounds can be readily obtained commercially or manufactured according to known methods or similar methods. Furthermore, the manufacturing intermediates produced in the following manufacturing methods may be isolated and purified by methods such as column chromatography (including normal-phase and reverse-phase) using silica gel, alumina, etc., recrystallization, reprecipitation, distillation, etc., or they may be used directly in the next reaction without isolation and purification. All patent documents, non-patent documents, or references explicitly cited in this specification may be incorporated herein by reference as part of this specification. The compounds, their pharmaceutically acceptable salts, and their manufacturing intermediates can be manufactured by applying various known manufacturing methods, utilizing the characteristics based on their basic skeletons or the types of substituents. Known methods include those described in, for example, "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd edition, ACADEMIC PRESS, INC., 1989, and "Comprehensive Organic Transformations," 2nd edition, VCH Publishers Inc., 1999. In such cases, depending on the type of functional group present in the compound, it may be technically effective from a manufacturing standpoint to protect the functional group with an appropriate protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. Examples of such functional groups include amino groups, hydroxyl groups, formyl groups, carbonyl groups, and carboxyl groups, and examples of protecting groups for these include those described in, for example, "Protective Groups in Organic Synthesis," 5th edition, Wiley, by PG Wuts, 2014.Protecting groups, or groups readily convertible to such functional groups, may be appropriately selected and used according to the respective reaction conditions of the manufacturing method for compound production. Using such a method, after introducing the group and carrying out the reaction, the desired compound can be obtained by removing the protecting group or converting it to a desired group as needed. Prodrugs of compounds can be produced, similar to the protecting groups described above, by introducing a specific group at the raw material or intermediate stage, or by carrying out a reaction using the resulting compound. Reactions for producing prodrugs can be carried out by applying methods known to those skilled in the art, such as esterification, amidation, dehydration, and hydrogenation. Furthermore, the functional group conversion and the use of protecting groups in the manufacturing intermediates used in each step of the following methods can be carried out by known methods or similar methods, or by the methods described in the examples below or similar methods. In the following descriptions of general manufacturing methods, symbols used in formulas without definition have the same meaning as described above.

[0210] The following describes a general method for preparing the compound of formula (1) of the present invention. In the following description and examples, the abbreviations shown herein may be used. DMF: N,N-dimethylformamide DIPEA: N,N-diisopropylethylamine DBU: 1,8-diazabicyclo[5.4.0]-7-undecene HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate Boc: tert-butoxycarbonyl Cbz: benzyloxycarbonyl TFA: trifluoroacetic acid CDI: 1,1'-carbonyldiimidazole LHMDS: lithium hexamethyldisilazide LDA: lithium diisopropylamide SEM: 2-(trimethylsilyl)ethoxymethyl THF: tetrahydrofuran DCM: dichloromethane DMSO: dimethyl sulfoxide NMP: N-methylpyrrolidone

[0211] Among the compounds represented by formula (I), for example, in formula (II), Q １ is a cyclic amino group (the nitrogen atom of the cyclic amino group is ring Q) １It is a ring constituent atom of L １ L bonded to a carbonyl group １ａ And Q １ The amino group above and L １ａ Compound (1), represented by the following formula, in which the carbonyl group bonded to forms an amide bond, can be prepared according to the method described below. The general preparation method for each reaction site is shown in order, but the order of each step can be changed as appropriate, as long as it does not significantly affect the reaction substrate and reaction product.

[0212]

[0213] Step 1 is a step to obtain compound (1) by an amidation reaction between compound (2) and compound (3). The amidation in this step can be carried out, for example, by using a condensation reagent such as HATU in a solvent such as DMF and in the presence of a base such as DIPEA.

[0214] In the following formula, PG １ Q １ It is a protecting group for the amino group above, LG １ It is a leaving group that attaches to a carbonyl group.

[0215]

[0216] Step 2 is the Q of compound (4) １ Protecting group PG of the amino group above １ This step involves obtaining compound (2) by deprotection. The deprotection reaction in this step can be carried out by a commonly known method. For example, protecting group PG １ If the group is a Boc group, compound (2) can be obtained by using a strong acid such as hydrochloric acid or TFA.

[0217] Step 3 is the step of obtaining compound (4) from compound (5) and compound (6). The urea formation reaction in this step can be carried out, for example, by reacting compound (5) and compound (6) in a solvent such as DMF and in the presence of a base such as triethylamine.

[0218]

[0219] Step 4 involves adding the leaving group LG to the amino group of compound (7). １ This step involves introducing a carbonyl group to obtain compound (5). Compound (7) can be produced, for example, by following the methods described in US20090163469A1, WO2010029082Al, WO2011000855A1, etc. The introduction of the carbonyl group in this step can be carried out, for example, by using CDI or the like in a solvent such as DCM or DMF with compound (7). The reaction temperature can usually be from room temperature, preferably from 40°C to 60°C.

[0220] In the following formula, PG １ Q １ It is a protecting group for the amino group above. PG ２ and PG ３ Halo is a protecting group for the carboxyl group. 1 These include halo groups, triflate groups, etc.

[0221]

[0222] Step 5 is the carbamate protecting group (-COOPG) of compound (8). ２ This step involves obtaining compound (6) by deprotecting the protecting group PG. １ It can be carried out by ordinary, known methods under conditions that do not affect PG. For example, PG １ It is a Boc group, and PG ２ If the group is a benzyl group, compound (6) can be obtained by a reduction reaction using palladium or the like.

[0223] Step 6 is a step to obtain compound (8) by amidation of compound (9). The amidation in this step can be carried out, for example, by using compound (9) in a solvent such as DMF, an ammonia source such as ammonium chloride, in the presence of a base such as DIPEA, and a condensation reagent such as HATU.

[0224] Step 7 is the PG of compound (10) ３ This step involves obtaining compound (9) by deprotecting the protecting group. The deprotection reaction in this step involves the protecting group PG １ and PG ２This can be carried out by ordinary known methods under conditions that do not affect the compound. For example, compound (9) can be obtained by hydrolysis of an ester using a base such as sodium hydroxide.

[0225] Step 8 is a step to obtain compound (10) by protecting compound (11) with a carbamate group. The protection reaction in this step can be carried out, for example, by reacting compound (11) with a carbamate reagent such as N-(benzyloxycarbonyloxy)succinimide in a solvent such as DCM and in the presence of an organic base such as DIPEA.

[0226] Step 9 is a step to obtain compound (11) by deprotecting the 1-phenylethyl group of compound (12). The deprotection reaction in this step can be carried out, for example, by using a metal catalyst such as palladium-carbon in a solvent such as ethanol under a hydrogen atmosphere. The reaction temperature is preferably from room temperature to 50°C.

[0227] Step 10 is a step in which an organozinc reagent is prepared from compound (13), and then compound (12) is obtained by subjecting it to a Negishi coupling reaction with compound (14). The organozinc reagent in this step can be prepared, for example, by reacting compound (13) with a lithium strong base such as LHMDS or LDA in a solvent such as THF at a low temperature such as -78°C to generate a lithium enolate in situ, and then adding a zinc salt such as zinc bromide. The Negishi coupling reaction can be carried out using a palladium catalyst such as [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate with the organozinc reagent prepared from compound (13) and compound (14). The reaction temperature is preferably from room temperature to 50°C. Compound (13) can be produced by referring to US20160264582. Compound (14) can also be purchased from reagent companies as needed.

[0228] Furthermore, compound (6) can also be obtained by sequentially carrying out the deprotection of the carboxylic acid in step 7, the amidation in step 6, and the deprotection of the 1-phenylethyl group in step 9, without performing steps 9 and 8 from compound (12).

[0229] In the following equation, A １ and B １ These are L ２ and Q 2 These are functional groups that act as reaction sites when bonding, and each is L ２ａ and Q ２ａ It combines with A. １ and B １ Each of these can be independently exemplified as an amino group, a carbonyl group, or a halo group. Also, PG ４ It is a protecting group for the carboxyl group, and PG ５ is a protecting group for the glutarimide group of E, ａ This is a group obtained by removing a hydrogen atom from the glutarimide group of E. PG ５ In addition to the methods described below, the deprotection reaction can be carried out in a similar manner in an appropriate process, and through a series of reactions, PG ５ Protection of E by [this method] may not be necessary in some cases.

[0230]

[0231] Step 11 is the PG of compound (15) ４ This step involves obtaining compound (3) by deprotecting the group. The deprotection reaction in this step can be carried out by a commonly known method. For example, PG ４ If the compound is a benzyl group, compound (15) can be obtained by a reduction reaction using a palladium catalyst.

[0232] Step 12 is the PG of compound (16) ５ This step involves obtaining compound (15) by deprotecting the group. The deprotection reaction in this step can be carried out by a commonly known method. For example, PG ５ If it is an SEM group, it can be deprotected under acidic conditions using TFA or the like.

[0233] Step 13 is the process of compound (17) A １Group and compound (18) B １ Using the foundation as a starting point L ２ and Q ２ This is a step in which the compounds are combined to obtain compound (16).

[0234]

[0235] Step 13-1 is, for example, in compound (16), L 1ａ and Q ２ This is an amide bond (the nitrogen atom of the amide bond is ring Q). ２ It is a ring constituent atom of L ２ However, this is a step to obtain compound (16-1) which is -C(O)-. For example, L of compound (17) ２ａ -A １ Compound (17-1) whose group is a carboxyl group, and compound (18) B １ The base is ring Q ２ａ The amino group above (the nitrogen atom of this amino group is ring Q) ２ａ When using compound (18-1), which is a constituent atom of (17-1), compound (16-1) can be obtained by carrying out an amidation reaction of compound (17-1) and (18-1) in a solvent such as DMF in the presence of a base such as DIPEA and using a condensing agent such as HATU.

[0236]

[0237] In the above formula, L ２ａ teeth,

[0238]

[0239] This indicates a group selected from the group consisting of the above. In the above formula, *2 is L １ａ This is the bonding position with R Ｌ This is synonymous with the above.

[0240] Step 13-2 is, for example, A of compound (17) １ Compound (17-2) whose group is an aldehyde group or a keto group, and compound (18) B １ The base is ring Q ２ａ The amino group above (the nitrogen atom of this amino group is ring Q) ２ａWhen compound (18-1), which is a constituent atom of (17-2), is used, the process involves obtaining compound (16-2) by a reductive amination reaction. Specifically, for example, compound (16-2) can be obtained by subjecting compound (17-2) and compound (18-1) to a reductive amination reaction using a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as DMF or DMSO. In this reaction, the addition of an acid such as acetic acid is sometimes preferable. It is also possible to use an amine salt such as a hydrochloride salt as compound (18-1), in which case it is sometimes preferable to add sodium acetate instead of acetic acid.

[0241]

[0242] In the above formula, L ２ｂ teeth,

[0243]

[0244] This indicates a group selected from the group consisting of the above. In the above formula, *2 is L １ａ This is the bonding position with R Ｌ This is synonymous with the above.

[0245] Furthermore, compound (16-2) can also be produced by alkylation reaction. Step 13-3 is A of compound (17) １ Base (L above) ２ｂ Halo inside 2 Compound (17-3) is a compound in which ) is a halo group or a triflate group, and compound (18) B １ The base is ring Q ２ａ The amino group above (the nitrogen atom of this amino group is ring Q) ２ａ If compound (18-1) is a constituent atom of (17-3), then, for example, compound (16-2) can be obtained by subjecting compound (17-3) and (18-1) to an alkylation reaction in a solvent such as DMF or DMSO in the presence of a base such as DIPEA. The reaction temperature can be carried out from room temperature under heating conditions, preferably from room temperature to 80°C.

[0246]

[0247] Step 13-4 is the process in which, in steps 13-2 and 13-3, compound (17) A １ Group and compound (18) B １ If the combination of groups is reversed, that is, L of compound (17) ２ａ -A １ However, for example, a compound having a piperidine ring structure (17-4) and B １ The base is ring Q ２ａ Even when using the above-mentioned compound (18) which has a keto group or halo group, the corresponding compound (16-3) can be produced by a reductive amination reaction similar to that in step 13-2, or by an alkylation reaction similar to that in step 13-3.

[0248]

[0249] Step 13-5 is, for example, L of compound (17) ２ａ -A １ However, Halo is formed on the divalent aromatic hydrocarbon ring group Ar. 3 Compound (17-5) having a group (halo group or triflate group), and compound (18) B １ The base is ring Q ２ａ The amino group above (the nitrogen atom of this amino group is ring Q) ２ａ This step involves subjecting compound (18-1), which is a constituent atom of (18-1), to Buchwald's amination reaction to obtain compound (16-4). Specifically, for example, compound (17-5) and compound (18-1) can be heated in a solvent such as 1,4-dioxane, in the presence of a base such as cesium carbonate, using a palladium catalyst such as chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2), under a nitrogen atmosphere to obtain compound (16-4). The reaction temperature is preferably 80°C to 100°C.

[0250] In the following formula, PG ６ B １ It is a protecting group for B １ａ B １ A group from which a hydrogen atom has been removed, or B １ is a carbonyl group and PG６ If the group is an acetal group or a ketal group, PG is derived from the corresponding acetal group or ketal group. ６ It is a group from which a part has been removed, C １ is an amino group or a boron-containing functional group, Halo ４ Q is a halo group or a triflate group, and ２１ This is an aliphatic ring group or an aliphatic ring group having a partially unsaturated bond (the aliphatic ring group may be a hydrocarbon ring group or a heterocyclic ring group).

[0251]

[0252] Step 14 is the PG of compound (19) ６ This is a step to obtain compound (18) by deprotecting the group. The deprotection reaction in this step can be carried out by a commonly known method. For example, in compound (19), B １ The base is ring Q ２ａ The amino group above (the nitrogen atom of this amino group is ring Q) ２ａ (It is a constituent atom of PG) and PG ６ When the group is a Cbz group, compound (18) can be obtained by a palladium-catalyzed reduction reaction. Also, for example, in compound (19), B １ The base is ring Q ２ａ The above carbonyl groups are keto groups, aldehyde groups, etc., and PG ６ When the group is an acetal group, the deprotection reaction in this step can be carried out by using 1M hydrochloric acid in a solvent such as THF. The reaction temperature is preferably from room temperature to 50°C. Furthermore, for example, in compound (19), B １ The group is a carboxyl group, and PG ６ If the group is a benzyl group, the deprotection reaction in this step can be carried out by a reduction reaction using a palladium catalyst.

[0253] Step 15 is the Q in compound (20). ２１ When Q is an aliphatic ring group having a partially unsaturated bond, ２１This step involves obtaining compound (19) by subjecting the unsaturated bonds within the ring to a reduction reaction by hydrogenation. The reduction reaction by hydrogenation in this step can be carried out by a commonly known method. Specifically, for example, this step can be carried out by a reduction reaction using a palladium catalyst in an alcohol solvent such as ethanol under a hydrogen atmosphere. Q in compound (20) ２１ is an aliphatic ring group (Q ２ａ If this is the case, this step is unnecessary.

[0254] Step 16 is a step in which compound (20) is obtained from compounds (21) and (22) by an aromatic nucleophilic substitution reaction, a Buchwald amination reaction, or a Suzuki-Miyaura coupling reaction, etc. Compound (21) can also be purchased from a reagent company as appropriate.

[0255]

[0256] In step 16-1, for example, the C of compound (21) １ The group is a boron-containing functional group such as a boronic acid, boronic acid ester, or trifluoroborate salt, and Q ２１ If compound (21-1) is an aliphatic ring group having a partially unsaturated bond, compound (20) can be obtained by subjecting compound (21-1) and compound (22) to a Suzuki-Miyaura coupling reaction in a solvent such as 1,4-dioxane-water, in the presence of a base such as potassium carbonate, using a palladium catalyst such as [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and heating under a nitrogen atmosphere. The reaction temperature is preferably 80°C to 100°C.

[0257]

[0258] In step 16-2, for example, the C of compound (21) １ The base is ring Q ２１ The amino group above (the nitrogen atom of this amino group is ring Q) ２１If E is a ring constituent atom, compound (20-1) can be obtained by subjecting compound (21-2) and compound (22) to an aromatic nucleophilic substitution reaction in a solvent such as DMSO or NMP, in the presence of a base such as DIPEA, and under heating. The reaction temperature is preferably 80°C to 120°C. This step is particularly suitable when using a compound in which, in formula (I), E is a group represented by formula (b) and the position of * is fluorine-substituted. ａ This is a group from which a hydrogen atom has been removed from the glutarimide group of E. In this step, compound (20-1) can also be obtained by subjecting compound (21-2) and compound (22) to a Buchwald amination reaction in a solvent such as 1,4-dioxane, in the presence of a base such as cesium carbonate, and heating under a nitrogen atmosphere using a palladium catalyst such as chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2). The reaction temperature is preferably 80°C to 100°C.

[0259]

[0260] Step 17 is a step to protect the glutarimide group at E of compound (23) to obtain compound (22). For example, PG ５ If E is an SEM group, compound (22) can be obtained by using SEM chloride, etc., in a solvent such as DMF, in the presence of a base such as DIPEA or DBU, with compound (23). Compound (23), for example, in formula (I), if E is the group represented by formula (a), (b), or (c), can be purchased from a reagent company as appropriate (CAS registry numbers: 835616-60-9, 1010100-26-1, 2154343-24-3, 2300099-98-1, etc.). Compounds in which E is the group represented by formula (d) in formula (I) can be manufactured by referring to ACS Med. Chem. Lett. 2025, 16, 89-95, etc.

[0261]

[0262] In step 18, the protecting group PG of compound (24) ７ This is a step to deprotect the compound (17). １ａ is, A １ A group from which a hydrogen atom has been removed, or A １ is a carbonyl group and PG ７ If the group is an acetal group or a ketal group, PG is derived from the corresponding acetal group or ketal group. ７ This is a group from which a portion has been removed. The deprotection reaction in this step can be carried out by a commonly known method. For example, in compound (24), A １ It is an amino group and a protecting group PG ７ If is a Boc group, the deprotection reaction can be carried out by using an acid such as hydrochloric acid or TFA in a solvent such as DCM. Also, for example, in compound (24), A １ is a carbonyl group and PG ７ If is an acetal group, the deprotection reaction can be carried out by using an acid such as hydrochloric acid in a solvent such as THF with compound (24). Furthermore, for example, in compound (24), A １ It is a carboxyl group, and PG ４ is a benzyl group and PG ７ If the group is a tert-butyl group, the protecting group PG can be removed by using an acid such as hydrochloric acid or TFA. ７ It is possible to selectively deprotect them.

[0263] Step 19 is the step of obtaining compound (24) from compound (25) and compound (26). In the following formula, D １ and F １ These are L in compound (24), respectively. １ａ and L ２ａ These are functional groups that act as reaction sites when bonding, and each is L of compound (25). １ｂ and L of compound (26) ２ｃ Combine.

[0264]

[0265] A more specific example of step 19 is shown below.

[0266]

[0267] Step 19-1 is a step to obtain compound (24-1) from compound (25-1) and compound (26-1). Specifically, compound (24-1) can be obtained by carrying out an aldol reaction between compound (25-1) and compound (26-1) in a solvent such as THF at an extremely low temperature of -78°C using a strong base such as LHMDS. Compounds (25-1) and (26-1) can be purchased from reagent companies as appropriate.

[0268] Among the compounds represented by formula (I), for example, Q in formula (II) １ The nitrogen atom and L 1 The compound (27) in which the carbon atoms form a bond can be produced, for example, by the following method.

[0269]

[0270] In the above formula, L １ｃ teeth,

[0271]

[0272] This indicates a group selected from the group consisting of groups represented by , where *2 is L ２ The bond position with R is shown, Ｌ This indicates the same meaning as above.

[0273] Step 20 is, for example, Q １ The group is a cyclic amino group (the nitrogen atom of the cyclic amino group is ring Q). ２ If the compound is represented by compound (27), which is a constituent atom of (2), the step is to obtain compound (27) by subjecting compound (2) and compound (28) to a reductive amination reaction. Specifically, for example, compound (27) can be obtained by reacting compound (2) and compound (28) in a solvent such as DMF or DMSO with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. In this reaction, it is sometimes preferable to add an acid such as acetic acid. It is also possible to use the hydrochloride salt of compound (2), in which case it is sometimes preferable to add sodium acetate instead of acetic acid.

[0274] Other compounds represented by formula (I) can also be manufactured by appropriately selecting the reaction conditions and protecting groups as described in each of the above steps, or by appropriately adopting reactions known prior to filing or common technical knowledge of those skilled in the art.

[0275] <6. Activity> In one embodiment of the present invention, the compound of the present invention specifically binds to CRBN. The binding activity to CRBN can be measured using known methods, for example, by reacting a test substance (the compound of the present invention), a molecule known to specifically bind to CRBN (especially the CRBN ligand-binding region (LBD)) (e.g., HTRF Thalidomide-Red ligand), and CRBN (especially CRBN-LBD), and quantifying the decrease in the binding rate to CRBN by the molecule known to specifically bind to CRBN (e.g., IC 50 It can be measured by calculating the value. Generally, in such a test system, IC 50 Test substances with an IC50 value of 100 μM or less are considered to bind specifically to CRBN. Therefore, in one embodiment of the present invention, with respect to the reduction in the binding rate to CRBN by the compound of the present invention or a molecule known to bind specifically to CRBN (e.g., HTRF Thalidomide-Red ligand), the compound of the present invention has an IC50 value of 100 μM or less. 50 IC has a value, preferably 10 μM or less. 50 ICs having a value of 1 μM or less are particularly preferred. 50 It has a value. In another embodiment of the present invention, the compound of the present invention, in the test system and test conditions disclosed in Test Example 4 herein, has an IC of 100 μM or less in relation to the reduction in the binding rate to CRBN-LBD by the CRBN-specific binding molecule, HTRF Thalidomide-Red ligand. 50 IC has a value, preferably 10 μM or less. 50 ICs having a value of 1 μM or less are particularly preferred. 50 It has a value.

[0276] In one embodiment of the present invention, the compound of the present invention has PI3Kα degradation-inducing activity. PI3Kα degradation-inducing activity can be measured using known methods, for example, by adding the test substance to cells expressing PI3Kα, culturing them for a certain period, and then quantifying the expression level of PI3Kα. PI3Kα degradation-inducing activity can also be measured, for example, by knocking in an easily detectable peptide tag (e.g., a HiBiT tag) into the endogenous PI3Kα gene locus in cells expressing PI3Kα, adding the test substance to the cells, culturing them for a certain period, and then detecting the expression level of the peptide tag. Generally, in such a test system, a concentration (DC) that induces 50% degradation of PI3Kα is used. 50 Test substances with a DC (D3Kα) value of 100 μM or less are considered to have PI3Kα degradation-inducing activity. Therefore, in one embodiment of the present invention, the compound of the present invention has a DC of 100 μM or less relative to PI3Kα. 50 Having a value, preferably DC of 10 μM or less. 50 Having a value, and particularly preferably a DC of 1 μM or less. 50 It has a value. In another embodiment of the present invention, the compounds of the present invention are not particularly limited as long as they have PI3Kα degradation-inducing activity, but in the test system and test conditions disclosed in Test Example 1 herein, the DC is 100 μM or less relative to PI3Kα. 50 Having a value, preferably DC of 10 μM or less. 50 Having a value, and more preferably a DC of 1 μM or less 50 Having a DC value of 100 nM or less, and more preferably 100 nM or less. 50 Having a DC value of 10 nM or less, and particularly preferably 10 nM or less. 50 Having a value, most preferably DC of 1 nM or less. 50 It has a value.

[0277] In one embodiment of the present invention, the compound of the present invention has growth inhibitory activity against tumors in which PI3Kα is involved in their development and progression; in another embodiment of the present invention, the compound of the present invention has growth inhibitory activity against breast cancer; and in yet another embodiment of the present invention, the compound of the present invention has growth inhibitory activity against T-47D cells, a breast cancer cell line. The growth inhibitory activity against tumor cells can be measured using known methods, typically by adding the test substance (compound of the present invention) to model cells of the target tumor, culturing them for a certain period of time, and then quantifying the growth rate of the tumor cells. Generally, in such a test system, a concentration (GI) that inhibits tumor cell proliferation by 50% is used. 50 Test substances with a GI value of 100 μM or less are considered to have growth inhibitory activity. Therefore, in one embodiment of the present invention, the compound of the present invention has a GI value of 100 μM or less against tumor cells (e.g., T-47D cells). 50 Having a value, preferably GI of 10 μM or less. 50 Having a value, and particularly preferably a GI of 1 μM or less. 50 The compound of the present invention has a GI of 100 μM or less against tumor cells (e.g., T-47D cells) in the test system and test conditions disclosed in Test Example 2 herein. 50 Having a value, preferably GI of 10 μM or less. 50 Having a value, and particularly preferably a GI of 1 μM or less. 50 It has a value.

[0278] In one embodiment of the present invention, the antitumor activity of the compound of the present invention can be confirmed in an animal model (e.g., mouse) in which tumor cells involved in the development and progression of PI3Kα are subcutaneously transplanted. The antitumor activity in the transplantation model can be measured using any known method, for example, by the protocol described in Test Example 5 of this specification.

[0279] The present invention will be described in detail by the following embodiments, but these are merely embodiments and do not limit the present invention, and may be modified without departing from the scope of the present invention.

[0280] In the following examples, "%" indicates mol / mol% for yield, volume% for solvents used in chromatography, and weight% for others. "Room temperature" typically refers to a range of approximately 10°C to 35°C.

[0281] Nuclear magnetic resonance spectrum (hereinafter, 1 For 1H-NMR (resonance frequency 400 MHz or 500 MHz), tetramethylsilane was used as the standard substance, or the chemical shift value of the deuterated solvent used was used as the reference value, and the chemical shift value was expressed as a δ value (ppm).

[0282] Liquid chromatography-mass spectrometry (LC-MS) was performed under one of the following conditions: Condition A: Solvent: A soln.=0.1%HCOOH-H2O / B soln.= 0.1%HCOOH-H2O Column: Develosil Combi-RP-5 2.0×50 mm (Nomura Chemical) Ionization: APCI / ESI Flow: 1.2 mL / min; Analytical time: 4.5 min Gradient(B;%): 0 min: 2%, 3.6 min: 100%, 4.5 min: 100% Condition B: Solvent: A soln.=0.05%TFA-H2O / B soln.=MeCN Column: CAPCELL PAK ADME 4.6×150 mm, 3.0 μm (Osaka) Ionization: APCI / ESI Flow: 1.0 mL / min; Analytical time: 15 min Gradient(B;%): 0-2 min: 20%, 2-10 min: 95%, 10-12 min: 95%, 12-12.01 min: 20%, 12.01-15 min: 20% Typical conditions are conditions A and B above, but in some cases, columns such as InfinityLab Poroshell 120 EC-C18 2.7μM 3.0×50mm, Inertsil ODS-HL 2.1×50mm, and Eclipse XDB-C18 4.6 x 30 mm (1.8 mm) may be used.

[0283] Other abbreviations used in the text have the following meanings: s: singlet d: doublet dd: doublet of doublets t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: Hertz CDCl3: deuterated chloroform DMSO-D6: deuterated dimethyl sulfoxide CD3OD: deuterated methanol 1 H-NMR: Proton nuclear magnetic resonance; HPLC: High-performance liquid chromatography; SFC: Supercritical fluid chromatography; sCO2: Supercritical carbon dioxide; MeCN: Acetonitrile; APCI: Atmospheric pressure chemical ionization; ESI: Electrospray ionization; TLC: Thin-layer chromatography

[0284] Unless otherwise specified, the reagents, solvents, and equipment used in the following examples are commercially available. Furthermore, unless otherwise specified, the starting compounds are known compounds, commercially available, or synthesized and identified according to known or equivalent methods.

[0285] (Example 1A) 35.8 g of tert-butyl 4-({(2S,3R)-2-(methoxycarbonyl)-1-[(1S)-1-phenylethyl]pyrrolidine-3-yl}methyl)-3,6-dihydropyridine-1(2H)-carboxylate methyl N-buta-3-en-1-yl-N-[(1S)-1-phenylethyl]glycinate (CAS registry number: 432555-77-6, US20160264582) was dissolved in 200 mL of THF and cooled to -78°C. 170 mL of 1.3 M LHMDS / THF solution was added dropwise over 1 hour, and the mixture was then heated to 0°C and stirred for 1 hour. The reaction solution was cooled to -78°C, and a solution of zinc bromide (81.6 g) in THF (200 mL) was added dropwise over 1 hour. The mixture was then heated to room temperature and stirred for 2 hours to prepare a THF solution of the organozinc reagent. To this solution, 1-(tert-butoxy)-1,2,3,6-tetrahydropyridine-4-yl trifluoromethanesulfonate (CAS registry number: 138647-49-1) (40.0 g) and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS registry number: 1447963-75-8) (9.59 g) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with ethyl acetate, saturated saline solution was added, and the precipitated insoluble material was filtered off with Celite. The aqueous layer of the filtrate was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate) followed by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (34.8 g, yield: 67%) as an oil.

[0286] (Example 1B) tert-butyl 4-{[(2S,3R)-2-(methoxycarbonyl)pyrrolidine-3-yl]methyl}piperidine-1-carboxylate The compound obtained in Example 1A (34.8 g) was dissolved in ethanol (400 mL), 10% palladium carbon (20.0 g) was added, and the mixture was heated and stirred at 50°C for 6 hours under a hydrogen atmosphere. After the reaction mixture was cooled to room temperature, it was filtered by Celite, and the filtrate was concentrated under reduced pressure to obtain the marked compound (26.5 g, yield: quantitative) as an oil.

[0287] (Example 1C) 1-benzyl 2-methyl (2S,3R)-3-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxylate The compound obtained in Example 1B (26.5 g) was dissolved in DCM (270 mL), DIPEA (15.6 mL) and N-(benzyloxycarbonyloxy)succinimide (21.3 g) were added, and the mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with DCM, washed sequentially with 1 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate), and then by silica gel column chromatography (DCM / methanol) to obtain the marked compound (35.2 g, yield: 94%) as an oily substance.

[0288] (Example 1D) (3R)-1-[(benzyloxy)carbonyl]-3-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-L-proline A mixture of the compound obtained in Example 1C (35.2 g), THF (380 mL), and methanol (380 mL) was mixed with 1 M aqueous sodium hydroxide (380 mL) and stirred at room temperature for 41 hours. After removing most of the solvent from the reaction mixture under reduced pressure, 1 M hydrochloric acid (420 mL) was added and extracted by DCM. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the marked compound (30.0 g, yield: 88%) as a solid.

[0289] (Example 1E) tert-butyl 4-({(2S,3R)-1-[(benzyloxy)carbonyl]-2-carbamoylpyrrolidine-3-yl}methyl)piperidine-1-carboxylate. A mixture of the compound obtained in Example 1D (3.69 g), ammonium chloride (1.77 g), and HATU (4.08 g) in DMF (40 mL) was mixed with DIPEA (8.63 mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (3.63 g, yield: 99%) as a solid.

[0290] (Example 1F) tert-butyl 4-{[(2S,3R)-2-carbamoylpyrrolidine-3-yl]methyl}piperidine-1-carboxylate The compound obtained in Example 1E (3.56 g) was dissolved in ethanol (80 mL), 10% palladium carbon (3.50 g) was added, and the mixture was heated and stirred at 50°C for 4 hours under a hydrogen atmosphere. After the reaction mixture was cooled to room temperature, it was filtered by Celite, and the filtrate was concentrated under reduced pressure to obtain the marked compound (2.34 g, yield 94%) as a solid.

[0291] (Example 1G) 3-{5-[4-(dimethoxymethyl)piperidine-1-yl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione 3-(5-bromo-1-oxoisoindorin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (CAS Registry No.: 2409004-53-9, WO2021124172) (12.3 g), 4-(dimethoxymethyl)piperidine (CAS Registry No.: 188646-83-5) (5.63 g), cesium carbonate (13.3 g), and 1,4-dioxane (140 After degassing the mixture of (mL) by sonication, the mixture was heated and stirred to 100°C. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS registry number: 1310584-14-5) (1.07 g) was added to the mixture under a nitrogen atmosphere, and the mixture was stirred at 100°C for 9 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added and the mixture was separated. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (7.63 g, yield: 53%) as a solid.

[0292] (Example 1H) 1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-carbaldehyde A solution of the compound obtained in Example 1G (7.63 g) in DCM (70 mL) was mixed with TFA (30 mL) and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and toluene was added to the resulting residue and azeotropic reaction was performed. The resulting residue was dissolved in DCM (70 mL), and triethylamine (7.96 mL) and N,N'-dimethylethylenediamine (1.54 mL) were added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol). The fraction containing the target product was concentrated under reduced pressure, and acetic acid and toluene were added to the residue and concentrated again under reduced pressure. The resulting residue was mixed with ethyl acetate, and the resulting solid was filtered off to obtain the marked compound (3.33 g, yield: 65%) as a solid.

[0293] The compound of Example 1H can also be produced via the compounds obtained in Examples 1Ha to 1Hg.

[0294] (Example 1Ha) A mixture of 5-{4-[(benzyloxy)methyl]piperidine-1-yl}-2-benzofuran-1(3H)-one 5-bromophthalide (CAS registry number: 64169-34-2), 4-(benzyloxy)piperidine (CAS registry number: 76716-51-3) (1.2 equivalents), cesium carbonate (2 equivalents), and 1,4-dioxane was degassed by sonication, heated and stirred at 100°C, and under a nitrogen atmosphere, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS registry number: 1310584-14-5) (0.05 equivalents) was added and stirred at 100°C. The reaction mixture can be cooled to room temperature, followed by workup and purification to obtain the labeled compound.

[0295] (Example 1Hb) 4-{4-[(benzyloxy)methyl]piperidine-1-yl}-2-(hydroxymethyl)benzoic acid A mixture of the compound obtained in Example 1Ha, THF, and methanol is mixed with 5 equivalents of 1M aqueous sodium hydroxide solution and stirred at room temperature. The reaction mixture is neutralized with 1M hydrochloric acid and post-treatment is performed to obtain the marked compound.

[0296] (Example 1Hc) Ethyl 4-{4-[(benzyloxy)methyl]piperidine-1-yl}-2-(hydroxymethyl)benzoate. A mixture of the compound obtained in Example 1Hb, potassium carbonate (1.1 equivalents), and DMF is cooled on ice, ethyl iodide (1.25 equivalents) is added, and the mixture is stirred at room temperature. The marked compound can be obtained by post-treatment.

[0297] (Example 1Hd) Ethyl 4-{4-[(benzyloxy)methyl]piperidine-1-yl}-2-(bromomethyl)benzoate A THF solution of the compound obtained in Example 1Hc was cooled on ice, carbon tetrabromide (1.5 equivalents) and triphenylphosphine (1.5 equivalents) were added, and the mixture was stirred at room temperature. After work-up, the compound was purified to obtain the marked compound.

[0298] (Example 1He) tert-butyl 5-amino-4-(5-{4-[(benzyloxy)methyl]piperidine-1-yl}-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-5-oxopentanoate The compound obtained in Example 1Hd, tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (CAS registry number: 1323411-16-0) (1.1 equivalents), and MeCN are mixed with DIPEA (3.0 equivalents) and stirred at 80°C. The reaction mixture is cooled to room temperature, and after work-up, the compound can be purified to obtain the marked compound.

[0299] (Example 1Hf) 3-(5-{4-[(benzyloxy)methyl]piperidine-1-yl}-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione To a MeCN solution of the compound obtained in Example 1He, (+)-10-camphor sulfonic acid (CAS registry number: 3144-16-9) (2.25 equivalents) is added and the mixture is stirred at 80°C. The reaction mixture is cooled to room temperature, and after work-up, the compound can be purified to obtain the marked compound.

[0300] (Example 1Hg) 3-{5-[4-(hydroxymethyl)piperidine-1-yl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}piperidine-2,6-dione The compound obtained in Example 1Hf is dissolved in DCM and ethanol, 10% palladium carbon is added, and the mixture is stirred at room temperature under a hydrogen atmosphere. The marked compound can be obtained by performing post-treatment.

[0301] (Example 1H) 1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-carbaldehyde A DCM solution of the compound obtained in Example 1Hf is mixed with dess-martin periodinane (1.1 equivalents) and stirred. After workup, the compound can be purified to obtain the marked compound.

[0302] (Example 1I) N-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}-1H-imidazole-1-carboxamide 4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-amine (CAS registry number: 1357476-69-7) (1.00 g) and CDI (0.807 g) in DCM (40 mL) were stirred under reflux for 7 hours. The reaction mixture was cooled to room temperature, the resulting solid was filtered, and washed with DCM to obtain the marked compound (1.17 g, yield: 89%) as a solid.

[0303] (Example 1J) tert-butyl 4-{[(2S,3R)-2-carbamoyl-1-({4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}carbamoyl)pyrrolidine-3-yl]methyl}piperidine-1-carboxylate A mixture of the compound obtained in Example 1F (41.6 mg) and the compound obtained in Example 1I (55.5 mg) in DMF (1.0 mL) was mixed with triethylamine (0.056 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the marked compound (33.3 mg, yield: 39%) as a solid.

[0304] (Example 1K) (2S,3R)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}-3-(piperidine-4-ylmethyl)pyrrolidine-1,2-dicarboxamide hydrochloride A solution of the compound obtained in Example 1J (125 mg) in DCM (2.5 mL) was mixed with a 4 M hydrogen chloride / 1,4-dioxane solution (0.49 mL) and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure to obtain the marked compound (120 mg) as a solid.

[0305] (Example 1) (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide A mixture of the compound obtained in Example 1K (13.8 mg), the compound obtained in Example 1H (9.6 mg), and sodium acetate (2.1 mg) in DMF (1 mL) was mixed with sodium triacetoxyborohydride (12.0 mg) and stirred at room temperature for 5 days. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (DCM / methanol) to obtain the marked compound (15.8 mg, 2-step yield from Example 1K: 80%) as a solid.

[0306] (Example 2A) Using N-(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)-1H-imidazole-1-carboxamide 4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-amine (CAS Registry No.: 1395492-66-6, US20090163469) (9.65 g), the marked compound (10.2 g, yield: 81%) was obtained as a solid in the same manner as in Example 1I.

[0307] (Example 2B) Using the compound obtained in Example 2A (2.76 g) and the compound obtained in Example 1F (2.01 g), the marked compound (3.93 g, yield: 94%) was obtained as a solid by the same method as in Example 1J.

[0308] (Example 2C) (2S,3R)-N 1-(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)-3-(piperidine-4-ylmethyl)pyrrolidine-1,2-dicarboxamide - 4.17 g of the compound obtained in Example 2B was added to a mixture of DCM (32 mL) and TFA (16 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (DCM / methanol) to obtain the marked compound (3.53 g, yield: quantitative) as a solid.

[0309] (Example 2) (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide The compound obtained in Example 2C (39.8 mg) and the compound obtained in Example 1H (31.3 mg) were suspended in DMF (1.5 mL), acetic acid (0.0124 mL) was added, and the mixture was stirred at room temperature for 50 minutes. Then, under ice cooling, sodium triacetoxyborohydride (38.7 mg) was added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and it was extracted with chloroform / 2-propanol (4 / 1). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol), and then by amino silica gel column chromatography (DCM / 2-propanol). The fraction of the indicated compound was concentrated under reduced pressure and dissolved in DCM. Diethyl ether was added, and the resulting solid was filtered to obtain the indicated compound (27.5 mg, yield: 43%) as a solid.

[0310] (Example 3A) N-[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-1H-imidazole-1-carboxamide 5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-amine (CAS registry number: 790705-07-6) (91.6 mg) was mixed with CDI (71.8 mg) in a DMF solution and stirred at room temperature for 15 hours. CDI (48.0 mg) was added to the reaction mixture and stirred at 40°C for 5.5 hours, then CDI (48.0 mg) was added and stirred at 50°C for 3.5 hours. The reaction mixture was cooled to room temperature, and the resulting solid was filtered and washed with DCM to obtain the marked compound (84.2 mg, yield: 67%) as a solid.

[0311] (Example 3B) Using the compound obtained in Example 3A (82.0 mg) and the compound obtained in Example 1F (110 mg), the marked compound (138 mg, yield: 98%) was obtained as a solid by the same method as in Example 1J.

[0312] (Example 3C) (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-(piperidine-4-ylmethyl)pyrrolidine-1,2-dicarboxamide hydrochloride. Using the compound obtained in Example 3B (138 mg), the marked compound (123 mg) was obtained as a solid by the same method as in Example 1K.

[0313] (Example 3) (2S,3R)-N 1-[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide. The compound obtained in Example 3C (71.3 mg) and the compound obtained in Example 1H (58.6 mg) were suspended in DMF (2.6 mL), sodium acetate (13.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Then, under ice cooling, sodium triacetoxyborohydride (74.1 mg) was added, and the mixture was heated to room temperature and stirred for 3 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with chloroform / 2-propanol (4 / 1). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol), and the fraction of the labeled compound was concentrated under reduced pressure. The resulting solid was dissolved in DCM / methanol, and the resulting solid was filtered off to obtain the labeled compound (55.2 mg, 2-step yield from Example 3C: 50%) as a solid.

[0314] (Example 4A) Using N-(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-1H-imidazole-1-carboxamide 2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-amine (CAS registry number: 1163707-28-5) (1.49 g), the marked compound (1.82 g, yield: 89%) was obtained as a solid in the same manner as in Example 1I.

[0315] (Example 4B) Using the compound obtained in Example 4A (367 mg) and the compound obtained in Example 1F (462 mg), the marked compound (624 mg, yield: quantitative) was obtained as a solid by the same method as in Example 1J.

[0316] (Example 4C) (2S,3R)-N 1 Using the compound obtained in Example 4B (624 mg) -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-(piperidine-4-ylmethyl)pyrrolidine-1,2-dicarboxamide, the marked compound (444 mg, yield: 86%) was obtained as a solid by the same method as in Example 2C.

[0317] (Example 4) (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide Using the compound obtained in Example 4C (79.9 mg) and the compound obtained in Example 1H (87.2 mg), the marked compound (85.8 mg, yield: 63%) was obtained as a solid by the same method as in Example 2.

[0318] (Example 5A) N-(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-1H-imidazole-1-carboxamide 8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-amine (CAS Registry No.: 1260504-53-7, WO2011000855) (156 mg) was added to a mixture of DCM (4.5 mL) and DMF (0.45 mL) with CDI (202 mg) and stirred at room temperature for 14 hours. The resulting solid was filtered and washed with DCM to obtain the marked compound (160 mg, yield 75%) as a solid.

[0319] (Example 5B) Using the compound obtained in Example 5A (175 mg) and the compound obtained in Example 1F (232 mg), the marked compound (296 mg, yield: quantitative) was obtained as a solid by the same method as in Example 1J.

[0320] (Example 5C) (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-(piperidine-4-ylmethyl)pyrrolidine-1,2-dicarboxamide hydrochloride The compound obtained in Example 5B (285 mg) was used to obtain the marked compound (319 mg) in solid form by the same method as in Example 1K.

[0321] (Example 5) (2S,3R)-N 1-(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide Using the compound obtained in Example 5C (60.2 mg) and the compound obtained in Example 1H (41.7 mg), the marked compound (51.1 mg, 2-step yield from Example 5C: 66%) was obtained as a solid by the same method as in Example 3.

[0322] (Example 6A) tert-butyl 4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate 3-(5-bromo-1-oxoisoindorin-2-yl)piperidine-2,6-dione (CAS Registry No.: 1010100-26-1) (26.7 g), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS Registry No.: 286961-14-6) (30.6 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride A mixture of DCM adduct (6.74 g), sodium carbonate (17.5 g), DMF (550 mL), and water (110 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the resulting solid was filtered off and washed with ethyl acetate to obtain the marked compound (25.7 g, yield: 73%) as a solid.

[0323] (Example 6B) A mixture of the compound obtained in Example 6A (25.7 g), tert-butyl 4-[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-carboxylate, 10% palladium carbon (10.0 g), ethanol (400 mL), and DCM (600 mL) was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the marked compound (23.6 g, yield: 86%) as a solid.

[0324] (Example 6C) 3-[1-oxo-5-(piperidine-4-yl)-1,3-dihydro-2H-isoindole-2-yl]piperidine-2,6-dione monohydrochloride The compound obtained in Example 6B (23.6 g), a suspension of DCM (500 mL), and 4M hydrogen chloride / 1,4-dioxane (500 mL) was stirred at room temperature for 1.5 hours. Ethyl acetate (500 mL) was added to the reaction mixture, and the resulting solid was filtered to obtain the marked compound (20.0 g, yield: quantitative) as a solid.

[0325] (Example 6D) A 1.3 M lithium bis(trimethylsilyl)amide / THF solution (500 mL) of benzyl(8-hydroxy-1,4-dioxaspiro[4,5]decane-8-yl) acetate was cooled to -78°C. A 50 mL THF solution of benzyl acetate (58.6 g) was added dropwise over 1 hour at the same temperature. Subsequently, a 50 mL THF solution of 1,4-cyclohexanedione monoethylene ketal (CAS registry number: 4746-97-8) (20.3 g) was added dropwise over 40 minutes at the same temperature, and the mixture was stirred for 30 minutes at the same temperature. A saturated aqueous ammonium chloride solution (500 mL) was added to the reaction mixture, and the mixture was raised to room temperature and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (35.9 g, yield: 90%) as an oil.

[0326] (Example 6E) Benzyl (1-hydroxy-4-oxocyclohexyl) acetate. A solution of the compound obtained in Example 6D (7.60 g) in acetone (50 mL) was mixed with 2 M hydrochloric acid (25 mL) and stirred at room temperature for 3 hours. The reaction solution was cooled to 0°C, saturated sodium bicarbonate solution was added, and the mixture was heated to room temperature and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (6.11 g, yield: 89%).

[0327] (Example 6F) Benzyl(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl) acetate. A mixture of the compound obtained in Example 6C (1.00 g) and the compound obtained in Example 6E (1.08 g) in DMF (18 mL) was mixed with sodium acetate (248 mg) and stirred at room temperature for 2 hours. Then sodium triacetoxyborohydride (1.75 g) was added and stirred at room temperature for 3 days. The reaction mixture, cooled on ice, was extracted with saturated sodium bicarbonate solution using DCM. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate to obtain the marked compound (1.20 g, yield: 76%) as a solid.

[0328] (Example 6G) The compound obtained in Example 6F, benzyl(cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-[(trimethylsilyl)oxy]cyclohexyl) acetate (712 mg), triethylamine (1.03 mL), and 4-dimethylaminopyridine (15.2 mg) were mixed in DMF (6 mL). Chlorotrimethylsilane (0.784 mL) was added under ice cooling, and the mixture was heated to room temperature and stirred for 65 hours. After the reaction mixture was cooled on ice, saturated sodium bicarbonate solution and water were added, and the mixture was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol) to obtain the marked compound (371 mg, yield: 46%) as a solid, highly polar diastereomer.

[0329] (Example 6H) (cis-4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetic acid monohydrochloride. The compound obtained in Example 6G (10.35 g) was added to a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol (160 mL) and DCM (160 mL) with 10% palladium carbon (5.18 g) and stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. MeCN (160 mL) and 1 M hydrochloric acid (50 mL) were added to the resulting residue and stirred at room temperature for 17 hours. MeCN was added to the reaction mixture and the resulting solid was filtered to obtain the marked compound (8.20 g, yield: 98%) as a solid.

[0330] (Example 6) (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide] - a mixture of the compound obtained in Example 6H (292 mg) and DMF (10 mL) was mixed with DIPEA (0.485 mL) and HATU (229 mg) and stirred at room temperature for 20 minutes. Then, the free compound of Example 1K, obtained by treating the compound obtained in Example 1J in the same manner as in Example 2C (250 mg), was added and heated and stirred at 50°C for 3 hours. After cooling to room temperature, it was diluted with DCM / 2-propanol (4 / 1), washed with saturated sodium bicarbonate solution, water, and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (DCM / 2-propanol) followed by silica gel column chromatography (DCM / methanol) to obtain the marked compound (253 mg, yield: 54%) as a solid.

[0331] The compound of Example 6 can also be produced via the compound obtained in Example 6a below.

[0332] (Example 6a) tert-butyl 5-amino-4-[5-(1-{cis-4-[2-(4-{[(2S,3R)-2-carbamoyl-1-({4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}carbamoyl)pyrrolidine-3-yl]methyl}piperidine-1-yl)-2-oxoethyl]-4-hydroxycyclohexyl}piperidine-4-yl)-1-oxo-1,3-dihydro-2H-isoindole-2-yl]-5-oxopentanoate Add HATU (1.05 equivalents) and DIPEA (3.0 equivalents) to a DMF solution of the compound obtained in Reference Example 5, stir at room temperature, then add the compound obtained in Example 1K (1.0 equivalent) and stir at room temperature. The indicated compound can be obtained by performing post-processing and purification.

[0333] (Example 6) (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide A mixture of the compound obtained in Example 6a, MeCN, and dichloroethane is mixed with benzenesulfonic acid (4.0 equivalents) and heated under reflux at 90°C. The reaction mixture is cooled to room temperature, and after work-up, the compound can be purified to obtain the marked compound.

[0334] (Example 7) (2S,3R)-N 1-(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide The compound obtained in Example 6H (1.77 g) and HATU (1.30 g) were mixed in DMF (60 mL) and DIPEA (2.13 mL) were added and the mixture was stirred at room temperature for 1 hour. The compound obtained in Example 4C (1.40 g) was added to the reaction mixture and the mixture was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate solution and water were added to the reaction solution and extracted with DCM / 2-propanol (7:1). The combined organic layers were sequentially washed with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol) followed by amino silica gel column chromatography (DCM / 2-propanol). DCM, methanol, and ethyl acetate were added to the purified product and concentrated again under reduced pressure. Ethyl acetate was added to the resulting concentrate and sonicated, and the resulting solid was filtered to obtain the marked compound (1.65 g, yield: 60%) as a solid.

[0335] The compound of Example 7 can also be produced via the compound obtained in Example 7a below.

[0336] (Example 7a) tert-butyl 5-amino-4-{5-[1-(cis-4-{2-[4-({(2S,3R)-1-[(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)carbamoyl]-2-carbamoylpyrrolidine-3-yl}methyl)piperidine-1-yl]-2-oxoethyl}-4-hydroxycyclohexyl)piperidine-4-yl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}-5-oxopentanoate The marked compound can be obtained by using the compound obtained in Example 4C instead of the compound obtained in Example 1K in the method described in Example 6a.

[0337] (Example 7) (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide The marked compound can be obtained by using the compound of Example 7a instead of the compound of Example 6a in the method of Example 6a.

[0338] (Example 8) (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 The compound obtained in Example 6H (39 mg) and the compound obtained in Example 2C (40 mg) were used to carry out a reaction in the same manner as in Example 7. The crude product was purified by preparative HPLC (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile) to obtain the marked compound (22 mg, yield: 29%) as a solid.

[0339] The free compound (8b) of Example 8 can also be produced via the compound obtained in Example 8a below.

[0340] (Example 8a) tert-butyl 5-amino-4-{5-[1-(cis-4-{2-[4-({(2S,3R)-2-carbamoyl-1-[(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)carbamoyl]pyrrolidine-3-yl}methyl)piperidine-1-yl]-2-oxoethyl}-4-hydroxycyclohexyl)piperidine-4-yl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}-5-oxopentanoate The marked compound can be obtained by using the compound obtained in Example 2C instead of the compound obtained in Example 1K in the method described in Example 6a.

[0341] (Example 8b) (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide In the method described in Example 6, the marked compound can be obtained by using the compound of Example 8a instead of the compound of Example 6a.

[0342] (Example 9A) Using a THF solution (0.31 M, 19.0 mL) of the organozinc reagent prepared in the same manner as in Example 1A, and tert-butyl 4-(4-bromophenyl)-1-piperidinecarboxylate (CAS registry number: 769944-78-7) (2.00 g), the marked compound (482 mg, yield: 16%) was obtained as a solid in the same manner as in Example 1A.

[0343] (Example 9B) Using the compound obtained in Example 9A (218 mg), the marked compound (133 mg, yield: 63%) was obtained as a solid by the same method as in Example 1D. (3R)-3-{4-[1-(tert-butoxycarbonyl)piperidine-4-yl]benzyl}-1-[(1S)-1-phenylethyl]-L-proline

[0344] (Example 9C) Using the compound obtained in Example 9B (133 mg), the marked compound (110 mg, yield: 83%) was obtained as an oil by the same method as in Example 1E.

[0345] (Example 9D) tert-butyl 4-(4-{[(2S,3R)-2-carbamoylpyrrolidine-3-yl]methyl}phenyl)piperidine-1-carboxylate. The compound obtained in Example 9C (110 mg) was dissolved in ethanol (2 mL), 20% palladium-carbon hydroxide (63.0 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the marked compound (83 mg, yield: 96%).

[0346] (Example 9E) Using the compound obtained in Example 2A (96.0 mg) and the compound obtained in Example 9D (83.0 mg), the labeled compound (142 mg, yield: 91%) was obtained by the same method as in Example 1J.

[0347] (Example 9F) (2S,3R)-N 1-(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)-3-[4-(piperidine-4-yl)benzyl]pyrrolidine-1,2-dicarboxamide hydrochloride] The compound obtained in Example 9E (142 mg) was used to obtain the marked compound (136 mg) in solid form by the same method as in Example 1K.

[0348] (Example 9) (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 The compound obtained in Example 6H (113 mg) and the compound obtained in Example 9F (136 mg) were used to carry out the reaction in the same manner as in Example 7. The crude product was purified by preparative HPLC (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile) to obtain the marked compound (88 mg, 2-step yield from Example 9F: 40%) as a solid.

[0349] The free compound (9b) of Example 9 can also be produced via the compound obtained in Example 9a below.

[0350] (Example 9a) tert-butyl 5-amino-4-(5-{1-[cis-4-(2-{4-[4-({(2S,3R)-2-carbamoyl-1-[(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)carbamoyl]pyrrolidine-3-yl}methyl)phenyl]piperidine-1-yl}-2-oxoethyl)-4-hydroxycyclohexyl]piperidine-4-yl}-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-5-oxopentanoate The marked compound can be obtained by using the compound obtained in Example 9F instead of the compound obtained in Example 1K in the method described in Example 6a.

[0351] (Example 9b) (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide In the method described in Example 6, the marked compound can be obtained by using the compound obtained in Example 9a instead of the compound obtained in Example 6a.

[0352] (Example 10) (2S,3R)-N 1-[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide A suspension of the compound obtained in Example 6H (38.0 mg) in DMF (1.6 mL) was mixed with HATU (36.7 mg) and triethylamine (0.03 mL) and stirred at room temperature for 40 minutes. Then the compound obtained in Example 3C (40.0 mg) was added and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by diol silica gel column chromatography (DCM / methanol). The purified product was dissolved in chloroform / 2-propanol (4 / 1), washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting solid was dissolved in a small amount of chloroform / 2-propanol (4 / 1), diethyl ether was added, and the resulting solid was filtered to obtain the marked compound (32.1 mg, two-step yield from Example 3C: 38%) as a solid.

[0353] The compound of Example 10 can also be produced via the compound obtained in Example 10a below.

[0354] (Example 10a) tert-butyl 5-amino-4-[5-(1-{cis-4-[2-(4-{[(2S,3R)-1-{[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]carbamoyl}-2-carbamoylpyrrolidine-3-yl]methyl}piperidine-1-yl)-2-oxoethyl]-4-hydroxycyclohexyl}piperidine-4-yl)-1-oxo-1,3-dihydro-2H-isoindole-2-yl]-5-oxopentanoate The marked compound can be obtained by using the compound obtained in Example 3C instead of the compound obtained in Example 1K in the method described in Example 6a.

[0355] (Example 10) (2S,3R)-N 1-[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide In the method of Example 6, the marked compound can be obtained by using the compound obtained in Example 10a instead of the compound obtained in Example 6a.

[0356] (Example 11) (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide Using the compound obtained in Example 6H (55.8 mg) and the compound obtained in Example 5C (63.5 mg), the marked compound (37.0 mg, 2-step yield from Example 5C: 42%) was obtained as a solid by the same method as in Example 10.

[0357] The compound of Example 11 can also be produced via the compound obtained in Example 11a below.

[0358] (Example 11a) tert-butyl 5-amino-4-{5-[1-(cis-4-{2-[4-({(2S,3R)-1-[(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)carbamoyl]-2-carbamoylpyrrolidine-3-yl}methyl)piperidine-1-yl]-2-oxoethyl}-4-hydroxycyclohexyl)piperidine-4-yl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}-5-oxopentanoate The marked compound can be obtained by using the compound obtained in Example 5C instead of the compound obtained in Example 1K in the method described in Example 6a.

[0359] (Example 11) (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarbboxamide In the method of Example 6, the marked compound can be obtained by using the compound obtained in Example 11a instead of the compound obtained in Example 6a.

[0360] (Reference Example 1) A mixture of tert-butyl 5-amino-4-(5-bromo-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-5-oxopentanoate, 4-bromo-2-(bromomethyl)benzoate methyl (CAS registry number: 78471-43-9), tert-butyl 4,5-diamino-5-oxo-pentanoate hydrochloride (CAS registry number: 1323411-16-0) (1.2 equivalents), and MeCN is mixed with DIPEA (4.0 equivalents) and stirred at 80°C. The reaction mixture is cooled to room temperature, and after work-up, the compound can be purified to obtain the marked compound.

[0361] (Reference Example 2) Benzyl 4-[2-(1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate Compound obtained in Reference Example 1, benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (CAS Registry Number: To a mixture of 286961-15-7) (1.1 equivalents) and 1,4-dioxane, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.05 equivalents), sodium carbonate (2.0 equivalents), and water are added at 90°C and stirred at the same temperature under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, and after work-up, the product can be purified to obtain the product.

[0362] (Reference Example 3) tert-butyl 5-amino-5-oxo-4-[1-oxo-5-(piperidine-4-yl)-1,3-dihydro-2H-isoindole-2-yl]pentanoate. To an ethanol solution of the compound obtained in Reference Example 2, 10% palladium carbon is added and the mixture is stirred at 40°C under a hydrogen atmosphere. The reaction mixture is cooled to room temperature and post-treatment is performed to obtain the compound.

[0363] (Reference Example 4) tert-butyl 5-amino-4-[5-(1-{4-[2-(benzyloxy)-2-oxoethyl]-4-hydroxycyclohexyl}piperidine-4-yl)-1-oxo-1,3-dihydro-2H-isoindole-2-yl]-5-oxopentanoate A mixture of the compound obtained in Reference Example 3, the compound obtained in Example 6E (1.5 equivalents), and DMF is mixed with acetic acid (5.0 equivalents), stirred at room temperature, cooled on ice, and sodium triacetoxyborohydride (3.0 equivalents) is added and stirred at room temperature. After work-up, the diastereomer is separated by purification to obtain the marked compound.

[0364] (Reference Example 5) (cis-4-{4-[2-(1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetic acid. Add 10% palladium carbon to an ethanol solution of the compound obtained in Reference Example 4 and stir at 40°C under a hydrogen atmosphere. Cool the reaction mixture to room temperature and perform post-treatment to obtain the marked compound.

[0365] (Example 12A) N-{5-[6-(diethylamino)pyrazine-2-yl]-4-methyl-1,3-thiazole-2-yl}-1H-imidazole-1-carboxamide 5-[6-(diethylamino)pyrazine-2-yl]-4-methylthiazole-2-amine (CAS Registry No.: 1395492-84-8, US20090163469 A1) (106 mg) was added to a solution of DMF (4 mL) and CDI (78.3 mg) was stirred at room temperature for 1.5 hours, then the temperature was raised to 40°C and stirred for 22 hours. The reaction mixture was cooled to room temperature, CDI (52.3 mg) was added, and the mixture was stirred at 40°C for 1 hour. The reaction mixture was cooled to room temperature, and the resulting solid was filtered and washed with DCM to obtain the marked compound (83.7 mg, yield: 58%) as a solid.

[0366] (Example 12B) Using the compound obtained in Example 12A (83.7 mg) and the compound obtained in Example 1F (177.4 mg), the marked compound (160 mg) was obtained as a solid in the same manner as in Example 1J.

[0367] (Example 12C) (2S,3R)-N 1Using the compound obtained in Example 12B (160 mg), the marked compound (132 mg) was obtained as a solid in the same manner as in Example 1K.

[0368] (Example 12) (2S,3R)-N 1 -{5-[6-(diethylamino)pyrazine-2-yl]-4-methyl-1,3-thiazole-2-yl}-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide Using the compound obtained in Example 12C (132 mg) and the compound obtained in Example 1H (105 mg), the marked compound (94.9 mg, 3-step yield from Example 12B: 48%) was obtained as a solid by the same method as in Example 3.

[0369] (Example 13A) 3-{2-[4-(hydroxymethyl)piperidine-1-yl]-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl}piperidine-2,6-dione 3-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyridine-6(7H)-yl)piperidine-2,6-dione (CAS Registry No.: 2154343-24-3) (5.59 g), DIPEA (6.97 mL), and DMSO (20 mL) were mixed with 4-piperidinemethanol (CAS Registry No.: 6457-49-4) (2.30 g) and heated and stirred at 110°C for 6 hours. The reaction mixture was cooled to room temperature, purified by silica gel column chromatography (hexane / ethyl acetate → ethyl acetate / methanol), and the fraction of the marked compound was concentrated under reduced pressure. Methanol / ethyl acetate was added to the resulting concentrate, and the resulting solid was filtered to obtain the marked compound (2.74 g, yield: 38%) as a solid.

[0370] (Example 13B) 1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl]piperidine-4-carbaldehyde A mixture of the compound obtained in Example 13A (1.43 g), DCM (40 mL), and acetic acid (10 mL) was cooled on ice, and Des-Martin periodinane (2.04 g) was added. The mixture was heated to room temperature and stirred for 4 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). The fraction of the marked compound was concentrated under reduced pressure, and ethyl acetate was added to the concentrate. The resulting solid was filtered to obtain the marked compound (1.15 g, yield: 81%) as a solid.

[0371] (Example 13) (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 Using the compound obtained in Example 1K (30.0 mg) and the compound obtained in Example 13B (19.2 mg), the marked compound (20.9 mg, 2-step yield from Example 1K: 52%) was obtained as a solid by the same method as in Example 3.

[0372] (Example 14A) Benzyl {(E)-{[(benzyloxy)carbonyl]amino}[4-(hydroxymethyl)piperidine-1-yl]methylidene}carbamate. To a solution of 4-piperidinemethanol (CAS registry number: 6457-49-4) (1.5 g) in DCM (30 mL), N,N'-bis(carbobenzoxy)-1H-pyrazole-1-carboxamidine (CAS registry number: 152120-55-3) (5.4 g) and triethylamine (2.7 mL) were added and the mixture was stirred at room temperature for 2 days. 1 M hydrochloric acid was added to the reaction mixture and the liquid-liquid was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (6.0 g) as an oil.

[0373] (Example 14B) Benzyl {(E)-{[(benzyloxy)carbonyl]amino}[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]methylidene}carbamate To a solution of the compound obtained in Example 14A (6.0 g) in DMF (50 mL), imidazole (1.3 g) and tert-butyldimethylchlorosilane (2.1 g) were added under ice cooling, and the mixture was heated to room temperature and stirred for 3 days. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (7.0 g, 2-step yield from Example 14A: quantitative) as an oil.

[0374] (Example 14C) 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-carboxymidamide The compound obtained in Example 14B (5.0 g) was dissolved in ethanol (60 mL), 10% palladium carbon (1.0 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and hexane were added to the resulting solid, and the marked compound (1.9 g, yield: 76%) was obtained as a solid.

[0375] (Example 14D) Ethyl (2Z)-4-chloro-2-(ethoxymethylidene)-3-oxobutanoate 4-chloroacetoethyl acetate (CAS registry number: 638-07-3) (4.1 mL) was mixed with triethyl orthoformate (10 mL) and acetic anhydride (11.5 mL), and the mixture was heated and stirred at 110°C for 3 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and toluene was added to the resulting residue and concentrated under reduced pressure. Hexane was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered to obtain the marked compound (5.85 g, yield: 87%) as a solid.

[0376] (Example 14E) Ethyl 2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-4-(chloromethyl)pyrimidine-5-carboxylate. The compound obtained in Example 14C (1.00 g) and the compound obtained in Example 14D (0.813 g) were dissolved in THF (10 mL), to which DIPEA (1.26 mL) was added and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (0.946 g, yield: 60%) as a solid.

[0377] (Example 14F) A mixture of ethyl 2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-4-{[(2,6-dioxopiperidine-3-yl)amino]methyl}pyrimidine-5-carboxylate 3-aminopiperidine-2,6-dione hydrochloride (CAS registry number: 24666-56-6) (0.632 g) and DMF (2.0 mL) was mixed with DIPEA (1.31 mL), sodium iodide (0.345 g), and a solution of the compound obtained in Example 14E (0.822 g) in MeCN (16 mL), and the mixture was stirred at 50°C for 4 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, the resulting residue was diluted with ethyl acetate and washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (0.415 g, yield: 42%) as a solid.

[0378] (Example 14G) 3-{2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-yl}piperidine-2,6-dione A solution of the compound obtained in Example 14F (100 mg) in 1,4-dioxane (1.0 mL) was mixed with acetic acid (0.0551 mL) and heated to 110°C, stirring for 8 hours. After the reaction mixture was cooled to room temperature, the marked compound (90.9 mg, yield: quantitative) was obtained as a solid by concentration under reduced pressure.

[0379] (Example 14H) 3-{2-[4-(hydroxymethyl)piperidine-1-yl]-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-yl}piperidine-2,6-dione A mixture of the compound obtained in Example 14G (90.9 mg) and 1,4-dioxane (1.0 mL) was mixed with 4 M hydrogen chloride / 1,4-dioxane solution (0.48 mL) and stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, and water and saturated sodium bicarbonate solution were added and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. A suspension was obtained by adding a small amount of DCM / methanol (95 / 5) to the resulting residue and diluting it with diethyl ether while sonicating. The resulting solid was filtered to obtain the marked compound (50.8 mg, yield: 74%) as a solid.

[0380] (Example 14I) 1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl]piperidine-4-carbaldehyde A mixture of the compound obtained in Example 14H (48.0 mg) and DCM (20 mL) was mixed with Des-Martin periodinane (68.0 mg) and stirred at room temperature for 14 hours. Diluted with ethyl acetate, water and saturated sodium bicarbonate solution were added, and the mixture was extracted with a mixed solvent of DCM and a small amount of 2-propanol. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the marked compound (37.6 mg, yield: 79%) as a solid.

[0381] (Example 14) (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide The compound obtained in Example 1K (30.0 mg) and the compound obtained in Example 14I (18.4 mg) were used in the same manner as in Example 3 to obtain the marked compound (30.4 mg, 2-step yield from Example 1K: 76%) as a solid.

[0382] (Example 15A) 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione A mixture of 3-bromopiperidine-2,6-dione (CAS registry number: 62595-74-8) (8.20 g), DIPEA (14.9 mL), and DCM (100 mL) was cooled on ice, 2-(trimethylsilyl)ethoxymethyl chloride (9.82 mL) was added, and the mixture was heated to room temperature and stirred for 5 hours. Water and DCM were added to the reaction mixture and separated. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (12.6 g, yield: 92%) as an oil.

[0383] (Example 15B) {1-[6-(methylamino)-5-nitropyridine-2-yl]piperidine-4-yl}methanol A mixture of 6-chloro-N-methyl-3-nitro-2-pyridineamine (CAS registry number: 33742-70-0) (7.40 g), 4-piperidinemethanol (CAS registry number: 6457-49-4) (5.47 g), potassium carbonate (10.9 g), and DMF (45 mL) was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was collected by adding hexane / ethyl acetate (1 / 2) to the obtained residue and washing with hexane / ethyl acetate (1 / 2) to obtain the marked compound (9.34 g, yield: 89%) as a solid.

[0384] (Example 15C) 6-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-N-methyl-3-nitropyridine-2-amine The compound obtained in Example 15B (8.54 g) and imidazole (3.27 g) were dissolved in DMF (80 mL) and tert-butyldimethylchlorosilane (5.80 g) was added under ice cooling, and the mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (11.8 g, yield: 97%) as a solid.

[0385] (Example 15D) 5-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one A mixture of the compound obtained in Example 15C (11.8 g), THF (120 mL), and ethanol (60 mL) was mixed with 10% palladium carbon (3.31 g) and stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, washed with ethanol, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in DMF (100 mL), triethylamine (13.0 mL) and CDI (15.2 g) were added, and the mixture was stirred at 80 °C for 5 hours. After the reaction mixture was cooled to room temperature, it was cooled on ice, water and ethyl acetate were added, and the resulting solid was filtered and washed with diethyl ether. The organic layer of the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and sonication was performed. The resulting solid was filtered and washed with diethyl ether to obtain a solid. By combining this solid with the previously obtained solid, the marked compound (5.06 g, yield: 43%) was obtained.

[0386] (Example 15E) 3-{5-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione A suspension of the compound obtained in Example 15D (4.60 g) and cesium carbonate (11.9 g) in DMF (24 mL) was stirred at 60°C for 30 minutes. Then, a solution of the compound obtained in Example 15A (7.87 g) in DMF (6 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, cesium carbonate (11.9 g) and the compound obtained in Example 15A (7.87 g) were added, and the mixture was heated and stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature, then water and ethyl acetate were added, and the mixture was separated. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (7.16 g, yield: 95%) as a solid.

[0387] (Example 15F) 3-{5-[4-(hydroxymethyl)piperidine-1-yl]-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl}piperidine-2,6-dione A solution of the compound obtained in Example 15E (7.16 g) in DCM (50 mL) was mixed with TFA (50 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with toluene and concentrated under reduced pressure twice. Triethylamine (6.42 mL) and N,N'-dimethylethylenediamine (1.49 mL) were added to the resulting DCM (50 mL) mixture of residues, stirred at room temperature for 3 hours, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol). The fraction of the target substance was concentrated under reduced pressure, and the resulting residue was sonicated with DCM. The resulting solid was filtered and washed with DCM to obtain the marked compound (3.09 g, yield: 72%) as a solid.

[0388] (Example 15G) 1-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl]piperidine-4-carbaldehyde A mixture of the compound obtained in Example 15F (541 mg) and DCM (20 mL) was mixed with triethylamine (1.61 mL), DMSO (0.822 mL), and sulfur trioxide pyridine complex (922 mg). The mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (345 mg, yield: 64%) as a solid.

[0389] (Example 15) (2S,3R)-3-{[1-({1-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide The compound obtained in Example 1J was treated in the same manner as in Example 2C to obtain the free compound of Example 1K (434 mg), and the compound obtained in Example 15G (250 mg) were used to obtain the marked compound (365 mg, yield: 61%) as a solid in the same manner as in Example 2.

[0390] (Example 16A) 3-[2,6-bis(benzyloxy)pyridine-3-yl]-6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (CAS Registry No.: 1539296-59-7) (13.8 g), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS Registry No.: 2152673-80-6) (19.7 g), potassium carbonate (13.0 g), and a mixture of 1,4-dioxane (141 mL) / water (35 mL) containing [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM adduct (1.92 g) was added and stirred at 80°C for 4.5 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, saturated ammonium chloride aqueous solution and water were added and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was suspended in diethyl ether, the resulting solid was filtered, and washed with diethyl ether to obtain a solid. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). The residue obtained by concentrating the fraction of the labeled compound under reduced pressure was suspended in diethyl ether, the resulting solid was filtered, and washed with diethyl ether to obtain a solid. By combining this with the previous solid, the labeled compound (13.2 g, yield: 61%) was obtained as a solid.

[0391] (Example 16B) (1-{3-[2,6-bis(benzyloxy)pyridine-3-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl}piperidine-4-yl)methanol A mixture of the compound obtained in Example 16A (4.00 g) and DMSO (29 mL) was mixed with DIPEA (4.57 mL) and 4-piperidinemethanol (CAS registry number: 6457-49-4) (1.51 g), and the mixture was stirred at 100°C for 4.5 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (3.03 g, yield: 65%) as a solid.

[0392] (Example 16C) 3-[2,6-bis(benzyloxy)pyridine-3-yl]-6-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridine A solution of the compound obtained in Example 16B (3.00 g) in DMF (28 mL) was cooled on ice, and imidazole (572 mg) and tert-butyldimethylchlorosilane (1.01 g) were added. The mixture was heated to room temperature and stirred for 30 minutes. After cooling the reaction mixture on ice, saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (3.61 g, yield: 99%) as a solid.

[0393] (Example 16D) 3-{6-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-yl}piperidine-2,6-dione The compound obtained in Example 16C (3.61 g) was dissolved in ethanol (37 mL) / ethyl acetate (18.5 mL), ASCA-2 (N.E. Chemcat) (1.29 g) was added, and the mixture was stirred at 50°C for 2 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethanol / ethyl acetate and chloroform, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (1.51 g, yield: 58%) as a solid.

[0394] (Example 16E) 3-{6-[4-(hydroxymethyl)piperidine-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-yl}piperidine-2,6-dione A solution of the compound obtained in Example 16D (1.50 g) in THF (16 mL) was mixed with TBAF (1 mol / L THF solution, 15.9 mL) and acetic acid (1.09 mL), and the mixture was stirred at 40°C for 4 hours. After the reaction mixture was cooled to room temperature, saturated ammonium chloride aqueous solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol) to obtain the marked compound (985 mg, yield: 87%) as a solid.

[0395] (Example 16F) 1-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-4-carbaldehyde. To a solution of the compound obtained in Example 16E (985 mg) in DCM (28 mL), Dess-Martin periodinane (1.29 g) was added under ice cooling, and the mixture was heated to room temperature and stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was separated with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (704 mg, yield: 72%) as a solid.

[0396] (Example 16) (2S,3R)-3-{[1-({1-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide The compound obtained in Example 16F (140 mg) and the compound obtained in Example 1J were treated in the same manner as in Example 2C to obtain the free compound of Example 1K (213 mg), and the marked compound (257 mg, yield: 74%) was obtained as a solid in the same manner as in Example 2.

[0397] (Example 17A) Using methyl (3R)-3-(iodomethyl)-1-[(1S)-1-phenylethyl]-L-prolinatemethyl N-buta-3-en-1-yl-N-[(1S)-1-phenylethyl]glycinate (CAS registry number: 432555-77-6, US20160264582) (2.00 g), iodine (2.46 g) was gradually added to a THF solution of the organozinc reagent prepared in the same manner as in Example 1A, under ice cooling, and then the mixture was heated to room temperature and stirred for 1 hour. Saturated ammonium chloride aqueous solution and saturated sodium thiosulfate aqueous solution were added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (2.30 g, yield: 76%) as an oil.

[0398] (Example 17B) Methyl (3S)-3-(azidomethyl)-1-[(1S)-1-phenylethyl]-L-prolinate. 2.30 g of the compound obtained in Example 17A was dissolved in DMF (35 mL), and sodium azide (0.801 g) was added. The mixture was stirred at 50°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (1.37 g, yield: 77%) as an oil.

[0399] (Example 17C) Using the compound obtained in Example 17B (550 mg), the marked compound (455 mg, yield: 87%) was obtained as a solid in the same manner as in Example 1D. (3S)-3-(azidomethyl)-1-[(1S)-1-phenylethyl]-L-proline

[0400] (Example 17D) (3S)-3-(azidomethyl)-1-[(1S)-1-phenylethyl]-L-prolineamide The compound obtained in Example 17C (5.27 g) was used to obtain the marked compound (3.70 g, yield: 71%) in the same manner as in Example 1E.

[0401] (Example 17E) (3S)-3-{[(tert-butoxycarbonyl)amino]methyl}-1-[(1S)-1-phenylethyl]-L-prolineamide The compound obtained in Example 17D (3.70 g) was dissolved in THF (50 mL), triphenylphosphine (5.33 g) and water (50 mL) were added, and the mixture was stirred at 75°C for 1.5 hours. After the reaction mixture was cooled to room temperature, sodium bicarbonate (5.69 g) and di-tert-butyl dicarbonate (3.55 g) were added, and the mixture was stirred at room temperature for 17 hours. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (3.70 g, yield: 79%) as a solid.

[0402] (Example 17F) (3S)-3-{[(tert-butoxycarbonyl)amino]methyl}-L-prolineamide The compound obtained in Example 17E (3.70 g) was dissolved in ethanol (100 mL), 10% palladium carbon (500 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the marked compound (2.34 g, yield: 90%).

[0403] (Example 17G) tert-butyl{[(2S,3S)-2-carbamoyl-1-({4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}carbamoyl)pyrrolidine-3-yl]methyl}carbamate The compound obtained in Example 1I (1.04 g) and the compound obtained in Example 17F (0.608 g) were used to obtain the marked compound (1.41 g, yield: 99%) as a solid in the same manner as in Example 1J.

[0404] (Example 17H) (2S,3S)-3-(aminomethyl)-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide hydrochloride. Using the compound (1.00 g) obtained in Example 17G, the marked compound (1.06 g) was obtained as a solid by the same method as in Example 1K.

[0405] (Example 17I) To a solution of the compound obtained in Example 17H ​​(50.0 mg) and tert-butyl N,N-bis(2-oxoethyl)carbamate (CAS registry number: 103898-12-0) (22.2 mg) in methanol (0.5 mL), sodium acetate (30.2 mg) and sodium cyanotrihydroborate (12.7 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, then saturated sodium bicarbonate solution was added and the mixture was separated. The aqueous layer was extracted with DCM, and the combined organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol) to obtain the marked compound (22.7 mg, 2-step yield from Example 17H: 39%) as a solid.

[0406] (Example 17J) (2S,3S)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}-3-(piperazine-1-ylmethyl)pyrrolidine-1,2-dicarboxamide hydrochloride. Using the compound (50 mg) obtained in Example 17I, the labeled compound (52 mg) was obtained by the same method as in Example 1K.

[0407] (Example 17) (2S,3S)-3-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]methyl}-N 1 Using the compound obtained in Example 17J (30.0 mg) and the compound obtained in Example 1H (18.1 mg), the marked compound (35.6 mg, 2-step yield from Example 17J: 90%) was obtained as a solid by the same method as in Example 3.

[0408] (Example 18A) Methyl (3R)-3-[4-(dimethoxymethyl)benzyl]-1-[(1S)-1-phenylethyl]-L-prolinate A THF solution (0.15 M, 15.2 mL) of an organozinc reagent prepared in the same manner as in Example 1A and 4-bromobenzaldehyde dimethyl acetal (CAS registry number: 24856-58-4) (0.33 mL) were used to obtain the marked compound (445 mg, yield: 57%) as an oily substance in the same manner as in Example 1A.

[0409] (Example 18B) Methyl (3R)-3-[4-(dimethoxymethyl)benzyl]-L-prolinate Using the compound obtained in Example 18A (436 mg), the marked compound (288 mg, yield: 89%) was obtained as an oil by the same method as in Example 1B.

[0410] (Example 18C) Using the compound obtained in Example 18B (277 mg), the marked compound (381 mg, yield: 94%) was obtained as an oil by the same method as in Example 1C.

[0411] (Example 18D) Using the compound obtained in Example 18C (359 mg), the marked compound (280 mg, yield: 81%) was obtained as a solid by the same method as in Example 1D. (3R)-1-[(benzyloxy)carbonyl]-3-[4-(dimethoxymethyl)benzyl]-L-proline

[0412] (Example 18E) Benzyl (2S,3R)-2-carbamoyl-3-[4-(dimethoxymethyl)benzyl]pyrrolidine-1-carboxylate. Using the compound obtained in Example 18D (269 mg), the marked compound (261 mg, yield: 97%) was obtained as a solid by the same method as in Example 1E.

[0413] (Example 18F) (3R)-3-[4-(dimethoxymethyl)benzyl]-L-prolineamide Using the compound obtained in Example 18E (261 mg), the marked compound (151 mg, yield: 86%) was obtained as an oil by the same method as in Example 1F.

[0414] (Example 18G) (2S,3R)-3-[4-(dimethoxymethyl)benzyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide] was obtained as a solid (296 mg, yield: 97%) using the compound obtained in Example 1I (200 mg) and the compound obtained in Example 18F (146 mg), in the same manner as in Example 1J.

[0415] (Example 18H) (2S,3R)-3-(4-formylbenzyl)-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide] was dissolved in methanol (2.4 mL) of the compound obtained in Example 18G, to which 4 M hydrogen chloride / 1,4-dioxane solution (1 mL) was added and the mixture was stirred at room temperature for 6.5 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted by DCM. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / ethyl acetate) to obtain the marked compound (133 mg, yield: 50%) as a solid.

[0416] (Example 18) (2S,3R)-3-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}methyl)benzyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide A mixture of the compound obtained in Example 18H (9.6 mg), the compound obtained in Example 6C (7.8 mg), and DMF (0.6 mL) was mixed with sodium acetate (1.6 mg) and stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (9.1 mg) was added and stirred at room temperature for 4 days. Water and ethyl acetate were added to the reaction mixture, and it was extracted with chloroform / 2-propanol (4 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (DCM / methanol) to obtain the marked compound (3.6 mg, yield: 24%) as a solid.

[0417] (Example 19A) Methyl(3S)-3-{[5-(dimethoxymethyl)pyridine-2-yl]methyl}-1-[(1S)-1-phenylethyl]-L-prolinate A THF solution (0.189 mol / L, 27.4 mL) of the organozinc reagent prepared in the same manner as in Example 1A and 2-bromo-5-(dimethoxymethyl)pyridine (CAS registry number: 174608-37-8) (1.00 g) were used to obtain the marked compound (156 mg, yield: 9%) as an oily substance in the same manner as in Example 1A.

[0418] (Example 19B) (3S)-3-{[5-(dimethoxymethyl)pyridine-2-yl]methyl}-1-[(1S)-1-phenylethyl]-L-proline The compound obtained in Example 19A (177 mg) was dissolved in THF (2.2 mL) / methanol (2.2 mL), to which 1 M aqueous sodium hydroxide solution (1.78 mL) was added, and the mixture was heated and stirred at 70°C for 22 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid (1.78 mL) was added and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the marked compound (127 mg, yield: 74%) as a solid.

[0419] (Example 19C) (3S)-3-{[5-(dimethoxymethyl)pyridine-2-yl]methyl}-1-[(1S)-1-phenylethyl]-L-prolineamide Using the compound obtained in Example 19B (127 mg), the marked compound (106 mg, yield: 84%) was obtained as an oil by the same method as in Example 1E.

[0420] (Example 19D) (3S)-3-{[5-(dimethoxymethyl)pyridine-2-yl]methyl}-L-prolineamide A solution of the compound obtained in Example 19C (106 mg) in ethanol (2.8 mL) was mixed with 20% palladium-carbon hydroxide (80 mg) and stirred at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite and washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain the marked compound (68.3 mg, yield: 89%) as an oil.

[0421] (Example 19E) (2S,3S)-3-{[5-(dimethoxymethyl)pyridine-2-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide The compound obtained in Example 19D (68.3 mg) and the compound obtained in Example 1I (104 mg) were used to obtain the marked compound (155 mg) in the same manner as in Example 1J.

[0422] (Example 19F) (2S,3S)-3-[(5-formylpyridine-2-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide (155 mg) obtained in Example 19E was added to a solution of THF (2.5 mL) with 1 M hydrochloric acid (0.98 mL) and stirred at room temperature for 5 hours. Another 1 M hydrochloric acid (0.98 mL) was added to the reaction mixture and stirred at room temperature for 15 hours, then another 1 M hydrochloric acid (0.981 mL) was added and stirred at room temperature for 29 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate and neutralized with saturated sodium bicarbonate solution. The organic layer and aqueous layer were separated, and the organic layer was washed with saturated brine. The aqueous layer was extracted with DCM, combined with the organic layer, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol) to obtain the marked compound (84.7 mg, 2-step yield from Example 19E: 62%) as a solid.

[0423] (Example 19) (2S,3S)-3-{[5-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}methyl)pyridine-2-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide The compound obtained in Example 19F (40.0 mg) and the compound obtained in Example 6C (31.2 mg) were suspended in DMF (1.4 mL), to which triethylamine (0.0237 mL) and acetic acid (0.0204 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (37.8 mg) was added to the reaction mixture under ice cooling, and the mixture was heated to room temperature and stirred for 5.5 hours. The reaction mixture was diluted with DCM, saturated sodium bicarbonate solution was added, and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol), and the fraction of the labeled compound was concentrated under reduced pressure. The resulting residue was dissolved in DCM, diethyl ether was added, and the resulting solid was filtered to obtain the marked compound (23.0 mg, yield: 37%) as a solid.

[0424] (Example 20A) Using a THF solution (0.23 mol / L, 17.3 mL) of the organozinc reagent prepared in the same manner as in Example 1A, and tert-butyl 5-bromoisoindoline-2-carboxylate (CAS registry number: 201940-08-1) (1.00 g), the marked compound (885 mg, yield: 57%) was obtained as a solid in the same manner as in Example 1A.

[0425] (Example 20B) (3R)-3-{[2-(tert-butoxycarbonyl)-2,3-dihydro-1H-isoindole-5-yl]methyl}-1-[(1S)-1-phenylethyl]-L-proline The compound obtained in Example 20A (885 mg) was dissolved in methanol (9.5 mL) and THF (9.5 mL), to which 3.81 mL of 5 M aqueous sodium hydroxide solution was added and the mixture was heated and stirred at 60°C for 18 hours. Another 3.81 mL of 5 M aqueous sodium hydroxide solution was added to the reaction mixture and the mixture was heated and stirred at 60°C for 1.5 hours. After the reaction mixture was cooled to room temperature, 7.6 mL of 5 M hydrochloric acid was added to neutralize it, and the mixture was extracted with DCM. Most of the combined organic layer was concentrated under reduced pressure, the resulting residue was diluted again with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the marked compound (964 mg) as a solid.

[0426] (Example 20C) Using the compound obtained in Example 20B (964 mg), the marked compound (610 mg, 2-step yield from Example 20B: 72%) was obtained as a solid by the same method as in Example 1E. (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C) (Example 20C))

[0427] (Example 20D) Using the compound obtained in Example 20C (610 mg), the marked compound (439 mg, yield: 94%) was obtained as a solid in the same manner as in Example 19D. (Example 20D)

[0428] (Example 20E) Using the compound obtained in Example 1I (225 mg) and the compound obtained in Example 20D (197 mg), the marked compound (287 mg, yield: 75%) was obtained as a solid in the same manner as in Example 1J.

[0429] (Example 20F) (2S,3R)-3-(2,3-dihydro-1H-isoindole-5-ylmethyl)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide hydrochloride. Using the compound obtained in Example 20E (287 mg), the marked compound (280 mg) was obtained as a solid in the same manner as in Example 1K.

[0430] (Example 20) (2S,3R)-3-{[2-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)-2,3-dihydro-1H-isoindole-5-yl]methyl}-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide A mixture of the compound obtained in Example 1H (64.3 mg), the compound obtained in Example 20F (110 mg), and DMF (2 mL) was mixed with triethylamine (0.100 mL) and acetic acid (0.103 mL) and stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (95.9 mg) was added and stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer extracted with DCM was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol), and the fraction of the labeled compound was concentrated under reduced pressure. After adding DCM / diethyl ether, the resulting solid was filtered off. This solid was dissolved in DMSO and purified by preparative HPLC (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile), and the fraction of the labeled compound was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the resulting residue, and it was extracted with chloroform / 2-propanol (4 / 1). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in DCM / methanol, and the resulting solid was filtered off to obtain the labeled compound (19.2 mg, 2-step yield from Example 20F: 12%) as a solid.

[0431] (Example 21A) (2S,3R)-3-({1-[(8-hydroxy-1,4-dioxaspiro[4.5]decane-8-yl)methyl]piperidine-4-yl}methyl)-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide The compound obtained in Example 1J was treated in the same manner as in Example 2C to obtain the free compound of Example 1K (200 mg). This free compound was mixed with 2-propanol (8 mL) of 1,7,10-trioxadispiro[2.2.4(6).2(3)]dodecane (CAS registry number: 83365-44-0) (63.2 mg) and heated under reflux for 16 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol) to obtain the marked compound (134 mg, yield: 51%) as a solid.

[0432] (Example 21B) (2S,3R)-3-({1-[(1-hydroxy-4-oxocyclohexyl)methyl]piperidine-4-yl}methyl)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide A mixture of the compound obtained in Example 21A (134 mg), THF (3 mL), and 2M hydrochloric acid (6 mL) was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol) to obtain the marked compound (124 mg, yield: 99%) as a solid.

[0433] (Example 21) (2S,3R)-3-({1-[(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)methyl]piperidine-4-yl}methyl)-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide (highly polar diastereomer) A mixture of the compound obtained in Example 6C (67.9 mg), the compound obtained in Example 21B (124 mg), and DMF (4 mL) was mixed with DIPEA (0.096 mL) and acetic acid (0.053 mL), and stirred at room temperature for 40 minutes. Then sodium triacetoxyborohydride (59.3 mg) was added and stirred at room temperature for 13 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol) to obtain the marked compound (43.6 mg, yield: 24%) as a highly polar diastereomer.

[0434] (Example 22A) tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridine-3-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl}-3,6-dihydropyridine-1(2H)-carboxylate, compound obtained in Example 16A (524 mg), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS: 286961-14-6) (709 mg), tripotassium phosphate (487 mg), 1,4-dioxane (10 mL), and water (2.5 mL) To a mixture of (mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex (CAS registry number: 95464-05-4) (93.7 mg) was added and the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the marked compound (713 mg) as a solid.

[0435] (Example 22B) Using the compound obtained in Example 22A (713 mg), the marked compound (303 mg, 2-step yield from Example 22A: 62%) was obtained as a solid by the same method as in Example 16D. (Example 22B) (Example 22B) (Example 22B) (Example 22B) (Example 22B) (Example 22B)

[0436] (Example 22C) 3-[1-methyl-6-(piperidine-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]piperidine-2,6-dione trifluoroacetate. A solution of the compound obtained in Example 22B (285 mg) in DCM (5 mL) was mixed with TFA (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by diol silica gel column chromatography (DCM / methanol) to obtain the marked compound (287 mg, yield: 92%) as a solid.

[0437] (Example 22D) Benzyl(4-{4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-1-yl}-1-hydroxycyclohexyl) acetate (highly polar diastereomer) A mixture of the compound obtained in Example 22C (287 mg) and DMF (6.3 mL) was mixed with triethylamine (0.0967 mL), the compound obtained in Example 6E (184 mg), and acetic acid (0.182 mL) and stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (336 mg) was added to the reaction mixture under ice cooling, and the temperature was raised to room temperature and stirred for 4.5 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with DCM / 2-propanol (3 / 1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (DCM / methanol) to obtain the highly polar diastereomer of the labeled compound (154 mg, yield: 42%) as a solid.

[0438] (Example 22E) (4-{4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetic acid monohydrochloride. To a solution of the compound obtained in Example 22D (154 mg) in ethanol (2.7 mL), 20% palladium-carbon hydroxide (50 mg) was added and the mixture was stirred at 40°C for 1.5 hours under a hydrogen atmosphere. A mixed solvent consisting of 4M hydrogen chloride / 1,4-dioxane solution, DCM, and methanol (1 / 2 / 2) was added to the reaction mixture and filtered through Celite. After washing with the same solvent, the filtrate was concentrated under reduced pressure to obtain the marked compound (169 mg, purity 82%) as a solid.

[0439] (Example 22) (2S,3R)-3-({1-[(4-{4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1To a solution of the compound obtained in Example 22E (80.0 mg, 82% purity) -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide in DMF (1.26 mL), DIPEA (0.110 mL) and HATU (72.0 mg) were added and the mixture was stirred for 5 minutes. Then, the free compound of Example 1K, obtained by treating the compound obtained in Example 1J in the same manner as in Example 2C (68.0 mg), was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with DCM, water was added, and the mixture was extracted with DCM / 2-propanol (3 / 1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by diol silica gel column chromatography (DCM / methanol), and the fraction of the target product was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile), and the fraction of the labeled compound was concentrated under reduced pressure. The obtained residue was dissolved in chloroform / 2-propanol (3 / 1) and neutralized with saturated sodium bicarbonate solution. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a small amount of chloroform / 2-propanol, and the resulting solid was filtered off to obtain the labeled compound (33.1 mg, yield: 26%) as a solid.

[0440] (Comparative Example 1) (2S,3S)-3-(17-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}-3-oxo-6,9,12,15-tetraoxa-2-azaheptadec-1-yl)-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide (79.7 mg), the compound obtained in Example 17H, 1-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}-3,6,9,12-tetraoxapentadecane-15-acid (CAS registry number: 2138440-81-8) (92.9 mg), and DMF (1.4 mL) were mixed with HATU (84.0 mg) and triethylamine (61 μL). The mixture was stirred at room temperature for 1 hour and then allowed to stand in the refrigerator for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / methanol). The fraction of the target compound was dissolved in DCM, washed sequentially with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the resulting solid was filtered to obtain the marked compound (79.8 mg, 2-step yield from Example 17H: 51%) as a solid.

[0441] (Example 23) (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide 4-methylbenzenesulfonate A solution of the compound obtained in Example 6 (102 mg) in 1,4-dioxane / water (9 / 1) (10 mL) was mixed with aqueous solution of 4-methylbenzenesulfonic acid (1.0 mol / L) (107 μL). The resulting solution was dispensed in 4.5 mL portions and lyophilized. The resulting solid was exposed to dimethoxyethane / water (1 / 1) solvent vapor at 40°C for 8 days to obtain the marked compound (106 mg) as a solid. 1 (H NMR data indicated a 1:1 salt with 4-methylbenzenesulfonic acid.)

[0442] (Example 24) (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide 2-naphthalene sulfonate A solution of the compound obtained in Example 6 (101 mg) in 1,4-dioxane / water (9 / 1) (10 mL) was mixed with aqueous solution of 2-naphthalene sulfonic acid (1.0 mol / L) (106 μL). The resulting solution was dispensed in 4.5 mL portions and lyophilized. The resulting solid was exposed to solvent vapor of acetone / water (1 / 1) at 40°C for 9 days to obtain the marked compound (112 mg) as a solid. 1 (H NMR data indicated a 1:1 salt with 2-naphthalenesulfonic acid.)

[0443] (Example 25) (2S,3R)-N 1-(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide 4-methylbenzenesulfonate A solution of the compound obtained in Example 7 (1001 mg) in 1,4-dioxane / water (9 / 1) (60 mL) was mixed with an aqueous solution of 4-methylbenzenesulfonic acid (1.0 mol / L) (1.1 mL). The resulting solution was dispensed into 12 mL portions and lyophilized. The resulting solid was exposed to acetone / water (1 / 1) solvent vapor at 40°C for 3 days to obtain the marked compound (1022 mg) as a solid. 1 (H NMR data indicated a 1:1 salt with 4-methylbenzenesulfonic acid.)

[0444] (Example 26) (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide 2-naphthalene sulfonate A solution of the compound obtained in Example 7 (1000 mg) in 1,4-dioxane / water (9 / 1) (60 mL) was mixed with aqueous solution of 2-naphthalene sulfonic acid (1.0 mol / L) (1.1 mL). The resulting solution was dispensed into 12 mL portions and lyophilized. The resulting solid was exposed to dimethoxyethane solvent vapor at 25°C for 3 days to obtain the marked compound (1035 mg) as a solid. 1 (H NMR data indicated a 1:1 salt with 2-naphthalenesulfonic acid.)

[0445] Tables 1 to 40 show the chemical structures and physicochemical data of each compound described in the examples. In the tables, Ex indicates the example number, Rf indicates the reference example number, CE indicates the comparative example number, and Data indicates the physicochemical data. The abbreviations used in the chemical structures in the tables have the following meanings: Bn: benzyl, Cbz: benzyloxycarbonyl, Im: imidazolyl, HCl: hydrochloric acid, TMS: trimethylsilyl

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486] <Test Example 1> Evaluation of PI3Kα degradation induction effect on human PI3Kα mutant breast cancer cell line T-47D. Using human PI3Kα mutant breast cancer cell line T-47D cells (ATCC, HTB-133) as the host, T-47D PIK3CA-HiBiT cells, in which a HiBiT tag was knocked into the endogenous PI3Kα gene locus, were cultured in RPMI1640 medium (Thermo Fisher Scientific Inc.) containing 10% fetal bovine serum (Cytiva) and 5 μg / mL insulin (Merck KGaA) in a 5% CO2 incubator at 37°C. T-47D PIK3CA-HiBiT cells were seeded into 96-well plates (Corning) at a concentration of 5000 cells / 100 μL / well and cultured overnight in a 5% CO2 incubator at 37°C. The following day, DMSO solutions of each test compound were added to 96-well plates using a D300e Digital Dispenser (TECAN) and incubated for 24 hours in a 5% CO2 incubator at 37°C. The final DMSO concentration in the culture medium was increased to 0.1% (v / v) for all samples, and the concentration range of the test compounds was from 1000 nM to 0.015 nM with a common ratio of 4. After incubation, 50 μL / well of Nano-Glo® HiBiT Lytic Detection System (Promega, Cat. No. N3040) was added and mixed with a plate mixer. Subsequently, the luminescence signal was detected using a multimode plate reader (EnVision Xcite, PerkinElmer). The PI3Kα protein degradation rate was calculated based on the following formula using the luminescence values ​​(C) of the group without the test compound and the luminescence values ​​(T) of the group with the compound.

[0487]

[0488] From the obtained protein degradation rates, the concentration (DC) that induces 50% degradation of PI3Kα was determined by analysis using Excel. 50 The HiBiT DC value of the test compound corresponding to each example number was calculated. 50 The values ​​(in nM) are shown in Table 41.

[0489]

[0490] <Test Example 2> Evaluation of Proliferation Inhibitory Effect on Human PI3Kα Mutant Breast Cancer Cell Line T-47D T-47D cells were cultured in RPMI1640 medium (Thermo Fisher Scientific Inc.) containing 10% fetal bovine serum (Cytiva) and 5 μg / mL insulin (Merck KGaA) in a 5% CO2 incubator at 37°C. T-47D cells were seeded into 96-well plates (Corning) at a density of 1000 cells / 100 μL / well and cultured overnight in a 5% CO2 incubator at 37°C. The following day, DMSO solutions of each test compound were added to the 96-well plates using a D300e Digital Dispenser (TECAN) and cultured for 7 days in a 5% CO2 incubator at 37°C. The final concentration of DMSO in the culture medium was increased to 0.1% (v / v) in all cases, and the concentration range of the test compound was set from 1000 nM to 0.015 nM with a common ratio of 4.5. On the day of test compound addition (day 0) and on the 7th day of culture (day 7), 50 μL / well of CellTiter-Glo® 2.0 Assay (Promega) was added, and the luminescence signal was detected using a multimode plate reader (EnVision, PerkinElmer). The cell proliferation rate was calculated based on the following formula from the luminescence amount of the group without test compound addition on the day of test compound addition (C0), the luminescence amount of the group without test compound addition after 7 days of culture (C7), and the luminescence amount of the group with test compound addition (T7).

[0491]

[0492] From the obtained cell proliferation rates, the concentration (GI) of each test compound that inhibits the proliferation of T-47D cells by 50% was determined by analysis using Excel. 50 The value was calculated. T-47D GI of the test compound corresponding to each example number. 50 The values ​​(in nM) are shown in Table 42.

[0493]

[0494] <Test Example 3> Evaluation of PI3Kα kinase activity inhibitory effect The binding activity of each test compound to PI3Kα was evaluated using the PI3Kα kinase activity inhibitory effect of each test compound as an indicator. This evaluation can be performed using the ADP-Glo® assay contract service (lipid kinase panel) provided by Karna Biosciences Co., Ltd. The protein was obtained by co-expressing a PIK3CA / PIK3R1 protein solution (Full-length human PIK3CA [1-1068(end) amino acids of accession number NP_006209.2] and N-terminal DYKDDDDK tagged, biotinylated protein (128 kDa) with PIK3R1 [1-724(end) amino acids of accession number NP_852664.1]) at a final concentration of 30 ng / mL in 20 μL Assay buffer (50 mM MOPS, 1 mM DTT, pH 7.2) using a baculovirus expression system, and purifying it with anti-DYKDDDDK tagged antibody agarose, a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) solution at a final concentration of 10 μM, a MgCl2 solution at a final concentration of 5 mM, and final concentrations of 10, 3, 1, 0.3, 0.1. DMSO solutions of the test compound at concentrations of 0.03, 0.01, 0.003, 0.001, and 0.0003 μM were mixed and reacted at room temperature for 1 hour. 20 μL of ADP-Glo ​​solution (Promega) was added and reacted at room temperature for at least 40 minutes. 40 μL of Kinase Detection Reagent (Promega) was added and reacted at room temperature for at least 40 minutes, after which the kinase reaction was evaluated by relative luminescence intensity (RLU). The average signal of the control well containing all reaction components was defined as 0% inhibition, and the average signal of the background well (without PIK3CA / PIK3R1 protein) was defined as 100% inhibition. The inhibition rate was calculated from the average signal of each test compound added well. For each test compound, the concentration (IC) that inhibits kinase activity by 50% was determined. 50 The value was calculated. IC 50The values ​​were calculated by approximating a four-parameter logistic curve using a nonlinear least squares method, based on a plot of the test compound concentration and inhibition rate. The PI3Kα IC of the test compound corresponding to each example number was calculated. 50 The values ​​(in nM) are shown in Table 43.

[0495]

[0496] <Test Example 4> Evaluation of Binding Activity to CRBN The binding activity of each test compound to CRBN can be evaluated as follows, for example, by using competition with HTRF Thalidomide-Red ligand for the CRBN partial protein as an indicator. HTRF PROTAC Binding Buffer 1 (Revvity) was mixed with 150 nM His-Avi-3C-hCRBN (318-426, C366S), 80 nM HTRF Thalidomide-Red ligand, 0.8 μg / mL MAb Anti 6His-Eu cryptate, and DMSO solutions of each test compound (an 8-point dilution series was prepared from a final concentration of 50 μM with a common ratio of 3), and reacted at room temperature for 3 hours. The HTRF signal was measured using a plate reader (Biotek SynergyNEO2, Agilent). The ratio value for each well was calculated using the following formula.

[0497]

[0498] Next, the T / C ratio for each test compound treatment was calculated using the following formula.

[0499]

[0500] By analyzing the T / C ratio at each concentration using Screener (Genedata), the concentration at which each test compound inhibits the binding of HTRF Thalidomide-Red ligand to CRBN by 50% (IC) was determined. 50 The value was calculated for the CRBN-HTRF IC of the test compound corresponding to each example number. 50 The values ​​(in μM) are shown in Table 44.

[0501]

[0502] <Test Example 5> Evaluation of antitumor activity in a KPL-1 (MCF-7) cell subcutaneous transplantation model (breast cancer) 5.0 × 10 6 KPL-1 (MCF-7) cells from cells / head were subcutaneously transplanted into the right flank of female NSG mice, and the estimated tumor volume (long diameter × short diameter × short diameter / 2) was 150 to 200 mm². 3 At the point of group division, the mice were divided into groups of 5 to ensure there was no significant difference between groups. Female NSG mice were purchased from Jackson Laboratory Japan Co., Ltd. Each compound was administered intravenously at a dose of 1 mg / kg on the day of group division (Day 0). Individual estimated tumor volume was measured from the day of group division until 21 days after group division (Day 21). The vehicle-control group was administered a solvent mixture of N,N-dimethylacetamide (DMA), Tween 80, and physiological saline in a ratio of 1:1:8.

[0503] The antitumor activity of the KPL-1 (MCF-7) cell subcutaneous transplantation model in Test Example 5 was calculated using the following formulas.

[0504]

[0505] Table 45 shows the net tumor growth inhibition rate (TGIn) (in %) of the compound corresponding to each example number.

[0506]

[0507] The compound represented by formula (I) of the present invention, or a salt thereof (a pharmaceutically acceptable salt), induces the degradation of the target protein PI3Kα, and therefore can be used for the treatment of diseases related to PI3Kα, particularly cancers such as breast cancer. Furthermore, the compound represented by formula (I) of the present invention, or a salt thereof, can induce the degradation of PI3Kα by binding to CRBN and PI3Kα.

[0508] This application is based on Japanese Patent Application No. 2025-53789, filed in Japan on March 27, 2025, the contents of which are fully incorporated herein.

Claims

1. Formula (I): [In the formula (I), E represents the following formula: (In formulas (a) to (d), R ａ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy, and R ｂ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy, and R ｃ１ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy, and R ｃ２ is a hydrogen atom, C １－３ alkyl, a 3- to 7-membered aliphatic hydrocarbon ring group, or a 4- to 7-membered aliphatic heterocyclic group, and R ｄ１ is a hydrogen atom, halogen, C １－３ alkyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy, and R ｄ２ is a hydrogen atom, C １－３ alkyl, a 3- to 7-membered aliphatic hydrocarbon ring group, or a 4- to 7-membered aliphatic heterocyclic group, and X ａ , X ｂ , X ｃ , X ｄ , Y ａ , Y ｂ , Y ｃ , and Y ｄ are each independently a carbon atom or a nitrogen atom, and * is a bonding position to L. ), and L is of formula (II): {In formula (II), Q １ each represents G １ A divalent 6-membered aromatic hydrocarbon ring group, a 5- to 6-membered aromatic heterocyclic group, a 4- to 7-membered aliphatic hydrocarbon ring group, a 4- to 7-membered aliphatic heterocyclic group, or a bicyclic group combining these, which may be further substituted with one to three identical or different substituents selected from the group, G １ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ It consists of alkoxy, Q ２ These are G ２ A divalent, 4- to 7-membered aliphatic hydrocarbon ring group, a 4- to 7-membered aliphatic heterocyclic ring group, or a bicyclic group combining the same, which may be further substituted with 1 to 3 identical or different substituents selected from the group, G ２ The group consists of hydroxy, halogen, and C １－３ Alkyl and C １－３ Composed of alkoxy, L １ This is a single bond, methylene, -C(O)-, a divalent six-membered aromatic hydrocarbon ring group, or the following formula: (In the formula, *1 is Q) １ This is the bonding position with L, and *2 is L ２ This is the bonding position with R, and Ｌ (is a hydrogen atom, a fluorine atom, or a hydroxyl group.) is a divalent group selected from the group consisting of L ２ This is a single bond, methylene, -C(O)-, a divalent aromatic hydrocarbon ring group, or the following formula: (In the formula, *2 is L １ This is the bonding position with Q, and *3 is Q ２ This is the bonding position with R, and Ｌ The above is equivalent to the above.) A divalent group selected from the group consisting of, where * is the bond position with E, and the wavy line is the bond position with T. However, Q １ and L １ , L １ and L ２ , and L ２ and Q ２ These do not form bonds with each other's nitrogen atoms.} is a group represented by}, and T is the target protein PI3Kα binding motif. ] is a compound or salt thereof.

2. T is given by equation (III): [In formula (III), R １ and R ２ These are, independently, a hydrogen atom, a halogen, and C. １－６ Alkyl, or C １－３ It is either a haloalkyl or R １ and R ２ These atoms bond to each other, and together with the carbon atoms they bond to, form a 5- to 7-membered aliphatic hydrocarbon ring, Q ３ G ３ A divalent aromatic heterocyclic group which may be further substituted with one or two identical or different substituents selected from the group, G ３ The group consists of halogens, di(C) １－３ Alkyl)amino, morpholinyl, and the following formula: (In the formula, R ３ , R ４ , and R ５ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R ３ , R ４ , and R ５ Two of them bond to each other, and together with the carbon atoms they bond to, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, and ● is Q ３ The compound or salt thereof according to claim 1, comprising a group indicated by ) and the wavy line indicates the bond position with L.

3. E is given by the following formula: [In equations (a1) to (d1), R ａ , R ｂ , R ｃ１ , R ｄ１ , X ａ , Y ａ , Y ｃ , Y ｄ , and * are as defined in claim 1. The compound or salt thereof according to claim 1 or 2, wherein the group is selected from the group consisting of ].

4. E is given by the following formula: A compound or salt thereof according to any one of claims 1 to 3, wherein the group is selected from the group consisting of [wherein * is the same as in claim 1].

5. T is a group represented by the following formula: [wherein X １ is a nitrogen atom or a carbon atom, and R ６ , R ７ , and R ８ are each independently a hydrogen atom, C １－４ alkyl or C １－４ haloalkyl, or two of R ６ , R ７ , and R ８ are bonded to each other, and together with the carbon atom to which they are bonded form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocyclic ring, and R ９ , R １０ , and R １１ are each independently a hydrogen atom, C １－４ alkyl or C １－４ haloalkyl, or two of R ９ , R １０ , and R １１ are bonded to each other, and together with the carbon atom to which they are bonded form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocyclic ring, and R １２ , R １３ , and R １４ are each independently a hydrogen atom, C １－４ alkyl or C １－４ haloalkyl, or two of R １２ , R １３ , and R １４ are bonded to each other, and together with the carbon atom to which they are bonded form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocyclic ring, and the wavy line indicates the bonding position to L.] The compound or a salt thereof according to any one of claims 1 to 4, wherein 6. T is given by the following formula: The compound or salt thereof according to claim 5, wherein the group is represented by [wherein the formula, the dashed line is equivalent to that in claim 5.].

7. L is given by the following formula: [In the formula, m and n are each independently integers from 1 to 3, and m + n is an integer from 2 to 5, X ２ and X ３ Each is independently either a nitrogen atom or a carbon atom, and R １５ L is a hydrogen atom, a fluorine atom, or a hydroxyl atom. １ , L ２ The symbols * and wavy lines are as defined in claim 1. The compound or salt thereof according to any one of claims 1 to 6, wherein the group is represented by ].

8. The compound or salt thereof according to claim 7, wherein m is 2 and n is 2.

9. *1-L １ -L ２ -*3 is expressed by the following formula: A compound or salt thereof according to any one of claims 1 to 8, wherein the group is represented by [wherein *1 and *3 are as defined in claim 1.].

10. L is given by the following formula: A compound or salt thereof according to any one of claims 1 to 9, wherein the group is represented by [wherein * and the dashed line are as defined in claim 1.].

11. E is given by the following formula: (In the formula, * is the same as in claim 1.) The base is represented by the following formula, where T is: (In the formula, X １ R is a nitrogen atom or a carbon atom. ９ , R １０ , and R １１ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R ９ , R １０ , and R １１ Two of them bond to each other, and together with the carbon atoms to which they bond, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, R １２ , R １３ , and R １４ These are, independently, hydrogen atoms and C １－４ Alkyl, or C １－４ It is either a haloalkyl or R １２ , R １３ , and R １４ Two of these groups bond to each other, and together with the carbon atoms they bond to, form a 3- to 7-membered aliphatic hydrocarbon ring or a 3- to 7-membered aliphatic heterocycle, and the dashed lines indicate the bonding positions with L. ) These groups are represented by the formula below, and L is given by the formula below: [In the formula, m and n are each independently integers from 1 to 3, and m + n is an integer from 2 to 5, X ２ and X ３ Each is independently either a nitrogen atom or a carbon atom, and R １５ is a hydrogen atom, a fluorine atom, or a hydroxyl atom, *1-L １ -L ２ -*3 is expressed by the following formula: The compound or salt thereof according to claim 1, wherein the group is represented by (wherein *1 and *3 are as defined in claim 1), where * is the bonding site with E, and the wavy line is the bonding position with T.

12. (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -{5-[6-(diethylamino)pyrazine-2-yl]-4-methyl-1,3-thiazole-2-yl}-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrroridine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrorol[3,4-b]pyridine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[6-(2,6-dioxopiperidine-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3S)-3-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}methyl)benzyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3S)-3-{[5-({4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}methyl)pyridine-2-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[2-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)-2,3-dihydro-1H-isoindole-5-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-({1-[(4-{4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}-1-hydroxycyclohexyl)methyl]piperidine-4-yl}methyl)-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, and (2S,3R)-3-({1-[(4-{4-[3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-6-yl]piperidine-1-yl}-1-hydroxycyclohexyl)acetyl]piperidine-4-yl}methyl)-N 1 Any one compound selected from the group consisting of -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide or a salt thereof.

13. (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-{[1-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperidine-4-yl]methyl}pyrrolidin-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[4-(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)benzyl]-N 1 -(4-methyl-5-{2-[1-(trifluoromethyl)cyclobutyl]pyridine-4-yl}-1,3-thiazole-2-yl)pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -[5-(2-tert-butylpyrimidine-4-yl)-4-methyl-1,3-thiazole-2-yl]-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, and (2S,3R)-N 1 Any one compound selected from the group consisting of -(8-tert-butyl-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl)-3-[(1-{[cis-4-(4-{2-[2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl])pyrrolidine-1,2-dicarboxamide or a salt thereof.

14. (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide, and (2S,3R)-N 1 Any one compound selected from the group consisting of -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide or a salt thereof.

15. (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide, and (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 Any one compound selected from the group consisting of -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide or a salt thereof.

16. (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide 4-methylbenzene sulfonate.

17. (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide-4-methylbenzenesulfonate.

18. (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide 2-naphthalene sulfonate.

19. (2S,3R)-N 1 -(2-tert-butyl-4'-methyl[4,5'-bi-1,3-thiazole]-2'-yl)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]pyrrolidine-1,2-dicarboxamide-2-naphthalene sulfonate.

20. (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide 4-methylbenzenesulfonate.

21. (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide-4-methylbenzenesulfonate.

22. (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide 2-naphthalene sulfonate.

23. (2S,3R)-3-[(1-{[cis-4-(4-{2-[(3RS)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-1-yl)-1-hydroxycyclohexyl]acetyl}piperidine-4-yl)methyl]-N 1 -{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4-yl]-1,3-thiazole-2-yl}pyrrolidine-1,2-dicarboxamide-2-naphthalene sulfonate.

24. A pharmaceutical product containing a compound described in any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof as an active ingredient.

25. A pharmaceutical composition for inhibiting or degrading phosphatidylinositol 3-kinase alpha (PI3Kα), comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. The pharmaceutical product according to claim 24 for treating cancer.

27. The pharmaceutical product according to claim 26, wherein the cancer is breast cancer.

28. A method for treating cancer, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 23 to a subject in need of cancer treatment.

29. The method according to claim 28, wherein the cancer is breast cancer.

30. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

31. The compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer.

32. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 in the manufacture of a pharmaceutical for the treatment of cancer.

33. The use according to claim 32, wherein the cancer is breast cancer.

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