Heterocyclic compound for inducing degradation of SHP2 protein

Abstract

Provided is a compound useful as an active ingredient of a pharmaceutical composition for treating cancer.　The present inventors have studied compounds useful as active ingredients of pharmaceutical compositions for treating cancer, and have found that a heterocyclic compound, which is a compound according to the present invention, has an excellent activity of inducing the degradation of SHP2 protein and can be used as a therapeutic agent for cancer. This finding leads to the accomplishment of the present invention. A heterocyclic compound according to the present invention or a salt thereof can be used as a therapeutic agent for cancer.

Description

Heterocyclic compounds for inducing the degradation of SHP2 protein

[0001] This invention relates to a pharmaceutical composition and a heterocyclic compound that is excellent at inducing the degradation of SHP2 protein and is expected to be useful as an active ingredient in a pharmaceutical composition for cancer treatment.

[0002] The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, plays a crucial role in downstream signaling of the growth factor receptor signaling pathway and was the first oncogenic tyrosine phosphatase reported (Adv. Cancer Res. 106, 53-89 (2010)). Abnormal activation of SHP2 has been observed in multiple cancer types (Nature. 2016 Jul 7;535(7610):148-52), and while inhibitors such as TNO155 are currently undergoing clinical trials, no approved compounds have yet been identified. On the other hand, PROTACs are modalities that utilize the degradation mechanism of the ubiquitin-proteasome system to degrade specific proteins, and have been reported to not only enhance drug efficacy but also improve specificity compared to inhibitors (Cell Chem Biol. 2020 Aug 20;27(8):998-1014). PROTACs that exhibit SHP2 protein degradation-inducing activity have been reported in Patent Documents 1 and 2, and Non-Patent Document 1, respectively. For example, Non-Patent Document 1 describes the compound shown below as SHP2-D26.

[0003] However, no compounds that induce SHP2 proteolysis have yet been approved, and the therapeutic needs for SHP2-related diseases are not yet being met.

[0004] International Publication No. 2021236775, Chinese Patent Application Publication No. 117069698, International Publication No. 2023280237, International Publication No. 2023018155, Chinese Patent No. 112480081, International Publication No. 2024188209, International Publication No. 2025019666

[0005] Journal of Medicinal Chemistry 2020, 63, 7510

[0006] Provided is a heterocyclic compound that is excellent in the action of inducing the degradation of a SHP2 protein and is expected to be useful as an active ingredient of a pharmaceutical composition for treating cancer, particularly cancer in which the SHP2 protein is expressed.

[0007] As a result of intensive studies on compounds useful as active ingredients of pharmaceutical compositions for cancer treatment, the present inventors have found that the compound of formula (I) has an excellent action of inducing the degradation of the SHP2 protein, and thus completed the present invention. That is, the present invention relates to the compound of formula (I) or a salt thereof. (In the formula, A is a group represented by the following formula (II) or formula (III), A1 is CR A1 or N, A2 is CR A2 or N, A3 is CR A3 or N, A4 is CR A4 or N, A5 is CR A5 or N, provided that two or more of A1 to A5 are not simultaneously N, and R A1 , R A2 , R A3 , R A4 and R A5 are the same or different from each other and are H, optionally substituted C 1-3 alkyl, -O-(optionally substituted C 1-3 alkyl), halogen, cyano or a bond to A, provided that only one of R A1 , R A2 , R A3 , R A4 and R A5 is a bond to A, Y is one group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) and formula (XXV), n is the same or different from each other and is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different from each other and are 1 or 2, and R YN1 is H or C 1-3 alkyl, R YN2 is H or C 1-3 alkyl, and R YN3is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 Furthermore, adjacent nitrogen atoms may unite to form a substituted 4- to 6-membered saturated heterocycle, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), (XIV), (XXVI), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z are the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, which may be the same or different from each other, and L may be bonded or substituted. 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV), (XVI), (XVII), (XVIII-1), and (XIX): k is an integer from 1 to 8, and is either the same or different from each other. 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, Hy1 is an optionally substituted heteroarylene, and W is one group or bond selected from the group consisting of the following formulas (XX), (XXI), and (XXII). Hy2, Hy3, and Hy4 are all heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a combination with L, where p is an integer from 1 to 3, and R a C may be substituted. 1-3 Alkyl or NR a1 2, R a1 H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, or -E 2 -R a2 And R a2 C 1-3 Alkyl or aryl, E 2 is CO or SO2, R b H or C (which may be substituted) 1-3 It is an alkyl group, t is an integer from 0 to 2, and R c C may be substituted. 1-3 If it is alkyl, or if t is 2, R is bonded to a different carbon atom on the piperazine ring. c The combined structure may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, or R a and R b These are, together with the carbon atoms to which they are bonded, substituted or substituted 4- to 6-membered saturated heterorings or substituted C 3-8It may also form a cycloalkane, and EUB is given by the following formula (XXIII) or formula (XXIV): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 It is an alkyl or possibly substituted heteroaryl, where q is an integer from 1 to 3, Ar2 is an aryl or heteroaryl, and R Ar2 This includes H, halogens, and C, which may be substituted. 1-3 R7 is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8 (A cycloalkyl group, or a substituted 4- to 11-membered saturated heterocyclic group.)

[0008] Unless otherwise specified, if a symbol in a chemical formula is used in another chemical formula within this specification, the same symbol shall have the same meaning.

[0009] Furthermore, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0010] The present invention relates to a pharmaceutical composition for the treatment of cancer containing a compound of formula (I) or a salt thereof, and in one aspect, to a pharmaceutical composition for the treatment of cancer expressing the SHP2 protein. The pharmaceutical composition includes a cancer treatment agent containing a compound of formula (I) or a salt thereof. The present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer, and in one aspect, to cancer expressing the SHP2 protein; the use of a compound of formula (I) or a salt thereof for the treatment of cancer expressing the SHP2 protein; the compound of formula (I) or a salt thereof for use in the treatment of cancer expressing the SHP2 protein; and a method for treating cancer expressing the SHP2 protein, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a target.

[0011] Furthermore, "subject" refers to a human or other animal that requires treatment, and in some cases, it refers to a human being that requires treatment.

[0012] The compound of formula (I) or a salt thereof, which is the compound of the present invention, has an SHP2 protein degradation-inducing effect and can be used as a therapeutic agent for cancer, particularly cancers in which the SHP2 protein is expressed.

[0013] The present invention will be described in detail below.

[0014] In this specification, "may be substituted" means unsubstituted or having one to five substituents. In one embodiment, this means unsubstituted or having one to three substituents. If there are multiple substituents, they may be identical or different from one another.

[0015] "C 1-8 "Alkyl" refers to linear or branched alkyl groups with 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. (Hereafter, the number of carbon atoms will be expressed similarly). One embodiment is n-octyl. Similarly, "C 1-6"Alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, dimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl, and in certain embodiments, it is methyl, ethyl, n-propyl, isopropyl or sec-butyl, and in certain embodiments, it is methyl, ethyl, isopropyl or tert-butyl, and in certain embodiments, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, dimethylpropyl, and in certain embodiments, it is isopropyl or tert-butyl, and in certain embodiments, it is methyl, and in certain embodiments, it is ethyl, and in certain embodiments, it is isopropyl, and in certain embodiments, it is n-propyl. Similarly, "C 1-3 "Alkyl" means a linear or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, and in certain embodiments, it is methyl or ethyl, and in certain embodiments, it is n-propyl or isopropyl, and in certain embodiments, it is methyl or isopropyl, and in certain embodiments, it is ethyl or isopropyl, and in certain embodiments, it is methyl, and in certain embodiments, it is ethyl, and in certain embodiments, it is isopropyl, and in certain embodiments, it is n-propyl.

[0016] "C 3-8 "Cycloalkyl" means a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. In certain embodiments, it is cyclobutyl, cyclopentyl, or cyclohexyl, and in certain embodiments, it is cyclobutyl or cyclopentyl, and in certain embodiments, it is cyclopentyl or cyclohexyl, and in certain embodiments, it is cyclopropyl or cyclobutyl, and in certain embodiments, it is cyclopropyl, and in certain embodiments, it is cyclobutyl, and in certain embodiments, it is cyclopentyl, and in certain embodiments, it is cyclohexyl.

[0017] "C 1-8 "Alkylene" means a divalent group formed by removing a hydrogen atom from C 1-8 alkyl, which is a linear or branched C1-8 Alkylene, such as methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, etc. In certain embodiments, it is a linear or branched C 1-8 alkylene, and in certain embodiments, it is -(CH2)5-, -(CH2)6-, -(CH2)7-, and -(CH2)8-, and in certain embodiments, it is -(CH2)8-.

[0018] The term "C 1-6 alkylene" refers to a divalent group formed by removing a hydrogen atom from C 1-6 alkyl, and it is a linear or branched C 1-6 alkylene, such as methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, -(CH2)5-, -(CH2)6-, etc. In certain embodiments, it is a linear or branched C 1-6 alkylene, and in certain embodiments, it is -(CH2)5-, and -(CH2)6-, and in certain embodiments, it is -(CH2)6-.

[0019] The term "C 1-3 alkylene" refers to a divalent group formed by removing a hydrogen atom from C 1-3 alkyl, and it is a linear or branched C 1-3 alkylene, such as methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. In certain embodiments, it is a linear or branched C 1-3 alkylene, and in certain embodiments, it is methylene, ethylene or trimethylene, and in certain embodiments, it is methylene or ethylene, and in certain embodiments, it is methylene, and in certain embodiments, it is ethylene, and in certain embodiments, it is trimethylene.

[0020] The term "C 3-8 cycloalkane" refers to a saturated hydrocarbon ring having 3 to 8 carbon atoms, and a part of the C 3-8 cycloalkane may have an unsaturated bond, and the C 3-8 cycloalkane may have a cross-linked structure, and the C 3-8 cycloalkane may have a spiro structure. The C3-8 The cycloalkane may be fused with a benzene ring or a heterocycle; for example, dihydrocyclopentapyridine. 3-8 Certain embodiments of cycloalkanes include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0021] A "saturated heterocycle" is a saturated hydrocarbon ring containing heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. However, the saturated heterocycle may have unsaturated bonds in part, and the sulfur atoms as ring constituent atoms of the saturated heterocycle may be oxidized. Furthermore, the saturated heterocycle may have a bridging structure, and furthermore, the saturated heterocycle may have a spiro structure. In addition, the saturated heterocycle may be fused with a benzene ring, or fused with a heterocycle. In one embodiment, it is a 4- to 11-membered saturated heterocycle, and in another embodiment, it is a 4- to 6-membered saturated heterocycle.

[0022] A "4- to 11-membered saturated heteroring" is a saturated hydrocarbon ring with 4 to 11 members containing heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and may have a bridging structure or a spiro structure. Furthermore, the 4- to 11-membered saturated heteroring may be fused with a benzene ring or a heteroring. In one embodiment, it is a 4- to 11-membered saturated heteroring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. In another embodiment, it is a 4- to 6-membered saturated heteroring. A "4- to 6-membered saturated heteroring" is a saturated hydrocarbon ring with 4 to 6 members containing heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and may have a bridging structure or a spiro structure. Furthermore, the 4- to 6-membered saturated heteroring may be fused with a benzene ring or a heteroring. In one embodiment, it is a 4- to 6-membered saturated heteroring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms; in another embodiment, it is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, or tetrahydropyridine; in another embodiment, it is piperidine or piperazine; in another embodiment, it is piperidine; and in another embodiment, it is piperazine.

[0023] A "saturated heterocyclic group" is a saturated hydrocarbon ring group containing heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. However, the saturated heterocyclic group may have an unsaturated bond in part of the ring. Furthermore, the sulfur atom as a ring constituent atom of the saturated heterocyclic group may be oxidized. In addition, the saturated heterocyclic group may have a bridging structure, and furthermore, the saturated heterocyclic group may have a spiro structure. Furthermore, the saturated heterocyclic group may be fused with a benzene ring or a heterocyclic ring. In one embodiment, it is a 4-membered to 11-membered saturated heterocyclic group, and in another embodiment, it is a 4-membered to 6-membered saturated heterocyclic group.

[0024] A "4- to 11-membered saturated heterocyclic group" is a saturated heterocyclic group having 4 to 11 members, containing heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and may have a bridging structure, a spiro structure, or be fused with a benzene ring or heterocyclic ring. One embodiment of a "4- to 11-membered saturated heterocyclic group" is a saturated heterocyclic group having 4 to 11 members, containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms.

[0025] A "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and may have a bridging structure, a spiro structure, or be fused with a benzene ring or heterocyclic ring. One embodiment of a "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. One embodiment is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, or tetrahydropyridinyl, another embodiment is piperidinyl or piperazinyl, another embodiment is piperidinyl, and another embodiment is piperazinyl.

[0026] A "divalent group of a saturated heterocycle" is a divalent group of a 4- to 11-membered saturated heterocycle containing 1 to 2 nitrogen atoms as ring constituent atoms, and may further contain 1 to 2 oxygen atoms, and may be a divalent group of a saturated heterocycle having a spiro ring or a fused ring, or a divalent group of a saturated heterocycle having a fused ring structure with a benzene ring or a heterocycle, and may have an unsaturated bond in part of the saturated heterocycle. One embodiment of a "divalent group of a saturated heterocycle" is a divalent group of a 4- to 11-membered saturated heterocycle containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and another embodiment is a divalent group of a 4- to 6-membered saturated heterocycle containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. In some embodiments, the material is oxetanediyl, tetrahydrofrandiyl, tetrahydropyrandiyl, azetidinediyl, pyrrolidinediyl, piperidinediyl, oxazolidinediyl, imidazolidinediyl, piperazinediyl, morpholinediyl, thiomorpholinediyl, dioxothiomorpholinediyl, or tetrahydropyridinediyl; in some embodiments, it is piperidinediyl or piperazinediyl; in some embodiments, it is piperidinediyl; and in some embodiments, it is piperazinediyl.

[0027] "Aryl" is C 6-14 It is a monocyclic to tricyclic aromatic hydrocarbon ring group, including a partially hydrogenated ring group thereof. The "aryl" form is phenyl, naphthyl, tetrahydronaphthyl, indanyl, or indenyl, and in one form it is phenyl.

[0028] A "heterocycle" is an aromatic hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. Therefore, a "six-membered heterocycle" is a six-membered aromatic hydrocarbon ring containing a nitrogen atom as a ring constituent atom, and in some embodiments, it is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, or triazine ring, and in other embodiments, it is a pyridine ring. Furthermore, a "five-membered or six-membered heterocycle" is a five-membered or six-membered aromatic hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom, and in some embodiments, it is a pyrazole ring, triazole ring, imidazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, tetraazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, or triazine ring, and in other embodiments, it is a pyrazole ring, triazole ring, pyridine ring, or pyridazine ring. In other embodiments, it is a pyridine ring.

[0029] A "heteroaryl" is a heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. In some embodiments, it is a five-membered heteroaryl; in other embodiments, it is a six-membered heteroaryl; and in other embodiments, it is a five- to nine-membered heteroaryl.

[0030] A "5-membered heteroaryl" is a 5-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and in one embodiment it is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, in another embodiment it is thiazolyl, oxazolyl, triazolyl, or pyrazolyl, in another embodiment it is thiazolyl, isoxazolyl, or pyrazolyl, in another embodiment it is thiazolyl, in another embodiment it is isoxazolyl, in another embodiment it is pyrazolyl, and in another embodiment it is triazolyl.

[0031] A "six-membered heteroaryl" is a six-membered heterocyclic group containing one to three nitrogen atoms as ring constituent atoms, and in some embodiments it is pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, or triazinyl, and in some embodiments it is pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, and in some embodiments it is pyridyl, and in some embodiments it is pyrizinyl, and in some embodiments it is pyridadinyl. A "five- to nine-membered heteroaryl" is a five- to nine-membered heterocyclic group containing one to three nitrogen atoms as ring constituent atoms, and in some embodiments it is benzotriazolyl.

[0032] "Arylene" is a divalent group formed by removing a hydrogen atom from an aryl group. In some embodiments, it is phenylene, naphthylene, tetrahydronaphthylene, indanediyl, or indenediyl, and in other embodiments, it is phenylene.

[0033] A "heteroarylene" is a divalent group formed by removing a hydrogen atom from a heteroaryl group. In some embodiments, it is a five-membered heteroarylene; in other embodiments, it is a six-membered heteroarylene; and in other embodiments, it is a five- to nine-membered heteroarylene.

[0034] "Five-membered heteroarylene" refers to a five-membered heteroarylene containing one to three heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and in one embodiment it is pyrazolediyl, imidazolediyl, triazolediyl, tetrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, oxadiazolediyl, or thiadiazolediyl, in another embodiment it is thiazolediyl, isoxazolediyl, or pyrazolediyl, in another embodiment it is thiazolediyl, in another embodiment it is isoxazolediyl, in another embodiment it is pyrazolediyl, and in another embodiment it is triazolediyl.

[0035] "Six-membered heteroarylene" refers to a six-membered heteroarylene containing one to three nitrogen atoms as ring constituent atoms, and in one embodiment, it is pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl, or triazinediyl, and in one embodiment, it is pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl, and in one embodiment, it is pyridinediyl, and in one embodiment, it is pyrazinediyl, and in one embodiment, it is pyrazinediyl. "Five- to nine-membered heteroarylene" refers to a five- to nine-membered heteroarylene containing one to three nitrogen atoms as ring constituent atoms, and in one embodiment, it is benzotriazolediyl.

[0036] "Halogen" refers to F, Cl, Br, and I. In some forms it is F, Cl, or Br; in other forms it is F or Cl; in other forms it is F or Br; in other forms it is F; in other forms it is Cl; and in other forms it is Br.

[0037] "C is fine even if it is substituted" 1-8 "Alkylene", "C may be substituted" 1-6 Alkyl, C may be substituted. 1-3 In the case of "alkyl", acceptable substituents include -OC 1-3 It is alkyl, hydroxy, or halogen, and in some embodiments it is NH2, in some embodiments it is hydroxy, in some embodiments it is halogen, and in some embodiments it is oxo.

[0038] "C is fine even if it is substituted" 3-8 "Cycloalkyl group", "Saturated heterocyclic group which may be substituted", "Divalent group of saturated heterocyclic group which may be substituted", "Four- to six-membered saturated heterocyclic group which may be substituted", "C which may be substituted 3-8 In the case of "cycloalkanes," an acceptable substituent is a C that may be substituted with a halogen. 1-3 Alkyl, -OC 1-3 Alkyl, hydroxyl, halogen, cyano, or NH2, and in one embodiment, C 1-3It is alkyl or NH2.

[0039] In "arylenes that may be substituted," "aryls that may be substituted," "heteroarylenes that may be substituted," and "heteroaryls that may be substituted," an acceptable substituent is C that may be substituted with a halogen. 1-3 Alkyl, -OC 1-3 Alkyl, hydroxyl, halogen, or cyano, and in one embodiment, C 1-3 It is alkyl.

[0040] "Cancer" means a malignant tumor. In some cases, it is pancreatic cancer, lung cancer, colorectal cancer, skin cancer, uterine cancer, thyroid cancer, bladder cancer, stomach cancer, epithelial cancer, esophageal cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, kidney cancer, myeloma, lymphoma, or leukemia, and in other cases, it is colorectal cancer, lung cancer, or pancreatic cancer.

[0041] A certain embodiment of the compound of formula (I) or a salt thereof in the present invention is shown below.

[0042] (1-1) A is a compound of formula (I) or a salt thereof, wherein A is a group represented by formula (II) or formula (III) below. (1-2) A is a compound of formula (I) or a salt thereof, where A is the group represented by formula (II) below. (1-3) A is a compound of formula (I) or a salt thereof, where A is the group represented by formula (III) below.

[0043] (2-1-1) A1 is CR A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 Or N, and A4 is CR A4 Or N, and A5 is CR A5 or N, however, A1 to A5 cannot be N at two or more times, R A1 , R A2 , R A3 , R A4 and R A5 H may be the same or different from each other, and C may be substituted. 1-3A bond with alkyl, halogen, cyano, or A, however R A1 , R A2 , R A3 , R A4 and R A5 A compound of formula (I) or a salt thereof, wherein only one of the bonds is with A. (2-1-2) A1 is CR A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 Or N, and A4 is CR A4 Or N, and A5 is CR A5 or N, however, A1 to A5 cannot be N at two or more times, R A1 , R A2 , R A3 , R A4 and R A5 H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, -O- (may be substituted C) 1-3 A bond with alkyl, halogen, cyano, or A, however R A1 , R A2 , R A3 , R A4 and R A5 A compound of formula (I) or a salt thereof in which only one of the bonds is with A. (2-2) A1 is CR A1 Or N, and A2 is CR A2 A3 is a bond with A, and A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is a halogen, R A4 However, H is R A5 A compound of formula (I) or a salt thereof, wherein A1 is CR. A1 And A2 is CR A2 A3 is a coupling with A, and A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is a halogen, R A4However, H is R A5 A compound of formula (I) or a salt thereof, wherein A1 is CR. A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 And A4 is CR A4 And A5 is CR A5 or N, however, A1 to A5 cannot be N at two or more times, R A1 However, C may be substituted with H or halogen. 1-3 Alkyl, halogen, or cyano, R A2 However, C may be substituted with H or halogen. 1-3 Alkyl, halogen, or cyano, R A3 However, it is a bonding with A, and R A4 However, C may be substituted with H or halogen. 1-3 Alkyl, halogen, or cyano, R A5 However, C may be substituted with H or halogen. 1-3 A compound of formula (I) or a salt thereof, which is alkyl, halogen, or cyano. (2-5) A1 is CR A1 Or N, and A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, it is H or F, and R A2 However, it is H, F, Cl, or trifluoromethyl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 A compound of formula (I) or a salt thereof, wherein A1 is H or F. (2-6) A1 is CR A1 Or N, and A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is H, Cl or trifluoromethyl, and R A3However, it is a bonding with A, and R A4 However, H is R A5 A compound of formula (I) or a salt thereof, wherein A1 is CR. A1 And A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is Cl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 A compound of formula (I) or a salt thereof, wherein H is present.

[0044] (3-1-1) Y is one base selected from the group consisting of the following equations (IV), (V), (VI), (VII), (VIII), and (XXV): n is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different, and are 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 is H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 is CO or SO2, and also R A1 and R YN2 A compound of formula (I) or a salt thereof, in which the groups may together form a substituted 4- to 6-membered saturated heterocycle. (3-1-2) Y is one group selected from the group consisting of the following formulas (IV), (V), (VI), (VII), (VIII), and (XXV): n is an integer from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, n1 and n2 are either identical or distinct from each other, and R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 A compound of formula (I) or a salt thereof, wherein adjacent nitrogen atoms may form a substituted 4- to 6-membered saturated heterocycle together. (3-2) Y is one group selected from the group consisting of the following formulas (IV), (V), (VII), (VIII), and (XXV): n is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different and are 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YC1 is H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 is CO or SO2, and also R A1 and R YN2A compound of formula (I) or a salt thereof, wherein the two groups together may form a substituted 4- to 6-membered saturated heterocycle. (3-2-2) Y is one group selected from the group consisting of the following formulas (IV), (V), (VII), (VIII), and (XXV): n is an integer from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, n1 and n2 are either identical or distinct from each other, and R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 A compound of formula (I) or a salt thereof, wherein adjacent nitrogen atoms may form a substituted 4- to 6-membered saturated heterocycle together. (3-3) Y is of the following formula (IV) or formula (V-1), n is either 0 or 1, R YN2 H is H, and R A1 and R YN2 A compound of formula (I) or a salt thereof, which may form a 4- to 6-membered saturated heterocycle, which may be substituted together. (3-4-1) Y is one group selected from the group consisting of formulas (IV), (V), (VI), and (VIII), n is an integer from 0 to 8, m1 is 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, RYC1 is H or C 1-3 A compound of formula (I) or a salt thereof that is alkyl. (3-4-2) Y is one group selected from the group consisting of the following formulas (IV), (V), (VI), and (VIII): n are integers from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof that is alkyl. (3-5) Y is one group selected from the group consisting of the following formulas (IV-2), (V-2), and (VIII-2): A compound of formula (I) or a salt thereof, where n is an integer from 0 to 2. (3-6) Y is one group selected from the group consisting of formulas (IV), (V), (VII), (VIII), and (XXV), n is an integer from 0 to 2, either identical or distinct from each other, m1 is 1 or 2, n1 and n2 are either identical or distinct from each other, and R YN1 H is R YN2 H is R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2A compound of formula (I) or a salt thereof, wherein adjacent nitrogen atoms may form a substituted 4- to 6-membered saturated heterocycle together. (3-7) Y is one group selected from the group consisting of the following formulas (IV-3), (IV-4), and (V-3), (Z * This indicates that it bonds with Z at this position. (The same applies below.) R YN2 (3-8) A compound of formula (I) or a salt thereof in which Y is H.

[0045] (4-1) Z is a single base selected from the group consisting of the following equations (IX), (X), (XI), (XII), (XIII), (XIV), (XXVI), and (XXVII): Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof, wherein m is an alkyl group, and m is the same or different integer from 0 to 8. (4-2-1) Z is a group selected from the group consisting of the following formulas (IX), (X), (XI), (XIII), and (XXVI): Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z is H or C 1-3 A compound of formula (I) or a salt thereof, wherein it is alkyl and m is an integer from 0 to 8. (4-2-2) Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XIII), (XXVI), and (XXVII): Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z are the same or different from each other, H or C 1-3A compound of formula (I) or a salt thereof, wherein the alkyl group is the same or different integers from 0 to 8, and m is the same or different integer from 0 to 8. (4-3) A compound of formula (I) or a salt thereof, wherein Z is one group selected from the group consisting of the following formulas (IX-1), (IX-2), and (XI-1). (4-4) Z is a base selected from the group consisting of the following equations (IX), (X), (XI), (XII), (XIII), and (XXVII), Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other, Ar is an arylene which may be substituted, and R Z However, they are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof, wherein m is alkyl and m is the same or different integers from 0 to 8. (4-5) Z is one group selected from the group consisting of the following formulas (IX-1), (X-1), (XII-1), (XIII-1), (XIII-2), and (XXVII-1), R Z1 However, H or C 1-6 It is alkyl, R Z2 However, C 1-6 A compound of formula (I) or a salt thereof that is alkyl. (4-6) Z is one group selected from the group consisting of the following formulas (IX-A), (XA), (XII-A), (XIII-A), and (XXVII-A), A Z2 These are the same or different from each other, CR AZ2 or N, R AZ2 are the same or different from each other, H or C 1-3 It is alkyl, R Z However, they are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof, wherein the alkyl group is an arylene which may be substituted with Ar. (4-7) Z is one group selected from the group consisting of the following formulas (IX), (XI), (XIII), (XXVI), and (XXVII): Cy is the same or different from C 1-3A 4- to 11-membered saturated heterocyclic divalent group which may be substituted with a group selected from the group consisting of alkyl, halogen, and cyano, R Z (4-8) A compound of formula (I) or a salt thereof, wherein is H, and m is the same or different from each other, 0 or 1. Z is one group selected from the group consisting of the following formulas (IX-11), (IX-21), (IX-3), (XI-11), (XIII-11), and (XXVI-1), wherein Z is a compound of formula (I) or a salt thereof. (However, L * This indicates that it binds with L at this position. (The same applies below.) (4-9) A compound of formula (I) or a salt thereof, wherein Z is one group selected from the group consisting of the following formulas (IX-11), (IX-21), (XI-11), and (XIII-11). (4-10) A compound of formula (I) or a salt thereof, wherein Z is one group selected from the group consisting of formulas (IX-11), (IX-21), and (XI-11).

[0046] (5-1-1) L may be bonded or substituted C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV), (XVI), (XVII), (XVIII), and (XIX): k is an integer from 1 to 8, X 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 is H or C 1-3 A compound of formula (I) or a salt thereof, wherein it is alkyl and Hy1 is an optionally substituted heteroarylene. (5-1-2) L is a bonded, optionally substituted C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV), (XVI), (XVII), (XVIII-1), and (XIX): k is an integer from 1 to 8, and is either the same or different from each other. 2 is O, S, SO2 or NR X2 And R X2is H or C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof, wherein it is alkyl and Hy1 is an optionally substituted heteroarylene. (5-2-1) L is an optionally substituted C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 8, X 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 is H or C 1-3 A compound of formula (I) or a salt thereof that is alkyl. (5-2-2) L may be bonded or substituted C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 8, and is either the same or different from each other. 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof that is alkyl. (5-3) L is C 1-6 Alkylene, or the following formula (XV), k is an integer between 2 and 3, and is a compound of formula (I) or a salt thereof. (5-4-1) L is a compound of formula (I) or a salt thereof, and is the following formula (XVIII). (5-4-2) L is given by the following equation (XVIII-1), A compound of formula (I) or a salt thereof, wherein k is 1 or 2. (5-5) L is a bond, C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 3, and is either the same or different from each other. 2 is O or NRX2 And R X2 C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 A compound of formula (I) or a salt thereof that is alkyl. (5-6) L is a bond, C 1-3 Alkylene, or the following formula (XV-2), (W * This indicates that it combines with W at this position. (The same applies below.) k is an integer from 2 to 3, and R LC1 (5-7) L is a bond, C 1-3 Alkylene, or the following formula (XV-3), k is an integer between 2 and 3, the compound of formula (I) or a salt thereof. (5-8) L is the following formula (XV-3), k is an integer between 2 and 3, and is a compound or salt thereof of formula (I).

[0047] (6-1) W is one group or combination selected from the group consisting of the following formulas (XX), (XXI), and (XXII): Hy2, Hy3, and Hy4 are all heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5One of these is a bond with L, and p is an integer from 1 to 3, the compound of formula (I) or a salt thereof. (6-2) W is one group selected from the group consisting of the following formulas (XX) and (XXI), Hy2 and Hy3 are both heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 A compound of formula (I) or a salt thereof, wherein one of the bonds is with L. (6-3) W is of the following formula (XXI-1), B1 is CR B1 or N, R B1 (6-4) A compound of formula (I) or a salt thereof in which H is present. (6-5) A compound of formula (I) or a salt thereof in which W is a bond. Hy2 is a 5- to 9-membered heteroarylene, Hy3 is a 5-membered heteroarylene, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4and R B5 These are bonds with H, halogen, cyano, or L, which are identical or different from each other, except R B1 , R B2 , R B3 , R B4 and R B5 A compound of formula (I) or a salt thereof, wherein one of the bonds is with L. (6-6) W is of the following formula (XXI-2) or formula (XXI-3), (L * This indicates that it binds with L at this position. (The same applies below.) B1 is CR B1 Or N, and B2 is CR B2 Or N, and B4 is CR B4 or N, however B1, B2 and B4 cannot all be N at the same time, and if B1, B2 or B4 is N, then B1 and B4 are both N, B2 and B4 are both N, B1 is N, or B2 is N, R B1 , R B2 and R B4 (6-7) W is a compound of formula (I) or a salt thereof, wherein H is the same or different from each other. R B1 (6-8) W is a compound of formula (I) or a salt thereof, which is H or F.

[0048] (7-1) R a C may be substituted. 1-3 Alkyl or NR a1 2, R a1 H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, or -E 2 -R a2 And R a2 C 1-3 Alkyl or aryl, E 2 is CO or SO2, R bH or C (which may be substituted) 1-3 It is an alkyl group, t is an integer from 0 to 2, and R c C may be substituted. 1-3 If it is alkyl, or if t is 2, R is bonded to a different carbon atom on the piperazine ring. c The combined structure may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, or R a and R b These are, together with the carbon atoms to which they are bonded, substituted or substituted 4- to 6-membered saturated heterorings or substituted C 3-8 A compound of formula (I) or a salt thereof that may form a cycloalkane. (7-2) R a , NR a1 2, R a1 H is R b C 1-3 A compound of formula (I) or a salt thereof, which is alkyl and t is 0. (7-3) R a C may be substituted with NH2. 1-3 It is alkyl, R b C 1-3 A compound of formula (I) or a salt thereof, which is alkyl and t is 0. (7-4) R a and R b These are, together with the carbon atoms to which they are bonded, substituted or substituted 4- to 6-membered saturated heterorings or substituted C 3-8 A compound of formula (I) or a salt thereof that forms a cycloalkane. (7-5) R a and R b (7-6) R a and R b These may be substituted with the carbon atoms to which they are bonded. 3-8 A compound of formula (I) or a salt thereof that forms a cycloalkane. (7-7) R a C may be substituted with NH2. 1-3 Alkyl or NR a1 2, Ra1 are the same or different from each other, H or C 1-3 It is alkyl, and the C 1-3 The alkyl group may be substituted with -OMe or N(Me)2, R b is H or C 1-3 It is alkyl, or R a and R b These, together with the carbon atoms to which they are bonded, form a 4- to 6-membered saturated heterocycle or C 3-8 A cycloalkane may be formed, and the 4- to 6-membered saturated heteroring and C 3-8 Cycloalkanes are composed of NH2 and C 1-3 It may be substituted with one or two groups selected from the group consisting of alkyl groups, and t is 0 or 2, and when t is 2, R c R is bonded to different carbon atoms on the piperazine ring. c A compound of formula (I) or a salt thereof, which may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms. (7-8) R a C 1-3 Alkyl or NR a1 2, R a1 C may be identical or different from each other, and may be substituted with H or -OMe. 1-3 It is alkyl, R b C 1-3 It is alkyl, or R a and R b These may form a 4- to 6-membered saturated heterocycle together with the carbon atoms to which they are bonded, and this 4- to 6-membered saturated heterocycle may be substituted with 1 to 2 groups selected from the group consisting of NH2 and Me, and t is 0, the compound of formula (I) or a salt thereof. (7-9) R a , NR a1 2, R a1 H is R b C 1-3 It is alkyl, or R a and R bThese may form a 4- to 6-membered saturated heterocycle together with the carbon atoms to which they are bonded, and this 4- to 6-membered saturated heterocycle may be substituted with 1 to 2 groups selected from the group consisting of NH2 and Me, and t is 0, the compound of formula (I) or a salt thereof. (7-10) R a , NR a1 2, R a1 H is R b A compound or salt thereof of formula (I), where is Me and t is 0. (7-11) R a However, NR a1 2, R a1 However, C may be identical or different from each other, and may be H or substituted. 1-3 It is alkyl, R b However, C may be substituted. 1-3 It is alkyl, or R a and R b These are 4- to 6-membered saturated heterocycles, which may be substituted together with the carbon atoms to which they are bonded, or substituted C 3-8 A compound of formula (I) or a salt thereof, which may form a cycloalkane.

[0049] (8-1) EUB is given by the following formula (XXIII) or formula (XXIV): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 It is an alkyl or possibly substituted heteroaryl, where q is an integer from 1 to 3, Ar2 is an aryl or heteroaryl, and R Ar2 This includes H, halogens, and C, which may be substituted. 1-3R7 is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8 A compound of formula (I) or a salt thereof, which is a cycloalkyl or a substituted 4- to 11-membered saturated heterocyclic group. (8-2-1) EUB is of the following formula (XXIII), R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 A cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 A compound of formula (I) or a salt thereof, which is an alkyl or optionally substituted heteroaryl, where q is an integer from 1 to 3. (8-2-2) EUB is the following formula (XXIII), R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 A compound of formula (I) or a salt thereof, wherein the alkyl or possibly substituted heteroaryl is an integer from 1 to 3, and q is an integer from 1 to 3. (8-3) EUB is the following formula (XXIII-1), R5 may be replaced with a halogen. 1-6 It is an alkyl group, and R6 may be substituted with an OH group or a halogen. 1-6 It is alkyl, R Ar1 C may be substituted with an oxo. 1-3 Alkyl, or C 1-3A compound of formula (I) or a salt thereof, which may be a heteroaryl compound substituted with an alkyl group. (8-4) EUB is of the following formula (XXIV): Ar2 is aryl or heteroaryl, R Ar2 However, H, halogen, and C may be substituted. 1-3 It is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8 A compound of formula (I) or a salt thereof, which is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocycle. (8-5) EUB is of the following formula (XXIV-1), R Ar2 However, C 1-3 It is a heteroaryl that may be substituted with alkyl, where Ar3 is C 1-3 It is a heteroaryl that may be substituted with alkyl, and R7 is C 1-6 A compound of formula (I) or a salt thereof that is alkyl. (8-6) EUB is of the following formula (XXIII), R5 is C 1-6 Alkyl, C 3-8 It is a cycloalkyl group, and R6 may be substituted with H or OH. 1-6 It is alkyl, Ar1 is phenylene, R Ar1 C may be substituted with an oxo. 1-3 C is an alkyl or heteroaryl group, and the heteroaryl group may be substituted with an OH group. 1-3 The compound of formula (I) or a salt thereof, which may be substituted with alkyl, and q is 1. (8-7) EUB is the following formula (XXIII), R5 is C 1-6 It is an alkyl group, and R6 may be substituted with an OH group. 1-6 It is alkyl, Ar1 is phenylene, R Ar1 is acetyl, or C 1-3A five-membered heteroaryl which may be substituted with an alkyl group, wherein the five-membered heteroaryl is one group selected from the group consisting of thiazolyl, oxazolyl, triazolyl and pyrazolyl, and q is 1, the compound of formula (I) or a salt thereof. (8-8) EUB is the following formula (XXIII), R5 is isopropyl, R6 is methyl or hydroxymethyl, Ar1 is phenylene, R Ar1 C 1-3 A five-membered heteroaryl which may be substituted with an alkyl group, wherein the five-membered heteroaryl is one group selected from the group consisting of thiazolyl and pyrazolyl, and q is 1, the compound of formula (I) or a salt thereof. (8-9) EUB is the following formula (XXIII), R5 is isopropyl, R6 is methyl or hydroxymethyl, Ar1 is phenylene, R Ar1 A compound of formula (I) or a salt thereof, wherein is a thiazolyl which may be substituted with Me, and q is 1.

[0050] (9) A compound of formula (I) or a salt thereof, which is any two or more non-contradictory combinations from the embodiments described in (1-1) to (1-3), (2-1-1) to (2-7), (3-1-1) to (3-8), (4-1) to (4-10), (5-1-1) to (5-8), (6-1) to (6-8), (7-1) to (7-11), and (8-1) to (8-9) above.

[0051] Specifically, the following embodiments are examples of the combinations described in (9) above: (9-1) A compound of formula (I) or a salt thereof. (In the formula, A is a group represented by the following formula (II) or formula (III), A1 is CR A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 Or N, and A4 is CR A4 Or N, and A5 is CR A5 or N, however, A1 to A5 cannot be N at two or more times, R A1 , R A2, R A3 , R A4 and R A5 H may be the same or different from each other, and C may be substituted. 1-3 A bond with alkyl, halogen, cyano, or A, however R A1 , R A2 , R A3 , R A4 and R A5 Only one of them is a bond with A, and Y is a base selected from the group consisting of the following equations (IV), (V), (VI), (VII), (VIII), and (XXV): n is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different, and are 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 is H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 is CO or SO2, and also R A1 and R YN2 These may form a 4- to 6-membered saturated heteroring, which may be substituted, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), (XIV), (XXVI), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z are the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, which may be the same or different from each other, and L may be bonded or substituted. 1-8Alkylene, or one group selected from the group consisting of the following formulas (XV), (XVI), (XVII), (XVIII), and (XIX): k is an integer from 1 to 8, X 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 is H or C 1-3 It is alkyl, Hy1 is an optionally substituted heteroarylene, and W is one group or bond selected from the group consisting of the following formulas (XX), (XXI), and (XXII). Hy2, Hy3, and Hy4 are all heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a combination with L, where p is an integer from 1 to 3, and R a C may be substituted. 1-3 Alkyl or NR a1 2, R a1 H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, or -E 2 -R a2 And R a2 C 1-3 Alkyl or aryl, E 2is CO or SO2, R b H or C (which may be substituted) 1-3 It is an alkyl group, t is an integer from 0 to 2, and R c C may be substituted. 1-3 If it is alkyl, or if t is 2, R is bonded to a different carbon atom on the piperazine ring. c The combined structure may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, or R a and R b These are, together with the carbon atoms to which they are bonded, substituted or substituted 4- to 6-membered saturated heterorings or substituted C 3-8 It may also form a cycloalkane, and EUB is given by the following formula (XXIII) or formula (XXIV): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 It is an alkyl or possibly substituted heteroaryl, where q is an integer from 1 to 3, Ar2 is an aryl or heteroaryl, and R Ar2 This includes H, halogens, and C, which may be substituted. 1-3 R7 is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8 (9-2) Y is a cycloalkyl or a substituted 4- to 11-membered saturated heterocyclic group. n is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different and are 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YC1 is H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 is CO or SO2, and also R A1 and R YN2 These may form a 4- to 6-membered saturated heteroring, which may be substituted, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XIII), and (XXVI). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z is H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, and L may be substituted. 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 8, X 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 is H or C 1-3 It is alkyl, and W is one group selected from the group consisting of the following formulas (XX) and (XXI). Hy2 and Hy3 are both heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CRB5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a bond with L, and EUB is given by the following equation (XXIII): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 A cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 The compound or salt thereof described in (9-1), wherein the alkyl group is an optionally substituted heteroaryl group, and q is an integer from 1 to 3. (9-3) A is a group represented by the following formula (II), A1 is CR A1 Or N, and A2 is CR A2 A3 is a coupling with A, and A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is a halogen, R A4 However, H is R A5 H is given by the following equation (IV-1) or equation (V-1): n is either 0 or 1, R YN2 H is H, and R A1 and R YN2They may form a 4- to 6-membered saturated heterocycle, and Z is one group selected from the group consisting of the following formulas (IX-1), (IX-2), and (XI-1). L is C 1-6 Alkylene, or the following formula (XV-1), k is an integer between 2 and 3, and W is given by the following equation (XXI-1): B1 is CR B1 or N, R B1 H is R a C may be substituted. 1-3 Alkyl or NR a1 2, R a1 H is R b C 1-3 It is alkyl, t is 0, and EUB is given by the following formula (XXIII-1): R5 may be replaced with a halogen. 1-6 It is an alkyl group, and R6 may be substituted with an OH group or a halogen. 1-6 It is alkyl, R Ar1 C may be substituted with an oxo. 1-3 Alkyl, or C 1-3 A heteroaryl compound that may be substituted with an alkyl group, or a salt thereof, as described in (9-2). (9-4) A is a group represented by the following formula (II), Y is a base selected from the group consisting of the following equations (IV), (V), (VI), and (VIII): n is an integer from 0 to 8, m1 is 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 is H or C 1-3 It is an alkyl group, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), and (XXVII). Cy is a divalent group of a 4- to 11-membered saturated heterocycle, which may be identical or different from each other, and R Z However, they are the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, either the same or different from each other, and L is given by the following formula (XVIII): W is a bond, R a However, NR a1 2, R a1 However, H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, or -E 2 -R a2 And R a2 C 1-3 Alkyl or aryl, E 2 is CO or SO2, R b However, H or C may be substituted. 1-3 It is an alkyl group, t is an integer from 0 to 2, and R c C may be substituted. 1-3 If it is alkyl, or if t is 2, R is bonded to a different carbon atom on the piperazine ring. c The combined structure may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, or R a and R b These are 4- to 6-membered saturated heterocycles, which may be substituted together with the carbon atoms to which they are bonded, or substituted C 3-8 It may also form a cycloalkane, where EUB is given by the following formula (XXIV): Ar2 is aryl or heteroaryl, R Ar2 However, H, halogen, and C may be substituted. 1-3 It is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8A cycloalkyl compound or a substituted 4- to 11-membered saturated heterocycle, or a salt thereof, as described in (9-1). (9-5) A1 is CR A1 And A2 is CR A2 A3 is a coupling with A, and A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is a halogen, R A4 However, H is R A5 H is H, and Y is a base selected from the group consisting of the following equations (IV-2), (V-2), and (VIII-2): n is an integer from 0 to 2, and Z is a base of unity selected from the group consisting of the following equations: (IX-1), (X-1), (XII-1), (XIII-1), (XIII-2), and (XXVII-1). R Z1 However, H or C 1-6 It is alkyl, R Z2 However, C 1-6 It is alkyl, and EUB is given by the following formula (XXIV-1), R Ar2 However, C 1-3 It is a heteroaryl that may be substituted with alkyl, where Ar3 is C 1-3 It is a heteroaryl that may be substituted with alkyl, and R7 is C 1-6 A compound or salt thereof that is alkyl, as described in (9-4). (9-1-1) A compound of formula (I) or a salt thereof. (In the formula, A is a group represented by the following formula (II) or formula (III), A1 is CR A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 Or N, and A4 is CR A4 Or N, and A5 is CR A5 or N, however, A1 to A5 cannot be N at two or more times, R A1 , R A2 , R A3 , RA4 and R A5 H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, -O- (may be substituted C) 1-3 A bond with alkyl, halogen, cyano, or A, however R A1 , R A2 , R A3 , R A4 and R A5 Only one of them is a bond with A, and Y is a base selected from the group consisting of the following equations (IV), (V), (VI), (VII), (VIII), and (XXV): n is an integer from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, n1 and n2 are either identical or distinct from each other, and R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 Furthermore, adjacent nitrogen atoms may unite to form a substituted 4- to 6-membered saturated heterocycle, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), (XIV), (XXVI), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Zare the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, which may be the same or different from each other, and L may be bonded or substituted. 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV), (XVI), (XVII), (XVIII-1), and (XIX): k is an integer from 1 to 8, and is either the same or different from each other. 2 is O, S, SO2 or NR X2 And R X2 is H or C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, Hy1 is an optionally substituted heteroarylene, and W is one group or bond selected from the group consisting of the following formulas (XX), (XXI), and (XXII). Hy2, Hy3, and Hy4 are all heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a combination with L, where p is an integer from 1 to 3, and R a C may be substituted. 1-3 Alkyl or NR a1 2, R a1 H may be the same or different from each other, and C may be substituted.1-3 Alkyl, or -E 2 -R a2 And R a2 C 1-3 Alkyl or aryl, E 2 is CO or SO2, R b H or C (which may be substituted) 1-3 It is an alkyl group, t is an integer from 0 to 2, and R c C may be substituted. 1-3 If it is alkyl, or if t is 2, R is bonded to a different carbon atom on the piperazine ring. c The combined structure may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, or R a and R b These are, together with the carbon atoms to which they are bonded, substituted or substituted 4- to 6-membered saturated heterorings or substituted C 3-8 It may also form a cycloalkane, and EUB is given by the following formula (XXIII) or formula (XXIV): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 It is an alkyl or possibly substituted heteroaryl, where q is an integer from 1 to 3, Ar2 is an aryl or heteroaryl, and R Ar2 This includes H, halogens, and C, which may be substituted. 1-3 R7 is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8(9-2-1) Y is a cycloalkyl or a substituted 4- to 11-membered saturated heterocyclic group. n is an integer from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, n1 and n2 are either identical or distinct from each other, and R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 Furthermore, adjacent nitrogen atoms may unite to form a substituted 4- to 6-membered saturated heterocycle, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XIII), (XXVI), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z H or C are the same or different from each other. 1-3 It is an alkyl group, m is an integer from 0 to 8 that is the same or different from each other, and L is a C which may be bonded or substituted. 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 8, and is either the same or different from each other. 2 is O, S, SO2 or NR X2 And R X2 is H or C1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, and W is one group selected from the group consisting of the following formulas (XX) and (XXI). Hy2 and Hy3 are both heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a bond with L, and EUB is given by the following equation (XXIII): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 The compound or salt thereof described in (9-1-1), where q is an alkyl or possibly substituted heteroaryl, and q is an integer from 1 to 3. (9-3-1) A is a group represented by the following formula (II), A1 is CR A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 And A4 is CR A4and A5 is CR A5 or N, provided that two or more of A1 to A5 are not simultaneously N, and R A1 is H, C optionally substituted with halogen 1-3 alkyl, halogen or cyano, and R A2 is H, C optionally substituted with halogen 1-3 alkyl, halogen or cyano, and R A3 is a bond to A, and R A4 is H, C optionally substituted with halogen 1-3 [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​A 4- to 11-membered saturated heterocyclic divalent group which may be substituted with a group selected from the group consisting of alkyl, halogen, and cyano, R Z H is H, m is the same or different from each other, 0 or 1, L is bonded, C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 3, and is either the same or different from each other. 2 is O or NR X2 And R X2 C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, and W is one group selected from the group consisting of the following formulas (XX) and (XXI). Hy2 is a 5- to 9-membered heteroarylene, Hy3 is a 5-membered heteroarylene, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 These are bonds with H, halogen, cyano, or L, which are identical or different from each other, except R B1 , R B2 , R B3 , R B4 and R B5 Of these, one is a bonding with L, and R a C may be substituted with NH2. 1-3 Alkyl or NR a1 2, R a1 are the same or different from each other, H or C 1-3 It is alkyl, and the C 1-3 The alkyl group may be substituted with -OMe or N(Me)2, R b is H or C1-3 It is alkyl, or R a and R b These, together with the carbon atoms to which they are bonded, form a 4- to 6-membered saturated heterocycle or C 3-8 A cycloalkane may be formed, and the 4- to 6-membered saturated heteroring and C 3-8 Cycloalkanes are composed of NH2 and C 1-3 It may be substituted with one or two groups selected from the group consisting of alkyl groups, and t is 0 or 2, and when t is 2, R c R is bonded to different carbon atoms on the piperazine ring. c The EUB may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, and the EUB is given by the following formula (XXIII): R5 is C 1-6 Alkyl, C 3-8 It is a cycloalkyl group, and R6 may be substituted with H or OH. 1-6 It is alkyl, Ar1 is phenylene, R Ar1 C may be substituted with an oxo. 1-3 C is an alkyl or heteroaryl group, and the heteroaryl group may be substituted with an OH group. 1-3 The compound or salt thereof described in (9-2-1) may be substituted with an alkyl group, and q is 1. (9-4-1) A is a group represented by the following formula (II), A1 is CR A1 Or N, and A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, it is H or F, and R A2 However, it is H, F, Cl, or trifluoromethyl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 is H or F, and Y is one base selected from the group consisting of the following formulas (IV-3), (IV-4), and (V-3): (Z *indicates binding to Z at this position. (The same applies hereinafter) R YN2 is H, and Z is one group selected from the group consisting of the following formulas (IX-11), (IX-21), (IX-3), (XI-11), (XIII-11), and (XXVI-1): (L * indicates binding to L at this position. (The same applies hereinafter) L is a bond, C 1-3 alkylene, or the following formula (XV-2): (W * indicates binding to W at this position. (The same applies hereinafter) k is an integer from 2 to 3, and R LC1 is the same or different from each other, and is H or methyl, and W is the following formula (XXI-2) or formula (XXI-3): (L * indicates binding to L at this position. (The same applies hereinafter) B1 is CR B1 or N, B2 is CR B2 or N, B4 is CR B4 or N, provided that B1, B2, and B4 do not all become N at the same time. When B1, B2, or B4 becomes N, B1 and B4 are both N, B2 and B4 are both N, B1 is N, or B2 is N, and R B1 , R B2 and R B4 are the same or different from each other and are H or F, and R a is C 1-3 alkyl or NR a1 2, and R a1 is the same or different from each other and is C 1-3 alkyl optionally substituted with H or -OMe, and R b is C 1-3 alkyl, or R a and R b may together with the carbon atom to which they are attached form a 4- to 6-membered saturated heterocycle, and the 4- to 6-membered saturated heterocycle may be substituted with one or two groups selected from the group consisting of NH2 and Me, t is 0, and EUB is the following formula (XXIII): R5 is C 1-6It is an alkyl group, and R6 may be substituted with an OH group. 1-6 It is alkyl, Ar1 is phenylene, R Ar1 is acetyl, or C 1-3 A five-membered heteroaryl which may be substituted with an alkyl group, the five-membered heteroaryl is one group selected from the group consisting of thiazolyl, oxazolyl, triazolyl and pyrazolyl, and q is 1, the compound or salt thereof as described in (9-3-1). (9-5-1) A is a group represented by the following formula (II), A1 is CR A1 Or N, and A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is H, Cl or trifluoromethyl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 H is H, and Y is a single base selected from the group consisting of the following equations (IV-3) and (V-4), Z is a single base selected from the group consisting of the following equations (IX-11), (IX-21), (XI-11), and (XIII-11): L is bond, C 1-3 Alkylene, or the following formula (XV-3), k is an integer between 2 and 3, and W is a base of 1 selected from the group consisting of the following equations: (XXI-3), (XXI-4), (XXI-5), (XXI-6), (XXI-7), and (XXI-8). R B1 is H or F, and R a , NR a1 2, R a1 H is R b C 1-3 It is alkyl, or R a and R bThese may form a 4- to 6-membered saturated heterocycle together with the carbon atom to which they are bonded, and this 4- to 6-membered saturated heterocycle may be substituted with 1 to 2 groups selected from the group consisting of NH2 and Me, t is 0, and EUB is given by the following formula (XXIII), R5 is isopropyl, R6 is methyl or hydroxymethyl, Ar1 is phenylene, R Ar1 C 1-3 A five-membered heteroaryl which may be substituted with an alkyl group, the five-membered heteroaryl is one group selected from the group consisting of thiazolyl and pyrazolyl, and q is 1, the compound or salt thereof as described in (9-4-1). (9-6-1) A is a group represented by the following formula (II), A1 is CR A1 And A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is Cl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 H is H, and Y is a single base selected from the group consisting of the following equations (IV-3) and (V-4), Z is a single base selected from the group consisting of the following equations (IX-11), (IX-21), and (XI-11): L is given by the following equation (XV-3): k is an integer between 2 and 3, and W is given by the following equation (XXI-3) or equation (XXI-4-1): R a , NR a1 2, R a1 H is R b is Me, t is 0, and EUB is given by the following equation (XXIII): R5 is isopropyl, R6 is methyl or hydroxymethyl, Ar1 is phenylene, R Ar1is a thiazolyl which may be substituted with Me, and q is 1, the compound or salt thereof as described in (9-5-1). (9-7-1) A is a group represented by the following formula (II), Y is a base selected from the group consisting of the following equations (IV), (V), (VI), and (VIII): n are integers from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, R YN1 is H or C 1-3 It is alkyl, R YN2 is H or C 1-3 It is alkyl, R YN3 is H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is an alkyl group, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other, Ar is an arylene which may be substituted, and R Z However, they are the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, either the same or different from each other, and L is given by the following formula (XVIII-1): k is 1 or 2, W is a bond, R a However, NR a1 2, R a1 However, C may be identical or different from each other, and may be H or substituted. 1-3 It is alkyl, R b However, C may be substituted. 1-3 It is alkyl, or R a and R b These are 4- to 6-membered saturated heterocycles, which may be substituted together with the carbon atoms to which they are bonded, or substituted C 3-8 It may also form a cycloalkane, where EUB is given by the following formula (XXIV): Ar2 is aryl or heteroaryl, RAr2 However, H, halogen, and C may be substituted. 1-3 It is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8The compound described in (9-1-1) or a salt thereof, which is a cycloalkyl or a substituted 4- to 11-membered saturated heterocycle. (9-8-1) The compound is (4R)-1-[(2S)-2-{4-[3-(2-{[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]oxy}ethoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-(2-{[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]oxy}ethoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(3-{2-[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-(3-{4-[{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}(oxo)acetyl]piperazine-1-yl}propoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-N-[(1S)-1-(4-acetylphenyl)ethyl]-1-{(2S)-2-[4-(4-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{3-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]propoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{3-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]propyl}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(5-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}pyridine-2-yl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(3-{2-[1-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperidine-4-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, and, A compound selected from the group consisting of (4R)-1-{(2S)-2-[4-(4-{2[4-({5-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-chloro-1-oxo-1,3-dihydro-2H-isoindole-2-yl}acetyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, the compound described in (9-1) or a salt thereof. (9-8-2) The compound is (4R)-1-[(2S)-2-{4-[3-(2-{[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]oxy}ethoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-(2-{[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]oxy}ethoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(3-{2-[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-(3-{4-[{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}(oxo)acetyl]piperazine-1-yl}propoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-N-[(1S)-1-(4-acetylphenyl)ethyl]-1-{(2S)-2-[4-(4-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{3-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]propoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{3-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]propyl}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(5-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}pyridine-2-yl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(3-{2-[1-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperidine-4-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,A compound selected from the group consisting of (4R)-1-{(2S)-2-[4-(4-{2-[4-({5-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-chloro-1-oxo-1,3-dihydro-2H-isoindole-2-yl}acetyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, or a salt thereof, as described in (9-1-1).

[0052] Compounds of formula (I) or salts thereof may exist as tautomers or geometric isomers depending on the type of substituent. In this specification, compounds of formula (I) or salts thereof may be described in only one form of isomer, but the present invention also includes other isomers, isolated isomers, or mixtures thereof. Furthermore, compounds of formula (I) or salts thereof may have a chiral center or axial chirality, and enantiomers (optical isomers) based on this may exist. Compounds of formula (I) or salts thereof include isolated individual (R) and (S) enantiomers, or mixtures thereof (including racemic and non-racemic mixtures). In some embodiments, the enantiomers are "stereochemically pure." "Stereochemically pure" means purity to the extent that a person skilled in the art can recognize it as substantially stereochemically pure. In another embodiment, the enantiomer is a compound having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or higher, 95% ee or higher, 98% ee or higher, or 99% ee or higher.

[0053] Furthermore, a salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and depending on the type of substituent, it may form an acid addition salt or a salt with a base. Specifically, examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine; and salts with various amino acids and amino acid derivatives such as acetylleucine, as well as ammonium salts.

[0054] Furthermore, the present invention also encompasses various hydrates and solvates of the compound of formula (I) or its salts, as well as crystalline polymorphs. The present invention also encompasses all pharmaceutically acceptable compounds of formula (I) or its salts labeled with one or more radioactive or non-radioactive isotopes. Examples of suitable isotopes used for isotope labeling of the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C, 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N etc.), oxygen ( 15 O, 17 O and 18 O etc.), fluorine ( 18 F etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), phosphorus ( 32 P, etc.), sulfur ( 35 Isotopes (such as 3S) are encapsulated. It can be used in research such as tissue distribution studies of compounds, drugs and / or substrates of the present invention that are labeled with isotopes. For example, tritium ( 3 H), carbon-14 ( 14Radioactive isotopes such as C) can be used for this purpose due to their ease of labeling and detection. Substitution with heavier isotopes, for example, hydrogen to deuterium ( 2 Substitution with H) may be therapeutically advantageous due to improved metabolic stability (e.g., increased half-life in vivo, reduced required dose, reduced drug interactions). Positron-emitting isotopes ( 11 C, 18 F, 15 O and 13 Substitution with N, etc., can be used in positron emission tomography (PET) studies to test substrate receptor occupancy. The isotope-labeled compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, or by a method similar to that of the examples or production examples, using appropriate isotope-labeled reagents instead of unlabeled reagents.

[0055] (Manufacturing Method) The compounds of the present invention can be manufactured by applying various known synthesis methods, utilizing their characteristics based on their basic structure or the type of substituents. In this case, depending on the type of functional group, it may be technically effective in manufacturing to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at a stage from the starting material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis (5th edition, 2014)" by PGM Wuts, and these can be appropriately selected and used depending on the reaction conditions. In this method, the desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary. A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, etc., by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, pp. 163-198. Furthermore, prodrugs of the present invention can be produced by introducing a specific group at a stage from the raw material to the intermediate, similar to the protecting groups described above, or by carrying out further reactions using the obtained compound of the present invention. The reactions can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, and dehydration. A typical method for producing the compound of formula (I) is described below. Each method can also be carried out by referring to the references attached to the description. Note that the production methods of the present invention are not limited to the examples shown below.

[0056] In this specification, the following abbreviations may be used: CDI: 1,1'-carbonyldiimidazole, DMAc or DMA: N,N-dimethylacetamide, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, DMSO: dimethyl sulfoxide, DIPEA: N,N-diisopropylethylamine, DOX: dioxane, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate, HOBt: 1-hydroxybenzotriazole, EDCI・HCl: 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DCM: dichloromethane, MTBE: methyl tert-butyl ether, TBAF: tetrabutylammonium fluoride, IPE: diisopropyl ether, TFA: trifluoroacetic acid, ODS: octadecylsilyl, DME: 1,2-dimethoxyethane, tBuOH or t-BuOH: tert-butyl alcohol, TEA: triethylamine, TBDMS or TBS: tert-butyldimethylsilyl, TMS: trimethylsilyl, NMP: N-methylpyrrolidone, Boc: tert-butoxycarbonyl, THP: tetrahydro-2H-pyran-2-yl, Pd / C: palladium-supported carbon. T4P: n-butylphosphonic anhydride, RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, Burgess reagent: N-(triethylammoniosulfonyl)methyl carbamate, Pd-118: [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[0057] (Manufacturing method 1) (P 1 (This indicates a protecting group for the nitrogen atom. The same applies below.)

[0058] This manufacturing method involves one R of the compound of formula (I). a1This is a method for producing the compound of formula (I-1) where is H and t is 0. Formula (I-1) is the protecting group P of compound (1). 1 This can be obtained by deprotecting the protecting group. Examples of protecting groups shown here include tert-butoxycarbonyl group, triphenylmethyl group, tetrahydro-2H-pyran-2-yl group, methoxymethyl group, dimethylmethanediyl group, tert-butylsulfinyl group, and 2-(trimethylsilyl)ethoxycarbonyl group. This deprotection reaction is carried out by stirring under cooling and then under heating and reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, ethers such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN or water, and mixtures thereof. Examples of deprotection reagents are not limited to those mentioned above, but include acids such as hydrogen chloride (DOX solution), hydrogen chloride (ethanol solution), hydrogen chloride (ethyl acetate solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. In the case of a 2-(trimethylsilyl)ethoxycarbonyl group, examples include tetrabutylammonium fluoride, potassium fluoride, and pyridine hydrogen fluoride. Furthermore, in this manufacturing method, if compound (1) A has a protecting group, P 1 Simultaneously with the deprotection of A, the protecting groups contained in A can also be deprotected. Here, the protecting group P can be used as a protecting group contained in A. 1These are similar to the groups listed above. For reference, see, for example: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th edition, John Wiley & Sons Inc., 2014. AR Katritzky and RJK Taylor, "Comprehensive Organic Functional Group Transformations II," Vol. 2, Elsevier Pergamon, 2005.

[0059] (Raw material synthesis 1) (In the formula, P 1 P indicates a protecting group for the amino group. 2 Z indicates a protecting group for hydroxyl groups, and also Z 1 This indicates a divalent group of a saturated heterocycle containing a nitrogen atom as a ring constituent atom in Z. (The same applies hereafter.) (In the formula, X 1 X represents a halogen, for example, Cl. 2 represents a halogen, for example, I. B(OR)2 represents a boronic acid or boronic acid ester (including cyclic boronic acid esters), and an example of a boronic acid ester is pinacol boronic acid ester. Y amide is -CO-NH- or -NH-CO-. R is C 1-3 It is alkyl. Note that A also includes compounds in which the -NH- group in A is protected by a protecting group. (The same applies hereafter.)

[0060] This manufacturing method involves compound (1), which is the raw material compound for manufacturing method 1, where Y is -Y amide -Y 1 -CO- and Y 1 The combination is C 1-3 Methylene or C which may be substituted with alkyl 1-3 Ethylene which may be substituted with alkyl, and Z is Z 1 And L is -L 1 -O- and L 1 C 1-3 C may be substituted with alkyl. 1-8It is an alkylene, and W is given by equation (XXI-1), and B 1 CR B1 And R B1 This is a method for producing compound (20) in which is H and EUB is of formula (XXIII).

[0061] (Step 1) This step is a method for producing compound (3) by the reaction of compound (2) with a diazo transfer reagent. In this reaction, compound (2) is treated with an equal or excess amount of the diazo transfer reagent in a solvent inert to the reaction, under cooling to heating, preferably from 0°C to 50°C, for usually 0.1 hours to 3 days. Examples of diazo transfer reagents are not particularly limited, but include trifluoromethanesulfonyl azide, 1H-imidazole-1-sulfonyl azide or its salts, 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), etc. It may be advantageous to carry out the reaction in the presence of organic bases such as TEA, 4-dimethylaminopyridine (DMAP), 2,6-lutidine, or a catalytic amount of copper salts such as CuSO4. Examples of solvents include halogenated hydrocarbons such as THF and dichloromethane, MeCN, alcohols, water, and mixtures thereof. [Literature] J. Org. Chem. 2012, 77, p.1760-1764 Nature 2019, 574, p.86-89 Org. Biomol. Chem. 2014, 12, p.4397-4406

[0062] (Step 2) This step involves preparing compound (4) by protecting the hydroxyl group of compound (3) with a protecting group. For example, when protecting with a tert-butyldimethylsilyl group, this reaction is carried out under basic conditions, with compound (3) in the presence of a tert-butyldimethylsilyl protecting reagent, by stirring under cooling to reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not limited, but include DMF. Examples of bases are not limited, but include imidazole. Examples of tert-butyldimethylsilyl protecting reagents are not limited, but include tert-butyldimethylsilyl chloride. For references on this reaction, see, for example, the following: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th edition, John Wiley & Sons Inc., 2014.

[0063] (Third Step) This step is a method for producing compound (6) by a cycloaddition reaction between compound (4) and compound (5). This reaction uses equal amounts of compound (4) and compound (5), or an excess amount of one, and the mixture is stirred for 0.1 hours to 5 days, preferably in the presence of a copper salt, more preferably in the presence of a copper salt and a reducing agent, in a solvent that is inert to the reaction, or without a solvent, under cooling to heating under reflux, preferably at 0°C to 100°C. Examples of solvents used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMSO, ethyl acetate, MeCN, tBuOH, water, and mixtures thereof. Examples of copper salts include CuI, CuSO4, and CuOTf. Examples of reducing agents include sodium ascorbate. The presence of TEA, DIPEA, N-methylmorpholine (NMM), 2,6-lutidine, and tris[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl]amine (TBTA) may be advantageous for facilitating the reaction. [Reference] Angew. Chem. Int. Ed. 2002, 41, p.2596-2599.

[0064] (Step 4) This step is a method for carrying out the Mitsunobu reaction between compound (6) and compound (7). Compound (6) and compound (7) are used in equal equivalent amounts or in excess equivalent amounts, and a phosphine reagent and an azodicarboxylic acid ester are used in a solvent that is inert to the reaction, and are stirred for 1 hour to 5 days, from cooling to heating, preferably from -20°C to 100°C. Examples of phosphine reagents used here include triphenylphosphine, tricyclohexylphosphine, and tri-n-butylphosphine. Examples of azodicarboxylic acid esters used here include dimethyl azodicarboxylic acid, diethyl azodicarboxylic acid, diisopropyl azodicarboxylic acid, and 1,1'-(azodicarbonyl)dipiperidine. The solvent used here is not particularly limited, but examples include ether-based solvents such as THF, diethyl ether, and DOX, benzene, toluene, and mixtures thereof. Alternatively, azodicarboxylic acid amides such as N,N,N',N'-tetramethylazodicarboxamide and bis(piperidinocarbonyl)diimide can be used instead of azodicarboxylic acid esters.

[0065] (Step 5) This step involves protecting the amino group P of the compound obtained in Step 4. 1 and the protecting group P of the hydroxyl group 2 This is a method for producing compound (8) by deprotecting P. 1 is a tert-butoxycarbonyl group, P 2 If is a tert-butyldimethylsilyl group, this reaction is P 1 and P 2The reaction is carried out by stirring the protected compound and the deprotection reagent in a solvent inert to the reaction, under cooling to heating, preferably from 0°C to room temperature, for typically 1 hour to 5 days. Examples of deprotection reagents used here include hydrogen chloride (DOX solution), hydrogen chloride (ethanol solution), hydrogen chloride (ethyl acetate solution), and trifluoroacetic acid. The solvent used here is not particularly limited, but ethanol, ethyl acetate, THF, DMF, acetonitrile, DCM, or mixtures thereof can be used. For reference, see, for example, the following: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th edition, John Wiley & Sons Inc., 2014.

[0066] (Step 6) This step is to obtain compound (11) by an ipso substitution reaction between compound (9) and compound (10). In this reaction, equal amounts of compound (9) and compound (10), or an excess amount of one, are used, and the mixture is stirred in a solvent inert to the reaction, or without a solvent, under cooling to heating under reflux, preferably at 0°C to 150°C, for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, MeCN, NMP, and mixtures thereof. Carrying out the reaction in the presence of organic bases such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK, and KHMDS, or inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate, can sometimes be advantageous for the reaction to proceed smoothly.

[0067] (Step 7-1) This step is a method for producing compound (14) or compound (15) by a Suzuki-Miyaura coupling reaction using compound (11) and compound (12) or compound (13), which is a boronic acid derivative. In this reaction, equal amounts or an excess amount of compound (11) and compound (12) or compound (13), which is a boronic acid derivative, are used, and the mixture is stirred in a reaction-inert solvent, in the presence of a base and a palladium catalyst, from room temperature to reflux, preferably from 20°C to 140°C, for a period of 0.1 hours to 5 days. Examples of solvents used here are not limited to halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidined-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium, PdCl2(PPh3)2, PdCl2(dppf), or their CH2Cl2 adducts such as PdCl2(dppf)・CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. The presence of ligands such as SPhos, RuPhos, and 1,1'-bis(diphenylphosphin)ferrocene may be advantageous for smooth reaction. Furthermore, heating the mixture by microwave irradiation may also be advantageous for smooth reaction. [References] J. Am. Chem. Soc., 2005, 127, p.4685-4696; Org. Lett. 2011, 13, p.3948-3951; Org. Lett. 2012, 14, p.1278-1281

[0068] (Step 7-2) This step involves hydrolyzing the ester of compound (15) to obtain compound (16). This reaction is carried out by stirring compound (15) under cooling and then under heating and reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include alcohols, acetone, DMF, and THF. In some cases, a mixed solvent of the above solvent and water may be preferable for the reaction. Examples of hydrolysis reagents are not particularly limited, but include lithium hydroxide monohydrate or its aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and trimethyltin hydroxide. For references on this reaction, see, for example, the following: The Chemical Society of Japan, ed., "Experimental Chemistry Course (5th Edition)," Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0069] (Step 8) This step is to carry out an amidation reaction using compound (17) with compound (14) and compound (18) with compound (16). This reaction uses equal amounts of an amine and a carboxylic acid, or an excess amount of one, and stirs the mixture in a reaction-inert solvent in the presence of a condensing agent, under cooling to heating, preferably from -20°C to 60°C, for 0.1 hours to 5 days to obtain an amide compound. Examples of solvents are not particularly limited, but include aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride (EDCI・HCl), N,N'-dicyclohexylcarbodiimide (DCC), CDI, diphenyl phosphate azide (DPPA), etc. The use of additives (e.g., HOBt or dimethylaminopyridine) may be preferable for the reaction. Carrying the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, may be advantageous for smooth reaction. Alternatively, a method can be used in which compound (16) or compound (17), which is a carboxylic acid, is converted into a reactive derivative before the acylation reaction. Examples of reactive carboxylic acid derivatives include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, and active esters obtained by condensation with 1-hydroxybenzotriazole. The reaction between these reactive derivatives and compound (18) or compound (14) can be carried out in a solvent that is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling to heating, preferably at -20°C to 120°C.[References] S.R. Sandler and W. Karo, "Organic Functional Group Preparations," 2nd edition, Vol. 1, Academic Press Inc., 1991. The Chemical Society of Japan, ed., "Experimental Chemistry Course (5th edition)," Vol. 16 (2005) (Maruzen).

[0070] (Step 9) This step involves hydrolyzing the ester portion of the compound obtained in Step 8 to obtain compound (19). The reaction conditions for this step are the same as those for Step 7-2 of this raw material synthesis 1.

[0071] (Step 10) This step involves obtaining compound (20) by amidation using compound (19) and compound (8). The reaction conditions for this step are the same as those for step 8 of this raw material synthesis 1.

[0072] (Raw material synthesis 2) (In the formula, X 3 indicates a halogen, for example, Br. 11 and P 12 These are either identical or distinct from each other, and represent protecting groups for amino groups.

[0073] This manufacturing method involves compound (1), which is the raw material compound for manufacturing method 1, where Y is -Y amide -Y 1 -CO- and Z is Z 2 Z 2 A is a single base selected from the group consisting of the following formulas (IX-A), (XA), (XII-A), (XIII-A), and (XXVII-A), and A Z2 They are the same or different from each other, CR AZ2 or N, R AZ2 is H or C 1-3 It is alkyl, R Z However, H or C 1-3 This is a method for producing compound (30), wherein the alkyl group is an arylene which may be substituted, L is -CO-CH2-, W is a bond, and EUB is of formula (XXIV).

[0074] (Step 1) This step involves compound (21) and R Ar2This step involves a coupling reaction between -H and R under a metal catalyst to obtain compound (22). This reaction involves compound (21) and R Ar2 -H is used in equal amounts or in excess of one in the presence of a metal catalyst and a base, and the mixture is stirred in a reaction-inert solvent under cooling to heating under reflux, preferably at room temperature to 150°C, for usually 0.1 hours to 5 days. The metal catalyst is not particularly limited, but examples include palladium acetate. The base is not particularly limited, but examples include potassium acetate. Examples of solvents used here are not particularly limited, but examples include DMF, DMAc, NMP, and mixtures thereof.

[0075] (Second step) This step involves hydrolyzing the ester of compound (22) to obtain compound (23). The reaction conditions for this step are the same as those for step 7-2 of raw material synthesis 1.

[0076] (Third step) This step involves an amidation reaction between compound (23) and compound (24) to obtain compound (25). The reaction conditions for this step are the same as those for the eighth step of raw material synthesis 1.

[0077] (Step 4) This step is to obtain compound (26) by deprotecting the protecting group of the amino group of compound (25). The reaction conditions for this step are the same as those for production method 1. As an example, P 11 If the amino group is a 2-(trimethylsilyl)ethoxycarbonyl group, this reaction is performed when the amino group is P 11The reaction is carried out by stirring the protected compound and the deprotection reagent in a solvent inert to the reaction, under cooling to heating, preferably from 0°C to 100°C, for 30 minutes to 5 days. Examples of deprotection reagents used here include tetrabutylammonium fluoride, potassium fluoride, and pyridine hydrogen fluoride. The solvent used here is not particularly limited, but THF, DMF, and acetonitrile are used. For reference, see, for example, the following: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th edition, John Wiley & Sons Inc., 2014.

[0078] (Step 5) This step involves the amidation reaction of compound (26) and compound (27) to obtain compound (28). The reaction conditions for this step are the same as those for step 8 of raw material synthesis 1.

[0079] (Step 6) This step involves deprotecting the amino group protecting group of compound (28) to obtain compound (29). The reaction conditions for this step are the same as those for production method 1.

[0080] (Step 7) This step involves obtaining compound (30) by amidation reaction between compound (29) and compound (19). The reaction conditions for this step are the same as those for step 8 of raw material synthesis 1.

[0081] (Raw material synthesis 3) (In the formula, LG represents a leaving group, which in one embodiment is a halogen and in another embodiment is Br. P This represents a protecting group for carboxylic acids, and in one embodiment, C 1-3 It is alkyl.

[0082] This method is another method for producing compound (8) as described in Raw Material Synthesis 1.

[0083] (Step 1) This step is a method for obtaining compound (32) by reacting compound (31) and compound (5). This reaction is carried out by using equal amounts of compound (31) and compound (5), or an excess amount of one, and reacting the mixture in the presence of a base, in a solvent that is inert to the reaction, under cooling to heating under reflux, preferably at 0°C to 80°C, for usually 0.1 hours to 5 days. The solvent used here is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of bases are not limited to organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK, and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. It may be advantageous to carry out the reaction in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride. For references on this reaction, see, for example, the following: The Chemical Society of Japan, ed., "Experimental Chemistry Course," 5th edition, Vol. 14, Maruzen, 2005. In addition, compound (31) can be produced by halogenating a compound in which the part corresponding to LG is a hydroxyl group, thereby producing a compound in which LG is a halogen. Examples of halogenating agents used here are not limited to organic bases such as thionyl chloride, phosphorus oxychloride, hydrobromic acid, and phosphorus tribromide. Furthermore, the corresponding compound in which LG is Br can also be produced by the reaction of carbon tetrabromide and triphenylphosphine with a compound having a hydroxyl group. For references on this reaction, see, for example, the following.The Chemical Society of Japan (ed.), "Experimental Chemistry Course," 5th edition, Vol. 13, Maruzen, 2004. Angewandte Chemie International Edition in English 14 (12): 801-811. European Journal of Medicinal Chemistry (2020), 203, 112579. Furthermore, compound (31) can be produced by sulfonyling a compound in which the part corresponding to LG is a hydroxyl group in the presence of a base, thereby producing a compound in which LG is a sulfonyloxy group. Examples of sulfonyling reagents used here are not particularly limited, but include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, etc. Examples of bases are not particularly limited, but include TEA, DIPEA, pyridine, tetramethylethylenediamine, etc. For references to this reaction, see, for example, Synthesis 1999, 9, p.1633-1636.

[0084] Furthermore, compound (32) can also be synthesized from compound (31) by going through the second and third steps. (Second step) This step is a method for carrying out the alkylation reaction between compound (31) and compound (33). The reaction conditions are the same as those of the fourth step in raw material synthesis 1.

[0085] (Third Step) This step involves reacting the alkylated compound obtained in the second step with compound (34) to obtain compound (32), which is an alkyne. In this reaction, equal amounts or an excess amount of the corresponding alkylated compound and compound (34) are used, and the mixture is stirred in a reaction-inert solvent, in the presence of a base, under cooling to heating under reflux, preferably at 0°C to room temperature, for usually 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include alcohols such as methanol. Examples of bases used here are not particularly limited, but include potassium carbonate. For references on this reaction, see, for example, Synth., Commun. 1989, 19, p. 561.

[0086] (Fourth step) This step is to obtain compound (36) by an azide reaction of compound (35). The reaction conditions for this step are the same as those for the first step of raw material synthesis 1.

[0087] (Step 5) This step is to obtain compound (37) by a cyclization reaction between compound (36) and compound (32). The reaction conditions for this step are the same as those for step 3 of raw material synthesis 1.

[0088] (Step 6) This step involves hydrolyzing compound (37) under basic conditions, R P This is a method for producing carboxylic acid compounds, which are deprotected products of [component name]. The reaction is carried out by stirring compound (37) under cooling, then under heating and reflux, usually for 0.1 hours to 5 days. Examples of solvents used are not particularly limited, but include alcohols, acetone, DMF, and THF. In some cases, a mixed solvent of the above solvents with water may be preferable for the reaction. Examples of hydrolysis reagents are not particularly limited, but include lithium hydroxide monohydrate, lithium hydroxide aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, etc. For references regarding this reaction, see, for example, the following: "Experimental Chemistry Course (5th Edition)," Vol. 16 (2005), edited by The Chemical Society of Japan (Maruzen). Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0089] (Step 7) This step is a method for producing a corresponding amide compound by an amidation reaction between the corresponding carboxylic acid compound and compound (38). The reaction conditions for this step are the same as those for step 8 of raw material synthesis 1.

[0090] (Step 8) This step is a method for producing compound (8) by a deprotection reaction of the corresponding amide compound. The reaction conditions for this step are the same as those for production method 1.

[0091] (Raw material synthesis 4) (In the formula, L 2 is C 1-8 It is alkylene, Z 2 This represents the group shown in raw material synthesis 2, with formula (IX-A), and P1X (This indicates a protecting group for the amino group.)

[0092] This method is a method for producing compound (8-1), in which the L portion differs from compound (8) described in raw material synthesis 1, and it can undergo an amidation reaction with compound (19).

[0093] (First step) This step involves obtaining compound (40) through a cyclization reaction between compound (4) and compound (39). The reaction conditions for this step are the same as those for the third step of raw material synthesis 1.

[0094] (Second Step) This step involves the oxidation of the hydroxyl group of compound (40) to obtain the corresponding aldehyde compound. This reaction is carried out using equal or excess equivalents of compound (40) and an oxidizing agent in a solvent that is inert to the reaction, and stirring is performed under ice cooling or at room temperature, usually for 1 hour to 5 days. An example of an oxidizing agent used here is dess-martin periodinane. As for the solvent, there are no particular limitations, but aromatic hydrocarbons such as benzene and halogenated hydrocarbons such as dichloromethane can be used.

[0095] (Third Step) This step involves obtaining the corresponding amine compound by a reductive amination reaction between the corresponding aldehyde compound and compound (41). This reaction is carried out by stirring the aldehyde compound and compound (41) in equal or excess equivalent amounts, in a solvent inert to the reaction, under ice cooling or at room temperature, in the presence of a reducing agent and acetic acid, for typically 1 hour to 5 days. Examples of reducing agents used here are not particularly limited, but include NaBH(OAc)3, 2-picolinborane, NaBH3CN, etc. The solvent used here is not particularly limited, but halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as THF, diethyl ether, and dioxane, alcohol solvents such as MeOH and EtOH, or MeCN, etc. The addition of an acid such as acetic acid may accelerate the reaction and may be suitable for the reaction.

[0096] (Step 4) This step involves protecting the hydroxyl group P of the amine compound obtained in Step 3. 2and the protecting group P of amines 1X This step involves deprotecting the compound to obtain compound (8-1). The reaction conditions for this step are the same as those for step 5 of raw material synthesis 1.

[0097] The compound of formula (I) can be isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorph. Salts of the compound of formula (I) can also be produced by conventional salt-forming reactions. Isolation and purification are carried out by applying normal chemical operations such as extraction, fractional crystallization, and various fractional chromatography methods. Various isomers can be produced by selecting appropriate starting compounds, or by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods for racemates (e.g., fractional crystallization leading to diastereomer salts with optically active bases or acids, or chromatography using chiral columns, etc.), or they can be produced from appropriate optically active starting compounds.

[0098] The pharmacological activity of the compound of the present invention can be confirmed by the following tests.

[0099] Test Example 1: Evaluation of the inhibitory effect of SHP2 protein on the reaction system. The inhibitory activity of human SHP2 protein on the reaction system was measured. A dilution series of the test compound was prepared as a DMSO solution 300 times the final concentration, and 20 nL each was added to a 384-well black plate (784076; Greiner) using a microdispenser (Echo; Beckman Coulter). Using an assay buffer containing 50 mM HEPES (15630-080; Gibco), 100 mM NaCl (31334-51; Nacalai), 1 mM DTT (049-08973; Fujifilm Wako Pure Chemical Industries), and 0.01% Tween-20 (161-0781; BioRad), a mixed solution of 0.3 nM SHP2 (1894-SH; R&D Systems) and 0.25 nM SHP-2 Activating Peptide (79319-1; BPS Bioscience) was prepared. 3 μL of this mixture was added to each 384-well plate containing the test compound and incubated at room temperature for 30 minutes. A 40 μM SHP2 Substrate DiFMUP (D6567; Invitrogen) solution was prepared using the assay buffer and 3 μL was added to each 384-well plate containing the test compound and enzyme. After incubation at room temperature for 30 minutes, fluorescence intensity at excitation wavelength 360 nm and fluorescence wavelength 460 nm was measured using an EnVision™ plate reader (Revvity). The inhibition rate (%) was calculated using the following formula, and 4-parameter logistic regression analysis was performed using XLFit (IDBS) to determine the 50% enzyme inhibition value (IC2). 50 The following table shows the results for the test compound and the comparative compound SHP099 (described in Journal of Medicinal Chemistry. 2016, 59 (17), 7773-7782), as the average of independent studies.

[0100]

[0101]

[0102]

[0103] Test Example 2: Evaluation of SHP2 Proteolytic Effect The SHP2 proteolytic effect of the test compound was evaluated by measuring the SHP2 protein expression level using In-Cell Western blotting. Human G12D mutant KRAS-positive pancreatic cancer cell line KP-4 cells (JCRB0182; JCRB cell bank) were used at a rate of 4.5 x 10⁶ cells per well. 3To develop into cells, 36 μL of cells were seeded into each well of a 384-well plate (356667; Corning). Cell culture conditions were followed using DMEM (high glucose; Fujifilm Wako Pure Chemical Industries) medium containing 10% fetal bovine serum (biosera) at 37°C in the presence of 5% CO2. The following day, a dilution series of the test compound and a negative control were prepared, and DMSO (Fujifilm Wako Pure Chemical Industries), the solvent of the test compound, were diluted 100-fold with fresh medium and added to each well in 4 μL (10 final concentrations of the test compound were prepared ranging from 1 μM to 0.03 nM). After overnight incubation, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde phosphate buffer (Fujifilm Wako Pure Chemical Industries) was added to each well. The cells were then fixed by standing at room temperature for 30 minutes. Subsequently, the supernatant was removed, and 20 μL of Phosphate buffer saline (PBS; Fujifilm Wako Pure Chemical Industries, Ltd.) containing 0.1% Triton X-100 (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed, and 20 μL of PBS containing 0.1% Triton X-100 was added again to each well. After standing at room temperature for 10 minutes, the supernatant was removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Nippon Gene Co., Ltd.) was added to each well. After standing at room temperature for 30 minutes, the supernatant was removed by centrifugation (using a centrifugal dehydrator; the same procedure was followed for subsequent supernatant removals), and 20 μL of blocking solution (Intercept Blocking Buffer; LI-COR Biosciences) was added to each well. After standing at room temperature for 60 minutes, the supernatant was removed, and 20 μL each of a mixed solution of rabbit anti-SHP2 antibody (ab32083; Abcam) and mouse anti-β-Actin antibody (ab8226; Abcam), diluted 200-fold and 1000-fold respectively with blocking solution, was added to each well as the primary antibody. After standing overnight at 4°C, the supernatant was removed, and a washing procedure was performed a total of three times, adding 20 μL each of PBS containing 0.05% Tween (Fujifilm Wako Pure Chemical Industries, Ltd.) to each well.After removing the supernatant, a mixed solution of Alexa Fluor 594-labeled anti-rabbit IgG antibody (A11037; Invitrogen) and Alexa Fluor 488-labeled anti-mouse IgG antibody (A11029; Invitrogen), diluted 1000-fold with blocking solution, was added to each well as a secondary antibody in 20 μL portions. After standing at room temperature for 60 minutes in the dark, the supernatant was removed, and the mixture was washed three times with PBS containing 0.05% Tween (Fujifilm Wako Pure Chemical Industries). The mixture was air-dried in a fume hood for at least one hour, and the fluorescence signal was measured using two channels of Cytation 5 (Agilent): GFP (excitation: 469 / 35 nm, emission: 525 / 39 nm) and Texas Red (excitation: 586 / 15 nm, emission: 647 / 57 nm). After correcting the signal value of the SHP2 protein measured with Texas Red with the signal value of β-Actin measured with GFP, the signal value with DMSO added was set to 100%, and a 4-parameter logistic regression analysis was performed using Prism 8 (GraphPad Software) to determine the 50% decomposition value of the SHP2 protein (DC). 50 The following table shows the results for the test compound and the comparative compound SHP2-D26 (Journal of Medicinal Chemistry 2020, 63, 7510: described in Non-Patent Document 1 above), as the average of independent studies.

[0104]

[0105]

[0106] Test Example 3: Evaluation of Proliferation Inhibitory Effect on KP-4 Cells The cell proliferation inhibitory effect of the test compound was evaluated under three-dimensional culture conditions. 5.0 x 10⁶ KP-4 cells were cultured per well. 2To develop into cells, 36 μL of cells were seeded into each well of a low-adsorption U-bottom 384-well plate (PrimeSurface; Sumitomo Bakelite). Cell culture conditions were maintained at 37°C in the presence of 5% CO2 using DMEM (high glucose; Fujifilm Wako Pure Chemical Industries) medium containing 10% fetal bovine serum (biosera). The following day, a dilution series of the test compound and DMSO, the solvent of the test compound, were diluted 100-fold in fresh medium and added to each well as a negative control (12 samples were prepared with final concentrations of the test compound ranging from 10 μM to 0.03 nM). After 6 days of culture, 40 μL of CellTiter-Glo Luminescent Cell Viability Assay (G7571; Promega) was added to each well. After shaking and mixing at room temperature for 10 minutes, the luminescence signal was measured using an EnSight multimode plate reader (PerkinElmer). The signal value in DMSO treatment was set to 100%, and 4-parameter logistic regression analysis was performed using Prism 8 (GraphPad Software). The 50% growth inhibition value (IC) was then defined. 50 The following calculations were performed. The results for the test compound and the control compound SHP2-D26 are shown in the table below as the average of independent studies.

[0107]

[0108]

[0109] Test Example 4: SHP2 Proteolytic Effect in KP-4 Cell Tumor-Bearing Mice The SHP2 proteolytic effect of the test compound was evaluated using KP-4 tumor-bearing mice. KP-4 cells were cultured at 37°C in the presence of 5% CO2 in DMEM (high glucose; Fujifilm Wako Pure Chemical Industries) medium containing 10% fetal bovine serum (biosera). The cells were harvested, and a cell suspension adjusted to approximately 5 x 10⁷ cells / mL with basement membrane extract (R&D Systems) was implanted subcutaneously into 7-week-old female nude mice (balb / c Slc nu / nu; SLC Japan) in a volume of 100 μL. Two to three weeks after planting, the test compound was dissolved in 10% DMSO (Fujifilm Wako Pure Chemical Industries), 10% Cremophor EL (Sigma), 20% PEG400 (Fujifilm Wako Pure Chemical Industries), and 60% H2O (Otsuka Pharmaceutical Co., Ltd.), and administered intraperitoneally at a dose of 10 or 30 mg / kg of body weight. One or seven days after administration of the test compound, the tumors were excised and cryopreserved at -80°C. 10 to 20 mg of tumor tissue was homogenized with a cell lysis reagent (C3228; Sigma) containing a phosphatase inhibitor (P5726; Sigma) and a protease inhibitor (04693132001; Roche), and the supernatant (lysate) was collected by centrifugation. The protein content of the lysates was quantified using the BCA Protein Assay Reagen kit (Pierce), and the protein concentration of each sample was adjusted to 0.5 mg / mL using sample buffer for SDS-PAGE (196-16142; Fujifilm Wako Pure Chemical Industries). 5 μL of each sample was added to an SDS-PAGE (Perfect NT Gel; DRC) and electrophoresis was performed at 300 V for 40 minutes. The gel was then placed on a membrane (iBlot 2; Invitrogen) and transferred at 20 V for 6 minutes and 50 seconds. The membrane was washed with 0.05% Tween-containing Tris Buffered Saline (TBS; Takara), reacted in blocking solution (NYPBR01; TOYOBO) at room temperature for 1 hour, and washed three times for 5 minutes each with 0.05% Tween-containing TBS.As primary antibodies, rabbit anti-SHP2 antibody (ab32083; Abcam) and rabbit anti-β-Actin antibody (A2066; Sigma) were reacted overnight at 4°C in solutions diluted 6000-fold and 1000-fold respectively with primary antibody dilution buffer (Can Get Signal Solution 1: TOYOBO). After washing three times for 5 minutes with 0.05% Tween-containing TBS, HRP-labeled anti-rabbit IgG antibody (NA934; Cytiva) was reacted for 1 hour at room temperature in a solution diluted 3000-fold with secondary antibody dilution buffer (Can Get Signal Solution 2: TOYOBO). After washing three times for 5 minutes with 0.05% Tween-containing TBS, the bands were induced using detection reagent (ECL Prime; Cytiva) and measured with Image Quant 800 (Cytiva). Subsequently, the signal intensity of the SHP2 protein and actin bands was quantified, and the SHP2 protein / actin ratio was calculated. The SHP2 protein / actin ratio in mouse tumors administered 0 mg / kg at each time point was set to 1, and the SHP2 protein / actin ratio (average value for 3 subjects in each group) after administration of the test compound is shown in the table below.

[0110] Test Example 5: Evaluation of Antitumor Effect in KP-4 Cell Tumor-Bearing Mice The antitumor effect of the test compound was evaluated using KP-4 tumor-bearing mice. KP-4 cells were cultured at 37°C in the presence of 5% CO2 in DMEM (high glucose; Fujifilm Wako Pure Chemical Industries) medium containing 10% fetal bovine serum (biosera). The cells were harvested and sterilized in basement membrane extract (R&D Systems) for approximately 5 x 10⁶ cells. 7Cell suspensions adjusted to a concentration of cells / mL were implanted subcutaneously in 100 μL volumes into 7-week-old female nude mice (balb / c Slc nu / nu; SLC Japan). Two to three weeks after implantation, the mice were divided into groups so that tumor volume and body weight were approximately equal, and administration of the test compound was started the following day. The study was conducted with 5 mice each in the solvent group and the test compound administration group. The test compound was dissolved in 10% DMSO (Fujifilm Wako Pure Chemical Industries), 10% Cremophor EL (Sigma), 20% PEG400 (Fujifilm Wako Pure Chemical Industries), and 60% H2O (Otsuka Pharmaceutical Co., Ltd.), and administered subcutaneously twice a week at a dose of 0.30 mg / kg of body weight. In another experiment, KP-4 cells were cultured at 37°C in the presence of 5% CO2 using RPMI-1640 (22400-089, Gibco) medium containing 10% fetal bovine serum (ExCell Bio). The cells were harvested and treated with a 1:1 mixture of DPBS (HDB) and BD Matrigel (Corning, 356234) for approximately 1 x 10⁶ cells. 7 Cell suspensions prepared at a concentration of cells / 0.2 mL were implanted subcutaneously into 200 μL of 7-week-old female nude mice (BALB / c Nude; Vital River Laboratory Animal). The mice were randomly divided into groups, and the average tumor volume was 150 mm². 3 From the point at which the patient reached a certain level, the test compound was dissolved in 8% Ethanol (Greagent), 2.2% 1N HCl (Sigma), 51.8% glucose solution (5%, SHENG AO), 2% HP-βCD solution (45%, Aladdin), 18% Cremophor EL (MCE), and 18% 0.1 N NAOH (Sigma), and administered intravenously at a dose of 15 mg / kg of body weight. Tumor diameter and body weight were measured twice a week. The following formula was used to calculate tumor volume: [Tumor volume (mm²)] 3 )] = [Longest diameter of tumor (mm)] x [Shortest diameter of tumor (mm)] 2The tumor growth inhibition rate (%) by the test compound was calculated based on the tumor volume on day 14 (the day before administration began) and day 28 after tumor cell transplantation, according to the following formula: Tumor growth inhibition rate (%) = {(Average increase in tumor volume in the solvent administration group) - (Increase in tumor volume in the drug administration group)} / (Average increase in tumor volume in the solvent administration group) × 100 The antitumor effect of the test compound is shown in the table below. Table 5-1 shows the test results for subcutaneous administration, and Table 5-2 shows the test results for intravenous administration.

[0111]

[0112]

[0113] The results of the above tests confirmed that the compound of the present invention has an enzymatic activity inhibitory effect on the SHP2 protein in vitro, thus binding to the SHP2 protein, has an SHP2 proteolytic effect, has an inhibitory effect on the proliferation of KP-4 cells, and has an SHP2 proteolytic effect and antitumor effect in KP-4 cell tumor-bearing mice. Therefore, the compound of the present invention can be used for the treatment of cancer, particularly cancers in which the SHP2 protein is expressed.

[0114] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers. Administration may be by oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or by parenteral administration in the form of intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0115] For oral administration, solid compositions such as tablets, powders, and granules are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a gastric-soluble or enteric-soluble film as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, or elixirs, and generally contain inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain auxiliary agents such as solubilizers, wetting agents, and suspensions, as well as sweeteners, flavoring agents, fragrances, and preservatives.

[0116] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These are sterilized, for example, by filtration through a bacterial retention filter, formulation with a bactericide, or irradiation. Alternatively, sterile solid compositions may be prepared and dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0117] For oral administration, the appropriate daily dose is approximately 0.001 to 100 mg / kg per body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered in one dose or divided into two to four doses. For intravenous administration, the appropriate daily dose is approximately 0.0001 to 50 mg / kg per body weight, administered in one to several doses per day. The dosage should be determined appropriately on an individual basis, taking into account symptoms, age, sex, etc.

[0118] Depending on the route of administration, dosage form, site of administration, and type of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in some embodiments, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof that are active ingredients.

[0119] Compounds of formula (I) or salts thereof can be used in combination with various therapeutic or prophylactic agents for diseases in which these compounds are considered effective. Such combination may be administered simultaneously, separately and consecutively, or at desired time intervals. The simultaneously administered formulation may be a combination formulation or formulated separately.

[0120] The method for producing the compounds of the present invention will be described in more detail below based on the examples. However, the present invention is not limited to the compounds described in the following examples. Furthermore, the method for producing the raw material compounds is shown as a production example, and the production of known compounds is shown as a reference example. Moreover, the method for producing the compounds of the present invention is not limited to the production methods of the specific examples shown below; the compounds of the present invention can also be produced by combinations of these production methods or by methods obvious to those skilled in the art.

[0121] Furthermore, the following abbreviations may be used in the examples, manufacturing examples, and the tables below.

[0122] PEx: Production example number, Ex: Example number, PSyn: Production example number produced by the same method, Syn: Example number produced by the same method (for example, Syn 1 indicates production by the same method as Example 1), Str: Chemical structural formula, n AcOH: Acetate (however, the salt coefficient is undetermined), n HCO2H: Formate (however, the salt coefficient is undetermined), n HCl: Hydrochloride (however, the salt coefficient is undetermined), HCl: Monohydrochloride, DAT: Physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] unless otherwise specified) + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [MH]) - ), NMR1: In DMSO-d6 at room temperature 1δ value (ppm) of the peak in 1H-NMR (300 MHz or 400 MHz), NMR2: in CDCl3 at room temperature. 1 δ value (ppm) of the peak in H-NMR (300 MHz or 400 MHz), NMR3: CD3OD, at room temperature. 1 The delta value (ppm) of the peak in 1H-NMR (300 MHz or 400 MHz) is given by: s: single line (spectrum), d: double line (spectrum), dd: double double line (spectrum), ddd: double double double line (spectrum), t: triple line (spectrum), dt: double triple line (spectrum), q: quadruple line (spectrum), m: multiline (spectrum), br: broadline (spectrum).

[0123] Furthermore, for convenience, concentration is expressed as M in mol / l. For example, a 1M sodium hydroxide solution means a 1 mol / l sodium hydroxide solution, and a 10 mM ammonium bicarbonate solution means a 10 mmol / l ammonium bicarbonate solution.

[0124] Furthermore, even if it is indicated that the compound was prepared by the same method as in PSyn or Syn, the resulting compound may differ in form from that shown in PSyn or Syn due to the acid or base contained in the developing solvent used in the preparative HPLC during the purification of the compound.

[0125] Preparation Example 1: To a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (18.8 g) in DMF (180 mL), tert-butyl(4-methylpiperidine-4-yl)carbamate (17.2 g) and DIPEA (17.3 g) were added, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was ground in MTBE at 25°C for 1 hour, collected by filtration, and tert-butyl[1-(3-iodo-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-methylpiperidine-4-yl]carbamate (27.5 g) was obtained as a solid.

[0126] Preparation Example 2 A mixed solution of tert-butyl[1-(3-iodo-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-methylpiperidine-4-yl]carbamate (3.70 g), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.46 g), tripotassium phosphate (5.14 g), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (571 mg) in dioxane (80.0 mL) and water (20.0 mL) was degassed, purged with nitrogen, and stirred at 90°C for 16 hours under a nitrogen atmosphere. This procedure was repeated two more times, the reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM), and the resulting crude product was ground in MTBE at 25°C for 1 hour, then collected by filtration to obtain tert-butyl{1-[3-(4-amino-2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (10.8 g) as a solid.

[0127] Preparation Example 3 A mixture of tert-butyl{1-[3-(4-amino-2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (5.00 g) and DMA (50 ml) was mixed with methylmalonyl chloride (1.41 mL) at room temperature and stirred for 1 hour at room temperature. Water and ethyl acetate were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. A mixture of the resulting residue, THF (150 ml), MeOH (100 ml), and water (50 ml) was mixed with lithium hydroxide monohydrate (2.29 g) at room temperature and stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and then acidified with 1 M hydrochloric acid at 0°C. The precipitate was collected by filtration and washed with water to obtain 3-[4-(6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1H-pyrazolo[3,4-b]pyrazine-3-yl)-3-chloroanilino]-3-oxopropanoic acid (3.67 g) as a solid.

[0128] Preparation Example 4: A mixture of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (10.0 g), 3,4-dihydro-2H-pyran (9.00 g), and THF (200 ml) was mixed with p-toluenesulfonic acid monohydrate (678 mg) at room temperature, and the mixture was stirred overnight at room temperature. Triethylamine (2.48 mL) was added to the reaction mixture at room temperature, and the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and THF was further added until the precipitate dissolved, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with IPE to obtain 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (9.30 g) as a solid.

[0129] Preparation Example 5 A mixture of 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (5.00 g), tert-butyl(4-methylpiperidine-4-yl)carbamate (2.94 g), and DMSO (25 ml) was mixed with DIPEA (3.58 mL) at room temperature and stirred at 80°C for 2 hours. Ethyl acetate and water were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was solidified in ethyl acetate / hexane, and the resulting solid was collected by filtration and washed with ethyl acetate / hexane to obtain a solid. The same procedure was repeated to obtain tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (6.46 g) as a solid.

[0130] Preparation Example 6: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (5.49 g), (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (3.00 g), sodium carbonate (3.22 g), DME (100 mL), and water (25 mL) was prepared at room temperature. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (827 mg) was added to the mixture. The mixture was degassed by repeated reduction in pressure and purging with nitrogen gas, and then stirred overnight at 80°C under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain a solid. The obtained solid was mixed with water (20 ml), MeOH (40 ml), and THF (60 ml) to which lithium hydroxide monohydrate (1.63 g) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was pulverized in ethyl acetate / hexane, collected by filtration, washed with ethyl acetate / hexane, and 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoic acid (2.54 g) was obtained as a solid.

[0131] Preparation Example 7: 2.54 g of 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoic acid, 838 mg of glycine methyl hydrochloride, 2.32 mL of DIPEA, and 50 mL of DMF were added to a mixture. The mixture was then stirred overnight at room temperature. Ethyl acetate and water were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain a solid. 560 mg of lithium hydroxide monohydrate was added to the obtained solid, a mixture of water (20 mL), MeOH (40 mL), and THF (60 mL) at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was ground in ethyl acetate / hexane, collected by filtration, washed with ethyl acetate / hexane, and yielded N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycine (1.58 g) as a solid.

[0132] Preparation Example 8: 5.00 g of L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride, 7.46 mL of triethylamine, and a mixture of 50 ml of THF and 50 ml of MeCN were added dropwise at 0°C to a mixture of 3.36 g of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate and 7 ml of MeCN. The mixture was stirred at 0°C for 1 hour. Water and ethyl acetate were added to the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with saturated ammonium chloride aqueous solution and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue and a mixture of 1.09 g of imidazole and 50 ml of DMF, 2.42 g of tert-butyldimethylchlorosilane was added at room temperature, and the mixture was stirred overnight at room temperature. Imidazole (728 mg) and tert-butyldimethylchlorosilane (1.61 g) were added, and the mixture was stirred at room temperature for 8 hours. Water and ethyl acetate were added to the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with saturated ammonium chloride aqueous solution and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-{[tert-butyldi(methyl)silyl]oxy}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (4.23 g) as a solid.

[0133] Preparation Example 9: A mixture of 4-((trimethylsilyl)ethynyl)phenol (0.95 g) and THF (5.0 mL) was mixed with 1 M TBAF / THF solution (5.5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue, (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-{[tert-butyldi(methyl)silyl]oxy}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (0.810 g), sodium L-ascorbate (422 mg), THF (14.2 mL), and water (14.2 mL) were mixed with copper(II) sulfate (67.9 mg) at room temperature, and the mixture was stirred at room temperature for 1 day. After adding aqueous ammonia and saturated brine to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(4-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (759.2 mg) as a solid.

[0134] Preparation Example 10: (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(4-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (1.50 g), tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylic acid (621 mg), toluene (21.8 mL), and THF (21.8 mL) were mixed at room temperature. 1,1'-(azodicarbonyl)dipiperidine (2.20 g) and tributylphosphine (2.69 mL) were then added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. The reaction mixture was concentrated under reduced pressure, and IPE was added to the residue. After removing insoluble matter by filtration, the residue was washed with IPE, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate), and further purified by NH-silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate) to obtain a solid. To the obtained solid, 2M hydrochloric acid / EtOH (8 mL) and 4M hydrochloric acid / ethyl acetate (8 mL) were added at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, then acetonitrile was added, and the mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (MeCN / 10 mM ammonium bicarbonate aqueous solution), and the fraction containing the target product was concentrated under reduced pressure. Toluene and MeOH were added to the resulting solid, and the solution was concentrated under reduced pressure to obtain (4R)-4-hydroxy-1-{(2S)-3-methyl-2-[4-(4-{2-[(piperidine-4-yl)oxy]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]butanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (777 mg) as a solid.

[0135] Preparation Example 11: (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(4-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (2.00 g), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylic acid (780 mg), toluene (29.0 mL), and THF (29.0 mL) were mixed at room temperature. 1,1'-(azodicarbonyl)dipiperidine (2.93 g) and tributylphosphine (3.58 mL) were then added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. After concentrating the reaction mixture under reduced pressure, IPE was added to the residue, and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate), followed by NH-silica gel column chromatography (ethyl acetate / hexane) to obtain an oily substance. The obtained oily substance was further purified by silica gel column chromatography (ethyl acetate / hexane) to obtain a solid. 2M hydrochloric acid / EtOH (5 mL) and 4M hydrochloric acid / ethyl acetate (5 mL) were added to the obtained solid at room temperature, and the mixture was stirred for 30 minutes at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was purified by ODS column chromatography (MeCN / 10 mM ammonium bicarbonate aqueous solution), and the fraction containing the target product was freeze-dried to obtain (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-{4-[3-(piperazin-1-yl)propoxy]phenyl}-1H-1,2,3-triazole-1-yl)butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (616.6 mg) as a solid.

[0136] Preparation Example 12: (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(4-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (1.37 g), 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl (919 mg), tributylphosphine (2.00 mL), and a mixture of THF (20 mL) and toluene (20 mL) were added at room temperature. The mixture was then stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated under reduced pressure, and IPE was added to the residue. Insoluble matter was removed by filtration, and the residue was washed with IPE. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate), followed by NH-silica gel column chromatography (ethyl acetate / hexane) to obtain an oily substance. To the obtained oily substance, 15 mL of 2 M hydrochloric acid / EtOH and 15 mL of 4 M hydrochloric acid / ethyl acetate were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After adding EtOH (70 mL) to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (MeCN / 10 mM ammonium bicarbonate aqueous solution). The fraction containing the target product was freeze-dried to obtain (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-1,2,3-triazole-1-yl)butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (1.07 g) as a solid.

[0137] Preparation Example 13: (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-{[tert-butyldi(methyl)silyl]oxy}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (5.00 g), 3-ethynylphenol (1.55 g), sodium L-ascorbate (2.60 g), THF (87.6 mL), and water (87.6 mL) were mixed with copper(II) sulfate (419 mg) at room temperature, and the mixture was stirred at room temperature for 18 hours. After adding aqueous ammonia and saturated brine to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through a silica gel short column (MeOH / ethyl acetate), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, then methanol / ethyl acetate) to obtain (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(3-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (5.76 g) as a solid.

[0138] Preparation Example 14: A mixture of (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(3-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (405.5 mg), 4-(2-hydroxyethoxy)piperidine-1-carboxylic acid tert-butyl (173.3 mg), and THF (10 ml) was mixed with 1,1'-(azodicarbonyl)dipiperidine (445.5 mg) and tributylphosphine (436 μL). The mixture was then stirred at 25°C for 10 hours under a nitrogen atmosphere. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate / hexane, then methanol / ethyl acetate). 2M hydrochloric acid / EtOH (5.5 ml) and 4M hydrochloric acid / ethyl acetate (5.5 ml) were added to the purified product, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by NH-silica gel column chromatography (methanol / ethyl acetate) to obtain (4R)-4-hydroxy-1-{(2S)-3-methyl-2-[4-(3-{2-[(piperidine-4-yl)oxy]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]butanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (229.0 mg) as a solid.

[0139] Preparation Example 15: A mixture of (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-{(2S)-2-[4-(3-hydroxyphenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (400.0 mg), 4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl (199.7 mg), 1,1'-(azodicarbonyl)dipiperidine (439.5 mg), and THF (10 ml) was mixed with tributylphosphine (430 μL) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and IPE was added to the residue. Insoluble matter was removed by filtration, and the residue was washed with IPE. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate) to obtain an oily substance. To the obtained oily substance, 2 mL of 2 M hydrochloric acid / EtOH and 2 mL of 4 M hydrochloric acid / ethyl acetate were added at room temperature, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and then MeCN was added and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: L-column 2 ODS, mobile phase: MeCN / 10 mM ammonium bicarbonate aqueous solution), and the fraction containing the target product was freeze-dried to obtain (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-{3-[2-(piperidine-4-yl)ethoxy]phenyl}-1H-1,2,3-triazole-1-yl)butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (82.2 mg) as a solid.

[0140] Preparation Example 16 A mixture of tert-butyl(1-(3-(4-amino-2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-methylpiperidine-4-yl)carbamate (5.00 g) and DMA (10 ml) was mixed with 2-chloro-2-oxoethyl acetate (1.34 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. A mixture of the obtained oily substance, THF (120 ml), MeOH (80 ml), and water (40 ml) was mixed with lithium hydroxide monohydrate (2.29 g) at room temperature, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, MeOH / ethyl acetate) to obtain [4-(6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1H-pyrazolo[3,4-b]pyrazine-3-yl)-3-chloroanilino](oxo)acetic acid (5.33 g) as a solid.

[0141] Preparation Example 17: Potassium carbonate (2.18 g) was added to a mixture of 4-[(trimethylsilyl)ethynyl]phenol (1.5 g) and DMF (20 mL), and the mixture was stirred at 25°C for 0.5 hours. Then, a solution of 4-(2-bromoethyl)piperazine-1-carboxylate tert-butyl (2.08 g) in DMF (5 mL) was added, and the mixture was stirred at 50°C for 12 hours. The reaction mixture was diluted with saturated brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[2-(4-ethynylphenoxy)ethyl]piperazine-1-carboxylate tert-butyl (1.3 g) as an oil.

[0142] Preparation Example 18: (tert-butoxycarbonyl)-L-valine (25 g) was dissolved in DMF (250 mL) and (4R)-4-hydroxy-L-proline methyl hydrochloride (25.1 g), HOBt (31.1 g), EDCI·HCl (44.1 g), and DIPEA (80.2 mL) were added. The mixture was then stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated saline, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance (37 g). The obtained oily substance (7 g) was dissolved in dioxane (20 mL) and 2M hydrochloric acid / dioxane (20.3 mL) was added. The mixture was then stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain an oily substance (5 g). The resulting oily substance (4.5 g) and 1H-imidazole-1-sulfonyl azide (3.33 g) were dissolved in MeOH (50 mL), to which potassium carbonate (4.43 g) and copper(II) sulfate pentahydrate (400.2 mg) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM. The aqueous layer was adjusted to pH=3 with 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the oily substance (3.7 g). The obtained oily substance (800.0 mg) was mixed with 4-[2-(4-ethynylphenoxy)ethyl]piperazine-1-carboxylate tert-butyl (0.8 g) in THF (5 mL) and t-BuOH (2 mL). Copper(II) sulfate pentahydrate (604.5 mg) and sodium L-ascorbate (1.44 g) in water (2 mL) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with saturated saline solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance. Lithium hydroxide monohydrate (230.5 mg) was added to a mixed solution of the obtained oily substance in MeOH (5 mL) and water (1 mL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM. The aqueous layer was adjusted to pH = 3 with 1M hydrochloric acid, and then extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R)-1-{(2S)-2-[4-(4-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}4-hydroxy-L-proline (1 g) as a solid.

[0143] Preparation Example 19 A mixture of tert-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate (0.5 g) and dioxane (3 mL) was mixed with tributyl(1-ethoxyvinyl) stannan (661.7 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (121.9 mg) under a nitrogen atmosphere at 25°C, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to 25°C, 1 M hydrochloric acid was added, and the mixture was stirred for 30 minutes, after which it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid. The resulting solid was mixed with 6 mL of 2 M hydrochloric acid / 1,4-dioxane and stirred at 25°C for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain 230 mg of 1-{4-[(1S)-1-aminoethyl]phenyl}ethane-1-one hydrochloride as a solid.

[0144] Preparation Example 20: To a solution of (4R)-1-{(2S)-2-[4-(4-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-L-proline (1 g) in DMF (15 mL), HOBt (460.6 mg), EDCI・HCl (653.5 mg), 1-{4-[(1S)-1-aminoethyl]phenyl}ethane-1-one hydrochloride (408.4 mg) and DIPEA (1.48 mL) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with saturated saline and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance. To the resulting oily solution of dioxane (5 mL), 2 M hydrochloric acid / dioxane (10 mL) was added and the mixture was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the residue was purified by preparative HPLC (column: Phenomenex Genimi NX C18, mobile phase: MeCN / 0.2% formic acid aqueous solution), and the fraction containing the target product was freeze-dried to obtain (4R)-N-[(1S)-1-(4-acetylphenyl)ethyl]-4-hydroxy-1-[(2S)-3-methyl-2-(4-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-1,2,3-triazole-1-yl)butanoyl]-L-prolineamide n-formate (170 mg) as a solid.

[0145] Preparation Example 21 3-(4-bromophenyl)propan-1-ol (1.01 g), ethynyltrimethylsilane (2.0 mL), DIPEA (821 μL), CuI (89.8 mg), and a mixture of TEA (9.43 mL) were mixed with bis(triphenylphosphine)palladium(II) dichloride (165 mg) at room temperature. After degassing by repeated reduction of pressure and nitrogen purging, the mixture was stirred at 80°C for 18 hours. Ethyl acetate was added to the reaction mixture, insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain an oily substance (986 mg). Potassium carbonate (258 mg) was added to a mixture of the obtained oily substance (217 mg) and MeOH (4.67 mL) at room temperature and the mixture was stirred at room temperature for 1.5 hours. Saturated brine was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue, a mixture of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-{[tert-butyldi(methyl)silyl]oxy}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (180 mg), sodium L-ascorbate (93.7 mg), and THF (3.15 mL) was mixed with copper(II) sulfate (15.1 mg) at room temperature, and the mixture was stirred at room temperature for 2.5 hours. After adding aqueous ammonia solution and saturated brine to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate / hexane) to obtain (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-[(2S)-2-{4-[4-(3-hydroxypropyl)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-N-{(1S)-1-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (154 mg) as a solid.

[0146] Preparation Example 22: A mixture of (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-[(2S)-2-{4-[4-(3-hydroxypropyl)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-N-{(1S)-1-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (714.5 mg), des-martin periodinane (621.8 mg), and dry DCM (7 mL) was slowly added at room temperature with a mixture of water (17.6 μL) and DCM (13.5 mL), and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction mixture, a few granules of sodium thiosulfate were added and extracted with DCM. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate) to obtain (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-[(2S)-3-methyl-2-{4-[4-(3-oxopropyl)phenyl]-1H-1,2,3-triazole-1-yl}butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (633.2 mg) as a solid.

[0147] Preparation Example 23: (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-[(2S)-3-methyl-2-{4-[4-(3-oxopropyl)phenyl]-1H-1,2,3-triazole-1-yl}butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (568 mg), piperazine-1-carboxylate tert-butyl (174 mg), and DCM (3.90 mL) were mixed with sodium triacetoxyborohydride (330 mg) at room temperature and stirred for 3 hours at room temperature. Water and ethyl acetate were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate) to obtain a solid. To the obtained solid, 2M hydrochloric acid / EtOH (8 mL) and 4M hydrochloric acid / ethyl acetate (8 mL) were added at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and MeCN and MeOH were added to the residue, which was then concentrated under reduced pressure. The residue was purified by ODS column chromatography (MeCN / 10 mM ammonium bicarbonate aqueous solution), and the fraction containing the target product was freeze-dried to obtain (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-{4-[3-(piperazin-1-yl)propyl]phenyl}-1H-1,2,3-triazole-1-yl)butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (504.9 mg) as a solid.

[0148] Preparation Example 24 A mixture of 5-hydroxypicorial hydrate (250 mg), 4-(2-bromoethyl)piperazine-1-carboxylate tert-butyl (595 mg), and DMF (4.06 mL) was mixed with cesium carbonate (1.32 g) at room temperature and stirred at 75°C for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, then MeOH / ethyl acetate) to obtain an oily substance. A mixture of the obtained oily substance, (1-diazo-2-oxopropyl)phosphonate dimethyl (303 μL), and MeOH (8.50 mL) was mixed with potassium carbonate (470 mg) at room temperature and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain 4-{2-[(6-ethynylpyridine-3-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (548.8 mg) as an oily substance.

[0149] Preparation Example 25: (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-{[tert-butyldi(methyl)silyl]oxy}-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (807 mg), 4-{2-[(6-ethynylpyridine-3-yl)oxy]ethyl}piperazine-1-carboxylic acid tert-butyl (492 mg), sodium L-ascorbate (420 mg), THF (14.8 mL), and water (14.8 mL) were mixed with copper(II) sulfate (67.7 mg) at room temperature, and the mixture was stirred at room temperature for 18 hours. After adding aqueous ammonia to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain a solid. To the obtained solid, 10 mL of 2 M hydrochloric acid / EtOH and 10 mL of 4 M hydrochloric acid / ethyl acetate were added at room temperature, and the mixture was stirred for 15 minutes at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was purified by ODS column chromatography (MeCN / 10 mM ammonium bicarbonate aqueous solution) to obtain (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-{5-[2-(piperazin-1-yl)ethoxy]pyridine-2-yl}-1H-1,2,3-triazole-1-yl)butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (969.7 mg) as a solid.

[0150] Preparation Example 26: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (1 g), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (560.9 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (134.9 mg), 2M sodium carbonate aqueous solution (1.84 mL), and dioxane (8 mL) was degassed, purged with nitrogen, and stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane) to obtain tert-butyl{1-[3-(4-amino-2-chlorophenyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (0.9 g) as a solid.

[0151] Preparation Example 27: To a solution of tert-butyl{1-[3-(4-amino-2-chlorophenyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (400 mg) in DCM (4 mL), TEA (224.0 mg) and ethyl 4-chloro-4-oxobutanoate (121.5 mg) in DCM (0.5 mL) were added, and the mixture was stirred at 25°C for 2 hours. Water was added to the reaction mixture, and it was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain an oily substance. To a solution of the obtained oily substance in THF (1 mL), 2 M lithium hydroxide aqueous solution (839.3 μL) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, then adjusted to an acidic pH of 3 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-4-oxobutanoic acid (360 mg) as a solid.

[0152] Preparation Example 28 A mixed solution of methyl 3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoate (11.2 g) in MeOH (80 mL) and water (40 mL) was mixed with lithium hydroxide monohydrate (7.15 g) and stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH = 5-6 with 3 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue and a solution of (4R)-4-hydroxy-L-proline benzyl hydrochloride (10.5 g) in DMF (80 mL) were mixed with DIPEA (31.9 mL), followed by HATU (18.6 g), and stirred at 20°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (15 g). 7.3 g of the obtained oily substance was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: MeCN / 0.225% TFA aqueous solution). The fraction containing compounds with long retention times was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolinebenzyl (3.4 g) as an oily substance.

[0153] Preparation Example 29: A mixture of (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline benzyl (3.3 g) and ethyl acetate (30 mL) was mixed with 10% Pd / C (454.4 mg) under an argon atmosphere. The mixture was degassed, purged with hydrogen, and stirred at 20°C for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite®, the residue was washed with ethyl acetate, and then concentrated under reduced pressure to obtain (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (2.3 g) as a solid.

[0154] Preparation Example 30: Thionyl chloride (4.46 mL) was slowly added dropwise to a solution of (3S)-3-amino-3-(4-bromophenyl)propanoic acid (10 g) in MeOH (100 mL), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid. 2M sodium bicarbonate aqueous solution (58.1 mL) was added to a solution of the obtained solid in THF (100 mL), and then N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (10.1 g) was added little by little, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl (3S)-3-(4-bromophenyl)-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoate (16.5 g) as a solid.

[0155] Preparation Example 31: A solution of methyl (3S)-3-(4-bromophenyl)-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoate (8 g) and 4-methylthiazole (3.62 mL) in DMF (80 mL) was mixed with potassium acetate (3.90 g) and palladium(II) acetate (223.2 mg), and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a gum-like substance. A mixed solution of the obtained gum-like substance in THF (30 mL) and water (30 mL) was mixed with lithium hydroxide monohydrate (1.44 g), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was adjusted to pH = 4 with 1 M hydrochloric acid, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (5.8 g) as a solid.

[0156] Preparation Example 32: (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (200 mg), (3S)-3-isopropylpiperazine-1-carboxylate tert-butyl (123.6 mg), DIPEA (257.1 μL), and DMF (3 mL) were mixed with HATU (280.6 mg), and the mixture was stirred at 15°C for 0.5 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure to obtain a solid. The obtained solid was mixed with 1 M TBAF / THF solution (972.6 μL) and stirred at 65°C for 1 hour, then concentrated under reduced pressure to obtain a solid (230 mg). The resulting solid (200 mg), (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (100 mg), DIPEA (176.4 μL), and DMF (3 mL) were mixed with HOBt (91.2 mg) and EDCI·HCl (129.4 mg), and the mixture was stirred at 15°C for 12 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain (3S)-4-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanoyl}3-(propan-2-yl)piperazine-1-carboxylate tert-butyl (230 mg) as a solid.

[0157] Preparation Example 33: (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (200.0 mg) and 4-(4-piperidylmethyl)piperazine-1-carboxylate tert-butyl (139.4 mg) were dissolved in DMF (2 mL), to which DIPEA (317.9 mg) and HATU (374.1 mg) were added, and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a gum-like substance. To a solution of the obtained gum-like substance in THF (1 mL), 1 M TBAF / THF solution (892.9 μL) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a solid. The obtained solid and (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (123.5 mg) were dissolved in DMF (2 mL), to which EDCI·HCl (159.8 mg), HOBt (112.7 mg), and DIPEA (269.4 mg) were added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[(1-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanoyl}piperidine-4-yl)methyl]piperazine-1-carboxylate tert-butyl (280 mg) as a gum-like substance.

[0158] Preparation Example 34: (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (200 mg) and 4-(4-aminophenyl)piperazine-1-carboxylate tert-butyl (150.1 mg) were dissolved in DMF (2 mL), to which DIPEA (254.3 mg) and HATU (374.1 mg) were added, and the mixture was stirred at 25°C for 0.5 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. To a solution of the obtained oily substance in THF (1 mL), 1 M TBAF / THF solution (901.0 μL) was added, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance (220 mg). To a solution of the obtained oily substance (180 mg) and (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (100 mg) in DMF (2 mL), EDCI·HCl (132.3 mg), HOBt (93.2 mg), and DIPEA (178.4 mg) were added, and the mixture was stirred at 25°C for 16 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-(4-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanamide}phenyl)piperazine-1-carboxylate tert-butyl (220 mg) as an oily substance.

[0159] Preparation Example 35: A mixture of (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (300 mg), piperazine-1-carboxylate tert-butyl (164.9 mg), and DMF (2 mL) was mixed with DIPEA (190.7 mg), EDCI-HCl (212.2 mg), and HOBt (149.6 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. A mixture of the obtained oily substance and THF (4 mL) was mixed with 1 M TBAF / THF solution (1.36 mL), and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain an oily substance (480 mg). A mixture of the obtained oily substance (300 mg), (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (206.5 mg), and DMF (3 mL) was mixed with DIPEA (180.1 mg), EDCI-HCl (200.4 mg), and HOBt (141.2 mg). The mixture was then stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanoyl}piperazine-1-carboxylate tert-butyl (220 mg) as an oily substance.

[0160] Preparation Example 36: A mixture of (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (200 mg), tert-butyl(4-methylpiperidine-4-yl)carbamate (126.5 mg), and DMF (2 mL) was mixed with DIPEA (127.2 mg), EDCI・HCl (141.5 mg), and HOBt (99.7 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. A mixture of the obtained oily substance and THF (3 mL) was mixed with 1 M TBAF / THF solution (1 mL), and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain an oily substance. The obtained oily substance, a mixture of (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (96.9 mg) and DMF (2 mL), was mixed with DIPEA (84.5 mg), EDCI・HCl (94.1 mg), and HOBt (66.3 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain tert-butyl(1-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanoyl}-4-methylpiperidine-4-yl)carbamate (106 mg) as an oily substance.

[0161] Preparation Example 37: To a solution of tert-butyl{1-[3-(4-amino-2-chlorophenyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (1.66 g) in DCM (20 mL), DIPEA (1.60 mL) and ethyl 3-chloro-3-oxopropanoate (691.1 mg) were added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with saturated saline and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (1.5 g). The resulting oily substance (1.40 g) was mixed with EtOH (20 mL) and water (5 mL), to which lithium hydroxide monohydrate (268.9 mg) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, adjusted to pH = 3 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoic acid (1.2 g) as a solid.

[0162] Preparation Example 38: (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (0.2 g) and 4-(4-piperidyl)piperazine-1-carboxylate tert-butyl (132.5 mg) were dissolved in DMF (2 mL). EDCI·HCl (188.6 mg), HOBt (132.9 mg), and DIPEA (317.9 mg) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance (300 mg). To a solution of the obtained oily substance (150 mg) in THF (0.5 mL), 1 M TBAF / THF solution (465.9 μL) was added, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain an oily substance. To a solution of the obtained oily substance and (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (70 mg) in DMF (2 mL), EDCI·HCl (90.6 mg), HOBt (63.8 mg), and DIPEA (205.7 μL) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-(1-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanoyl}piperidine-4-yl)piperazine-1-carboxylate tert-butyl (150 mg) as an oily substance.

[0163] Preparation Example 39: A solution of tert-butyl{1-[3-(4-amino-2-chlorophenyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (0.2 g) and 2-chloro-2-oxo-ethyl acetate (49.5 μL) in DCM (1 mL) was mixed with triethylamine (154.1 μL) and stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. A mixed solution of the obtained oily substance with THF (2 mL) and water (1 mL) was mixed with lithium hydroxide monohydrate (16.8 mg) and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, the pH was adjusted to 2 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain {4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}(oxo)acetic acid (138 mg) as a solid.

[0164] Preparation Example 40: To a solution of 4-bromo-3-chlorobenzoic acid (1 g) in THF (10 mL), 8.92 mL of 1 M 2,2,6,6-tetramethylpiperidinyl magnesium chloride / lithium chloride complex / THF solution was added dropwise at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 1.5 hours. 490.2 μL of DMF was added dropwise to the reaction mixture at 0°C, and the mixture was stirred at room temperature for a further 2 hours. 1 M hydrochloric acid was added to the reaction mixture at 0°C, and the mixture was extracted by DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid (1.2 g). The resulting solid (800 mg), 2-methyl aminoacetate hydrochloride (762.5 mg), sodium triacetoxyborohydride (1.29 g), triethylamine (845.3 μL), and MeCN (15 mL) were mixed and stirred under a nitrogen atmosphere at 20°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain methyl (5-bromo-4-chloro-1-oxo-1,3-dihydro-2H-isoindole-2-yl)acetate (400 mg) as a solid.

[0165] Preparation Example 41: A mixture of (5-bromo-4-chloro-1-oxo-1,3-dihydro-2H-isoindole-2-yl)methyl acetate (400 mg), bis(pinacolato)diborone (382.6 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (91.9 mg), potassium acetate (246.5 mg), and dioxane (4 mL) was subjected to three degassing and nitrogen purging cycles, followed by stirring at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a gum-like substance. The resulting gum-like substance, along with a mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (593.4 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80.1 mg), sodium carbonate (231.9 mg), dioxane (5 mL), and water (2 mL), were subjected to three rounds of degassing and nitrogen purging, followed by stirring at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, acetic acid was added to adjust the pH to 5, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, then MeOH / ethyl acetate) to obtain {5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-chloro-1-oxo-1,3-dihydro-2H-isoindole-2-yl}acetic acid (350 mg) as a solid.

[0166] Preparation Example 42: (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (0.5 g) and (3S)-3-ethylpiperazine-1-carboxylate tert-butyl (316.3 mg) were dissolved in DMF (5 mL). EDCI·HCl (471.5 mg), HOBt (332.4 mg), and DIPEA (856.8 μL) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (0.7 g). To a solution of the obtained oily substance (0.4 g) in THF (3 mL), 1.33 mL of 1 M TBAF / THF solution was added, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a solid. To a solution of the obtained solid, (4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-proline (196.7 mg) in DMF (3 mL), EDCI·HCl (254.5 mg), HOBt (179.4 mg), and DIPEA (578.1 μL) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain (3S)-3-ethyl-4-{(3S)-3-({(4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazole-5-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanoyl}piperazine-1-carboxylate tert-butyl (335 mg) as an oily substance.

[0167] Preparation Example 43: 395.8 μL of 1-(trimethylsilyl)-1-propyne was added to a 1 mL THF solution, and the mixture was stirred at 25°C for 5 minutes. The reaction mixture was then added to a mixed solution of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-L-prolinemethyl (200 mg), sodium L-ascorbate (439.8 mg), and copper(II) sulfate pentahydrate (184.8 mg) in 10 mL THF and 2 mL water, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance. A mixture of the obtained oily substance with THF (1 mL) and water (1 mL) was mixed with lithium hydroxide monohydrate (51.4 mg), stirred at 25°C for 1.5 hours, and then concentrated under reduced pressure. The residue was diluted with water, adjusted to pH = 3 with 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-methyl-1H-1,2,3-triazole-1-yl)butanoyl]-L-proline (220 mg) as a solid.

[0168] Preparation Example 44: (3S)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]-3-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)propanoic acid (150 mg) and 4-(2-aminoethyl)piperidine-1-carboxylate tert-butyl (92.7 mg) were added to a solution of DMF (2 mL), to which HATU (280.6 mg) and DIPEA (257.1 μL) were added, and the mixture was stirred at 25°C for 0.5 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain an oily substance. To a solution of the obtained oily substance in THF (2 mL), 1 M TBAF / THF solution (875.4 μL) was added, and the mixture was stirred at 25°C for 16 hours, followed by 65°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-(2-{(3S)-3-amino-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanamide}ethyl)piperidine-1-carboxylate tert-butyl (105 mg) as an oily substance.

[0169] Preparation Example 45: A solution of 4-(2-{(3S)-3-amino-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanamide}ethyl)piperidine-1-carboxylate tert-butyl (155 mg) and (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-methyl-1H-1,2,3-triazole-1-yl)butanoyl]-L-proline (130 mg) in DMF (1 mL) was mixed with EDCI·HCl (125.7 mg), HOBt (88.6 mg), and DIPEA (285.6 μL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-(2-{(3S)-3-({(4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-methyl-1H-1,2,3-triazole-1-yl)butanoyl]-L-prolyl}amino)-3-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]propanamide}ethyl)piperidine-1-carboxylate tert-butyl (144 mg) as an oily substance.

[0170] Preparation Example 46: Potassium carbonate (22.9 g) and L-valine (9.33 g) were added to a solution of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (16.4 g) in DMSO (150 mL), and the mixture was stirred at 110°C for 2.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through Celite®, and the residue was washed with ethyl acetate. The filtrate was diluted with water, and 1 M hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. To a solution of the obtained solid in DMF (200 mL), HOBt (16.5 g), EDCI·HCl (23.4 g), and DIPEA (53.1 mL) were added, and (4R)-4-hydroxy-L-proline methyl hydrochloride (12.2 g) was added, and the mixture was stirred at 20°C for 3 hours. After the reaction mixture was diluted with water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain N-[5-(benzyloxy)-2-nitrophenyl]-L-valyl-(4R)-4-hydroxy-L-prolinemethyl (22.0 g) as a solid.

[0171] Preparation Example 47: A mixture of N-[5-(benzyloxy)-2-nitrophenyl]-L-valyl-(4R)-4-hydroxy-L-prolinemethyl (22.0 g), ammonium chloride (20.0 g), water (50 mL), and EtOH (150 mL) was mixed with iron powder (13.0 g), and the mixture was stirred at 70°C for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was filtered through Celite® to remove unwanted materials, and the residue was washed with EtOH. The filtrate was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution and water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. Isopentyl nitrite (16.7 g) was added to a solution of the obtained oily substance in MeCN (150 mL), and the mixture was stirred at 20°C for 15 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with water and saturated sodium sulfite aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. To the obtained solid, a mixture of 4-dimethylaminopyridine (5.94 g), imidazole (13.2 g), and DCM (250 mL) was added with tert-butyldimethylchlorosilane (22.0 g) at 10°C, and the mixture was stirred under a nitrogen atmosphere at 20°C for 1.5 hours. Water was added to the reaction mixture at 10°C, and it was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain (4R)-1-{(2S)-2-[6-(benzyloxy)-1H-1,2,3-benzotriazol-1-yl]-3-methylbutanoyl}-4-{[tert-butyldi(methyl)silyl]oxy}-L-prolinemethyl (26.0 g) as a solid.

[0172] Preparation Example 48: (4R)-1-{(2S)-2-[6-(benzyloxy)-1H-1,2,3-benzotriazol-1-yl]-3-methylbutanoyl}-4-{[tert-butyldi(methyl)silyl]oxy}-L-prolinemethyl (8.00 g) was added to a mixed solution of MeOH (50 mL) and THF (20 mL) with 10% palladium / carbon (1.50 g, 55% water-wetted) under an argon atmosphere. The reaction mixture was degassed several times, purged with hydrogen, and then stirred under a hydrogen atmosphere (30 psi) at 30°C for 5 hours. The reaction mixture was filtered, and the residue was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-[(2S)-2-(6-hydroxy-1H-1,2,3-benzotriazol-1-yl)-3-methylbutanoyl]-L-prolinemethyl (5.50 g) as a solid.

[0173] Preparation Example 49 A mixture of vinyl acetate (1.83 mL), 4-hydroxypiperidine-1-carboxylate tert-butyl (1.00 g), sodium carbonate (527 mg), bis(1,5-cyclooctadiene)diiridium(I) dichloride (334 mg), and dioxane (10 mL) was degassed three times, purged with nitrogen, and stirred at 100°C for 2.5 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-(ethenyloxy)piperidine-1-carboxylate tert-butyl (700 mg) as an oil.

[0174] Preparation Example 50: A mixture of (4R)-4-{[tert-butyldi(methyl)silyl]oxy}-1-[(2S)-2-(6-hydroxy-1H-1,2,3-benzotriazol-1-yl)-3-methylbutanoyl]-L-prolinemethyl (530 mg) and TEA (338 mg) in DCM (5 mL) was mixed with trifluoromethanesulfonic acid anhydride (376 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with saturated saline and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. A mixture of the obtained oily substance and 4-(ethenyloxy)piperidine-1-carboxylate tert-butyl (523 mg) in DMF (7 mL) was mixed with palladium(II) acetate (25.8 mg), TEA (175 mg), and triphenylphosphine (60.3 mg), and the mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. To a solution of the obtained oily substance in MeOH (5 mL), 10% palladium / carbon (77.6 mg, 55% water-wet) was added under a nitrogen atmosphere. The reaction mixture was degassed three times, purged with hydrogen, and then stirred under a hydrogen atmosphere (30 psi) at 25°C for 2 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain 4-[2-(1-{(2S)-1-[(2S,4R)-4-{[tert-butyldi(methyl)silyl]oxy}-2-(methoxycarbonyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-benzotriazole-6-yl)ethoxy]piperidine-1-carboxylic acid tert-butyl (420 mg) as an oily substance.

[0175] Preparation Example 51: 4-[2-(1-{(2S)-1-[(2S,4R)-4-{[tert-butyldi(methyl)silyl]oxy}-2-(methoxycarbonyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-benzotriazole-6-yl)ethoxy]piperidine-1-carboxylate tert-butyl (420 mg) was added to a solution of THF (7 mL) and stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and then saturated citric acid aqueous solution was added to adjust the pH to 5. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance (420 mg). The resulting oily substance (200 mg) and (1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethane-1-amine hydrochloride (90.7 mg) were mixed in DCM (2 mL). T4P / ethyl acetate solution (50 wt%, 855 mg) and TEA (300 mg) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[2-(1-{(2S)-1-[(2S,4R)-4-{[tert-butyldi(methyl)silyl]oxy}-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-benzotriazole-6-yl)ethoxy]piperidine-1-carboxylate tert-butyl (47.0 mg) as an oily substance.

[0176] Preparation Example 52: To a solution of 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoic acid (100 mg) in DMF (2 mL), HOBt (47.3 mg), EDCI・HCl (67.1 mg), N-methylglycine methyl hydrochloride (29.3 mg) and DIPEA (90.5 mg) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with saturated saline and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. A mixture of the resulting oily substance with MeOH (1 mL) and water (0.2 mL) was mixed with lithium hydroxide monohydrate (9.02 mg), and the mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and the aqueous layer was washed with DCM. 1 M hydrochloric acid was added to the aqueous layer to adjust the pH to 3, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}-N-methylglycine (46.0 mg) as a solid.

[0177] Preparation Example 53: A mixture of (4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (6.40 g) and N-(tert-butoxycarbonyl)-L-valine (3.10 g) in DMF (100 mL) was mixed with HATU (7.90 g) and DIPEA (15.1 mL), and the mixture was stirred under a nitrogen atmosphere at 25°C for 16 hours. The reaction mixture was poured into water, and the precipitate was filtered off. The filtered material was washed with water and dried under reduced pressure to obtain a solid (10.5 g). The resulting solid (10.0 g) was mixed with 2 M hydrochloric acid / dioxane (9.42 mL) and stirred at 25°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (8.00 g) as a solid.

[0178] Preparation Example 54: A mixture of L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (2.50 g) in MeCN (20 mL) and THF (20 mL) was mixed with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (2.50 g) and TEA (5.20 mL), and the mixture was stirred at 20°C for 16 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (2.20 g) as a solid.

[0179] Preparation Example 55 A mixture of 4-cyano-4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl (500 mg) and DCM (5 mL) was mixed with DIPEA (1.05 mL), 4-dimethylaminopyridine (24.0 mg), and p-toluenesulfonyl chloride (449 mg), and the mixture was stirred at 0°C for 15 minutes, then at 25°C for 2 hours. A saturated aqueous solution of ammonium chloride was slowly added to the reaction mixture, and it was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance (420 mg). A mixture of 4-[(trimethylsilyl)ethynyl]phenol (93.1 mg) and DMF (5 mL) was mixed with the obtained oily substance (400 mg) and potassium carbonate (270 mg), and the mixture was stirred at 60°C for 16 hours. Water was slowly added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 120 mg of tert-butyl 4-cyano-4-[2-(4-ethynylphenoxy)ethyl]piperidine-1-carboxylate as an oily substance.

[0180] Preparation Example 56: A mixture of 4-cyano-4-[2-(4-ethynylphenoxy)ethyl]piperidine-1-carboxylate tert-butyl (100 mg), (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (128 mg), sodium L-ascorbate (167 mg), THF (2 mL), water (0.5 mL), and t-BuOH (1 mL) was mixed with copper(II) sulfate (45.0 mg), and the mixture was stirred at 20°C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-cyano-4-{2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperidine-1-carboxylate tert-butyl (210 mg) as an oily substance.

[0181] Preparation Example 57 A mixture of 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl (330 mg), 4-[(trimethylsilyl)ethynyl]phenol (253 mg), and THF (4 mL) was mixed with triphenylphosphine (700 mg) and diisopropyl azodicarboxylate (540 mg), and the mixture was stirred at 60°C for 30 minutes. The reaction mixture was concentrated under reduced pressure at 45°C, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-fluoro-4-(2-{4-[(trimethylsilyl)ethynyl]phenoxy}ethyl)piperidine-1-carboxylate tert-butyl (200 mg) as an oil.

[0182] Preparation Example 58: A mixture of 4-fluoro-4-(2-{4-[(trimethylsilyl)ethynyl]phenoxy}ethyl)piperidine-1-carboxylate tert-butyl (200 mg) and MeOH (2 mL) was mixed with potassium carbonate (131 mg) and stirred at 25°C for 0.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. The resulting oily substance was mixed with (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (220 mg) in THF (3 mL). A mixture of copper(II) sulfate (64.3 mg) and sodium L-ascorbate (239 mg) in water (1 mL) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain 4-fluoro-4-{2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperidine-1-carboxylate tert-butyl (100 mg) as an oily substance.

[0183] Preparation Example 59: A mixture of 4-(2-hydroxyethyl)piperidine-1-carboxylate tert-butyl (500 mg), TEA (607 μL), and DCM (7 mL) was mixed with p-toluenesulfonyl chloride (831 mg) and stirred at 27°C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. A mixture of 4-[(trimethylsilyl)ethynyl]phenol (300 mg), potassium carbonate (544 mg), and DMF (1.5 mL) was stirred at 27°C for 20 minutes. After adding a solution of the obtained oily substance in DMF (1.5 mL), the mixture was stirred at 60°C for 12 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-[2-(4-ethynylphenoxy)ethyl]piperidine-1-carboxylate tert-butyl (650 mg) as a solid.

[0184] Preparation Example 61: A mixture of (4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (300 mg), N-(tert-butoxycarbonyl)-L-alanine (154 mg), and DMF (3 mL) was mixed with HATU (465 mg) and DIPEA (210 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance (315 mg). A mixture of the obtained oily substance (300 mg) and DCM (3 mL) was mixed with 4 M hydrochloric acid / dioxane (1 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure at 45°C to obtain L-alanyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (258 mg) as a solid.

[0185] Preparation Example 62: A mixture of L-alanyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (240 mg), 1H-imidazole-1-sulfonyl azide hydrochloride (125 mg), and MeOH (3 mL) was mixed with potassium carbonate (165 mg) and copper(II) sulfate pentahydrate (14.9 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-azidopropanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (220 mg) as a solid.

[0186] Preparation Example 63: A mixture of 4-[2-(4-ethynylphenoxy)ethyl]piperazine-1-carboxylate tert-butyl (138 mg), (4R)-1-[(2S)-2-azidopropanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (180 mg), sodium L-ascorbate (249 mg), THF (3 mL), water (1 mL), and t-BuOH (1.5 mL) was mixed with copper(II) sulfate (67.0 mg), and the mixture was stirred at 20°C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-{2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-1-oxopropan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (310 mg) as an oily substance.

[0187] Preparation Example 64: A mixture of (2S)-[(tert-butoxycarbonyl)amino]cyclopropyl)acetic acid (175 mg), (4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (300 mg) and DMF (3 mL) was mixed with DIPEA (210 mg) and HATU (465 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance (420 mg). A mixture of the obtained oily substance (400 mg) and DCM (3 mL) was mixed with 2 M hydrochloric acid / dioxane (1 mL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure at 45°C to obtain (4R)-1-[(2S)-2-amino-2-cyclopropylacetyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (330 mg) as a solid.

[0188] Preparation Example 67: A mixture of 3-methyl-L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (300 mg), 1H-imidazole-1-sulfonyl azide hydrochloride (141 mg), and MeOH (5 mL) was mixed with potassium carbonate (186 mg) and copper(II) sulfate pentahydrate (16.8 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-azido-3,3-dimethylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (301 mg) as an oily substance.

[0189] Preparation Example 69: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (5.49 g), 2-chloro-4-(methoxycarbonyl)phenylboronic acid (3.00 g), sodium carbonate (3.22 g), water (25 mL), and DME (100 mL) was prepared. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (827 mg) was added at room temperature. After degassing and purging with nitrogen, the mixture was stirred overnight at 80°C under a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-methyl chlorobenzoate (4.54 g) as a solid.

[0190] Preparation Example 70: 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-methyl chlorobenzoate (200 mg) was dissolved in DMF (2 mL), to which zinc cyanide (80.2 mg) and RuPhos Pd G3 (28.5 mg) were added, and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain methyl 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-cyanobenzoate (100 mg) as an oily substance.

[0191] Preparation Example 71: A mixture of methyl 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-cyanobenzoate (100 mg) in THF (2 mL) and water (2 mL) was mixed with lithium hydroxide monohydrate (29.1 mg), and the mixture was stirred at 25°C for 1 hour. 1 M hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and after dilution with water, the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. The obtained solid was mixed with glycine ethyl hydrochloride (21.4 mg) in DMF (2 mL), to which EDCI·HCl (54.6 mg), HOBt (38.4 mg), and DIPEA (92.0 mg) were added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid. The obtained solid was mixed with water (1 mL) and THF (1 mL), to which lithium hydroxide monohydrate (20.9 mg) was added, and the mixture was stirred at 25°C for 1 hour. 1 M hydrochloric acid was added to the reaction mixture to adjust the pH to 4, diluted with water, and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-cyanobenzoyl}glycine (77.0 mg) as a solid.

[0192] Preparation Example 72 A mixed solution of 4-(2-bromoethyl)piperazine-1-carboxylate tert-butyl (500 mg) and 2-fluoro-4-iodophenol (405 mg) in DMF (5 mL) was mixed with potassium carbonate (471 mg) and stirred at 50°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. The obtained oily substance was mixed with a solution of ethinyltri(methyl)silane (738 μL) in TEA (1 mL) and THF (10 mL), to which copper(I) iodide (67.6 mg) and bis(triphenylphosphine)palladium(II) dichloride (124 mg) were added and stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure at 45°C, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (800 mg). Potassium carbonate (197 mg) was added to a solution of the obtained oily substance (300 mg) in MeOH (2 mL), and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-[2-(4-ethynyl-2-fluorophenoxy)ethyl]piperazine-1-carboxylate tert-butyl (300 mg) as an oily substance.

[0193] Preparation Example 74 A mixture of 4-(2-bromoethyl)piperazine-1-carboxylate tert-butyl (500 mg) and 5-bromo-2-hydroxybenzonitrile (338 mg) in DMF (5 mL) was mixed with potassium carbonate (471 mg), and the mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. To a mixture of the obtained oily substance and ethinyltri(methyl)silane (452 ​​mg) in TEA (5 mL), copper(I) iodide (58.5 mg) and bis(triphenylphosphine)palladium(II) dichloride (108 mg) was added, and the mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure at 45°C, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-(2-{2-cyano-4-[(trimethylsilyl)ethynyl]phenoxy}ethyl)piperazine-1-carboxylate tert-butyl (500 mg) as an oily substance.

[0194] Preparation Example 76 A mixture of tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (500 mg) and 4-bromo-3-fluorophenol (325 mg) in DMF (5 mL) was mixed with potassium carbonate (471 mg) and stirred at 50°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. The obtained oily substance was mixed with a solution of ethynyltrimethylsilane (346 mg) in TEA (4 mL) and THF (1 mL), to which copper(I) iodide (44.8 mg) and bis(triphenylphosphine)palladium(II) dichloride (82.5 mg) were added and the mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure at 45°C, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-(2-{3-fluoro-4-[(trimethylsilyl)ethynyl]phenoxy}ethyl)piperazine-1-carboxylate tert-butyl (250 mg) as an oily substance.

[0195] Preparation Example 77: Potassium carbonate (164 mg) was added to a solution of 4-(2-{3-fluoro-4-[(trimethylsilyl)ethynyl]phenoxy}ethyl)piperazine-1-carboxylate tert-butyl (250 mg) in MeOH (2 mL), and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. The resulting oily substance was mixed with (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolinamide (398 mg) in THF (4 mL). A mixture of sodium L-ascorbate (399 mg) and copper(II) sulfate (107 mg) in water (1 mL) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain 4-{2-[3-fluoro-4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (220 mg) as an oily substance.

[0196] Preparation Example 78: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (441 mg), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (250 mg), dioxane (3 mL), and water (1 mL) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (66.4 mg) and tripotassium phosphate (345 mg), and the mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain tert-butyl(1-{3-[6-chloro-4-(trifluoromethyl)pyridine-3-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl}-4-methylpiperidine-4-yl)carbamate (250 mg) as an oily substance.

[0197] Preparation Example 79: To a solution of tert-butyl(1-{3-[6-chloro-4-(trifluoromethyl)pyridine-3-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl}-4-methylpiperidine-4-yl) carbamate (250 mg) in MeOH (3 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (30.7 mg) and TEA (84.9 mg) were added under a nitrogen atmosphere. The mixture was degassed three times, purged with carbon monoxide, and then stirred at 60°C for 16 hours under a carbon monoxide atmosphere (40 Psi). After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (220 mg). The resulting oily substance (170 mg) was mixed with water (0.5 mL) and MeOH (2 mL), to which lithium hydroxide monohydrate (57.6 mg) was added and the mixture was stirred at 25°C for 16 hours. 1 M hydrochloric acid was added to the reaction mixture to adjust the pH to 5, and after pouring into water, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-(trifluoromethyl)pyridine-2-carboxylic acid (150 mg) as an oily substance.

[0198] Preparation Example 80: A mixture of 5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-(trifluoromethyl)pyridine-2-carboxylic acid (100 mg), glycine methyl hydrochloride (20.7 mg), and DMF (2 mL) was mixed with DIPEA (42.7 mg), EDCI・HCl (47.5 mg), and HOBt (33.5 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. After adding lithium hydroxide monohydrate (34.1 mg) to a mixed solution of the resulting oily substance with MeOH (2 mL) and water (0.5 mL), the mixture was stirred at 25°C for 16 hours. The reaction mixture was then adjusted to pH = 5 with 1 M hydrochloric acid, and concentrated under reduced pressure to obtain N-{5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-(trifluoromethyl)pyridine-2-carbonyl}glycine (100 mg) as a solid.

[0199] Preparation Example 81: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (300 mg), bis(pinacolato)diborone (421 mg), potassium acetate (163 mg), and dioxane (10 mL) was purged with nitrogen for 3 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (40.5 mg) was added, and the mixture was stirred at 80°C for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate after adding water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl{4-methyl-1-[1-(oxan-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]piperidine-4-yl}carbamate (3.85 g) as a solid.

[0200] Preparation Example 82: A mixture of 4-bromo-3-chloro-2-fluorobenzoic acid (1.00 g), glycine methyl hydrochloride (991 mg), DIPEA (1.53 g), and DMF (25 mL) was mixed with HATU (1.80 g) and stirred at 27°C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain N-(4-bromo-3-chloro-2-fluorobenzoyl)glycine methyl (1.30 g) as a solid.

[0201] Preparation Example 83: A mixture of tert-butyl{4-methyl-1-[1-(oxan-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]piperidine-4-yl}carbamate (800 mg), N-(4-bromo-3-chloro-2-fluorobenzoyl)glycinemethyl (177 mg), tripotassium phosphate (232 mg), dioxane (10 mL), and water (2 mL) was purged with nitrogen for 3 minutes, Pd-118 (35.6 mg) was added, and the mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and it was extracted with ethyl acetate. After concentrating the organic layer under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloro-2-fluorobenzoyl}glycinemethyl (57.0 mg) as a solid.

[0202] Preparation Example 84: A mixture of 4-bromo-5-chloro-2-fluorobenzoic acid (1.10 g), glycine methyl hydrochloride (1.09 g), DIPEA (1.68 g), and DMF (25 mL) was mixed with HATU (1.98 g) and stirred at 27°C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain N-(4-bromo-5-chloro-2-fluorobenzoyl)glycine methyl (1.22 g) as a solid.

[0203] Preparation Example 86 A mixed solution of 4-amino-4-methylpiperidine-1-carboxylate tert-butyl (2.00 g) and 1-bromo-2-methoxyethane (1.95 g) in MeCN (15 mL) was mixed with potassium carbonate (2.58 g) and potassium iodide (155 mg), and the mixture was stirred at 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid. A solution of the obtained solid in DCM (6 mL) was mixed with 2 M hydrochloric acid / dioxane (12 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a solid (1.90 g). A mixed solution of the obtained solid (0.80 g) and 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (1.40 g) in DMSO (6 mL) was mixed with potassium carbonate (1.59 g), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain 1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-N-(2-methoxyethyl)-4-methylpiperidine-4-amine (1.50 g) as a gum-like substance.

[0204] Preparation Example 89: Dimethylaminoacetaldehyde hydrochloride (951 mg) was dissolved in MeOH (10 mL), to which DIPEA (995 mg) was added and the mixture was stirred at 25°C for 10 minutes. Then, 4-amino-4-methylpiperidine-1-carboxylate tert-butyl (1.50 g) and acetic acid (210 mg) were added, and the mixture was stirred further at 25°C for 0.5 hours. Sodium cyanoborohydride (879 mg) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain a gum-like substance. 2M hydrochloric acid / dioxane (20 mL) was added to a solution of the obtained gum-like substance in DCM (10 mL) and the mixture was stirred at 25°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain a gum-like substance. The resulting gum-like substance and 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (2.14 g) were mixed in DMSO (20 mL / 6 mL), to which potassium carbonate (2.43 g) was added, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain N2-{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}-N1,N1-dimethylethane-1,2-diamine (250 mg) as a solid.

[0205] Preparation Example 92 A mixture of 4-(2-chloroethyl)piperazine-1-carboxylate tert-butyl (4.90 g) and 4-hydroxybenzoate methyl (3.00 g) in DMF (30 mL) was mixed with potassium carbonate (5.45 g), and the mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (7.00 g) as a solid.

[0206] Preparation Example 93: To a solution of 4-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (3.00 g) in EtOH (30 mL), hydrazine monohydrate (purity 85%, 2.23 g) was added, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain a solid. To a mixed solution of the obtained solid and DIPEA (1.50 g) in DCM (14 mL), ethyl 2-(chlorocarbonyl)-3-methylbutanoate (0.80 g) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[2-(4-{2-[2-(ethoxycarbonyl)-3-methylbutanoyl]hydrazine-1-carbonyl}phenoxy)ethyl]piperazine-1-carboxylate tert-butyl (2.00 g) as an oily substance.

[0207] Preparation Example 94: Burgess reagent (2.61 g) was added to a solution of 4-[2-(4-{2-[2-(ethoxycarbonyl)-3-methylbutanoyl]hydrazine-1-carbonyl}phenoxy)ethyl]piperazine-1-carboxylate tert-butyl (1.90 g) in toluene (15 mL), and the mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid. A solution of the obtained solid in EtOH (10 mL) was added to a solution of lithium hydroxide monohydrate (214 mg) in water (10 mL), and the mixture was stirred at 25°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and then pH was adjusted to 3 by adding 1 M hydrochloric acid. The mixture was extracted with DCM / MeOH(10 / 1), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-[5-(4-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}phenyl)-1,3,4-oxadiazole-2-yl]-3-methylbutanoic acid (1.50 g) as a solid.

[0208] Preparation Example 95: A mixture of 2-[5-(4-{2-[4-(tert-butoxycarbonyl)piperazine-1-yl]ethoxy}phenyl)-1,3,4-oxadiazole-2-yl]-3-methylbutanoic acid (645 mg) and (4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide hydrochloride (0.50 g) in DMF (5 mL) was mixed with EDCI·HCl (521 mg), HOBt (367 mg), and DIPEA (878 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain 4-{2-[4-(5-{1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,3,4-oxadiazole-2-yl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (800 mg) as an oily substance.

[0209] Preparation Example 96: A mixture of 4-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (2.00 g) in MeOH (20 mL) and water (5 mL) was mixed with lithium hydroxide monohydrate (394 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and then pH was adjusted to 3 by adding 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid (2.10 g). The obtained solid (2.00 g) and a mixture of 3-(hydroxyamino)-3-iminopropanoate ethyl (918 mg) in DMF (20 mL) were mixed with HATU (2.60 g) and DIPEA (738 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain an oily substance. A solution of the obtained oily substance in DMF (15 mL) was stirred at 120°C for 16 hours, then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-(2-{4-[3-(2-ethoxy-2-oxoethyl)-1,2,4-oxadiazole-5-yl]phenoxy}ethyl)piperazine-1-carboxylate tert-butyl (649 mg) as an oily substance.

[0210] Preparation Example 97: A mixture of 4-(2-{4-[3-(2-ethoxy-2-oxoethyl)-1,2,4-oxadiazole-5-yl]phenoxy}ethyl)piperazine-1-carboxylate tert-butyl (649 mg) and 2-iodopropane (340 mg) in THF (6 mL) was mixed with 1 M potassium tert-butoxide tetrahydrofuran solution (1.69 mL) and stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. A solution of the obtained oily substance in EtOH (1 mL) was mixed with a solution of lithium hydroxide monohydrate (55.1 mg) in water (1 mL) and stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and then pH was adjusted to 3 by adding 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-[5-(4-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}phenyl)-1,2,4-oxadiazole-3-yl]-3-methylbutanoic acid (250 mg) as a solid.

[0211] Preparation Example 99 A mixture of 1,4-diiodobenzene (5.15 g), potassium carbonate (4.32 g), azetidine-3-ylmethanol hydrochloride (1.93 g), and DMSO (100 mL) was purged with nitrogen gas for 3 minutes. L-proline (719 mg) and copper(I) iodide (297 mg) were added, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain [1-(4-iodophenyl)azetidine-3-yl]methanol (2.30 g) as a solid.

[0212] Preparation Example 100: A mixture of [1-(4-iodophenyl)azetidine-3-yl]methanol (1.00 g), p-toluenesulfonyl chloride (1.98 g), TEA (1.05 g), and DCM (30 mL) was stirred at 27°C for 16 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid. The obtained solid, a mixture of piperazine-1-carboxylate tert-butyl (3.89 g), potassium carbonate (1.73 g), and DMF (15 mL) was stirred at 80°C for 12 hours, and water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-{[1-(4-iodophenyl)azetidine-3-yl]methyl}piperazine-1-carboxylate tert-butyl (960 mg) as a solid.

[0213] Preparation Example 101 A mixture of 4-{[1-(4-iodophenyl)azetidine-3-yl]methyl}piperazine-1-carboxylate tert-butyl (600 mg) and TEA (24 mL) was mixed with bis(triphenylphosphine)palladium(II) dichloride (92.1 mg) and copper(I) iodide (50.0 mg). The mixture was purged with nitrogen for 3 minutes, and then ethinyltrimethylsilane (644 mg) was added. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 2 hours and then concentrated under reduced pressure. Water was added to the residue, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[(1-{4-[(trimethylsilyl)ethynyl]phenyl}azetidine-3-yl)methyl]piperazine-1-carboxylate tert-butyl (405 mg) as a solid.

[0214] Preparation Example 102: Potassium carbonate (129 mg) was added to a mixture of 4-[(1-{4-[(trimethylsilyl)ethynyl]phenyl}azetidine-3-yl)methyl]piperazine-1-carboxylate tert-butyl (200 mg) and MeOH (2.2 mL) at 0°C, and the mixture was stirred at 20°C for 1 hour. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain 4-{[1-(4-ethynylphenyl)azetidine-3-yl]methyl}piperazine-1-carboxylate tert-butyl (170 mg) as a solid.

[0215] Preparation Example 103: A mixture of 4-{[1-(4-ethynylphenyl)azetidine-3-yl]methyl}piperazine-1-carboxylate tert-butyl (170 mg), (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (218 mg) and t-BuOH (10 mL) was added to a mixture of copper(II) sulfate pentahydrate (119 mg) and sodium L-ascorbate (284 mg) in water (4.5 mL), and the mixture was stirred at 25°C for 1.5 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-({1-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]azetidine-3-yl}methyl)piperazine-1-carboxylate tert-butyl (77.0 mg) as a solid.

[0216] Preparation Example 104: A mixture of 1-(2-chloroethoxy)-4-iodobenzene (900 mg), tert-butyl 4-aminopiperidine-1-carboxylic acid (1.28 g), potassium carbonate (1.32 g), and DMF (9 mL) was stirred at 90°C for 20 hours. Water was then added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-{[2-(4-iodophenoxy)ethyl]amino}piperidine-1-carboxylic acid tert-butyl (639 mg) as a solid.

[0217] Preparation Example 106: A mixture of 4-[(2-{4-[(trimethylsilyl)ethynyl]phenoxy}ethyl)amino]piperidine-1-carboxylate tert-butyl (550 mg) and THF (14 mL) was added dropwise with 1.34 mL of 1 M TBAF-THF solution at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance. The resulting oily substance was mixed with a solution of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolinamide (507 mg) in t-BuOH (5 mL). A solution of copper(II) sulfate pentahydrate (162 mg) and sodium L-ascorbate (385 mg) in water (2.2 mL) was added, and the mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / ethyl acetate) to obtain 4-({2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}amino)piperidine-1-carboxylate tert-butyl (362 mg) as a solid.

[0218] Preparation Example 107: To a solution of (2R)-2-amino-2-(4-bromophenyl)ethane-1-ol (5.00 g) in THF (70 mL), 34.7 mL of 2 M aqueous sodium bicarbonate solution was added, followed by 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (6.00 g) in small increments, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a gum-like substance (8.00 g). To a mixed solution of the obtained gum-like substance (7.60 g) and 4-methylthiazole (4.18 g) in DMF (100 mL), potassium acetate (4.14 g) and palladium(II) acetate (237 mg) were added, and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 2-(trimethylsilyl)ethyl{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate (5.50 g) as a solid.

[0219] Preparation Example 108: 2-(trimethylsilyl)ethyl{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate (600 mg) was dissolved in DCM (1 mL), to which 2 M hydrochloric acid / dioxane (4 mL) was added and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain (2R)-2-amino-2-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethane-1-ol hydrochloride (0.37 g) as a solid.

[0220] Preparation Example 109: A mixture of (4R)-1-{(2S)-2-[4-(4-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-L-proline (0.20 g) and (2R)-2-amino-2-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethane-1-ol hydrochloride (138 mg) in DMF (3 mL) was mixed with HATU (259 mg) and DIPEA (220 mg), and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-{2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (0.27 g) as a solid.

[0221] Preparation Example 110 A mixed solution of 4-(piperazin-1-yl)piperidine-1-carboxylate tert-butyl (581 mg) and 4-iodobenzaldehyde (500 mg) in DCE (10 mL) was mixed with sodium triacetoxyborahydride (913 mg) and stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-{4-[(4-iodophenyl)methyl]piperazin-1-yl}piperidine-1-carboxylate tert-butyl (0.70 g) as an oil.

[0222] Preparation Example 113: To a solution of 5-bromo-4-chloro-2-fluoropyridine (0.50 g) in dioxane (5 mL), bis(pinacolato)diborone (724 mg), potassium acetate (466 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (174 mg) were added, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.60 g) as a solid.

[0223] Preparation Example 115 A mixture of tert-butyl{1-[3-(4-chloro-6-fluoropyridine-3-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (250 mg) and glycine methyl hydrochloride (172 mg) in DMSO (1.5 mL) was mixed with potassium carbonate (190 mg) and stirred at 90°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a gum-like substance. A mixture of the obtained gum-like substance with THF (1 mL) and water (1 mL) was mixed with lithium hydroxide monohydrate (13.6 mg) and stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH = 4 by adding 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-{5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-chloropyridine-2-yl}glycine (30.0 mg) as a gum-like substance.

[0224] Preparation Example 116: A mixture of tert-butyl{1-[3-(4-chloro-6-fluoropyridine-3-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (130 mg) and β-alanine methyl hydrochloride (99.7 mg) in DMSO (2 mL) was mixed with potassium carbonate (98.7 mg) and stirred at 90°C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a gum-like substance. A mixture of the obtained gum-like substance with THF (1.5 mL) and water (1.5 mL) was mixed with lithium hydroxide monohydrate (5.34 mg) and stirred at 25°C for 1 hour. The reaction mixture was diluted with 1 M hydrochloric acid to adjust the pH to 4, then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-{5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-chloropyridine-2-yl}β-alanine (39.0 mg) as a gum-like substance.

[0225] Preparation Example 117: To a solution of 3-bromo-6-chloro-2-(trifluoromethyl)pyridine (0.50 g) in dioxane (5 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (140 mg), potassium acetate (377 mg), and bis(pinacolato)diborone (585 mg) were added under a nitrogen atmosphere, and the mixture was stirred at 80°C for 16 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (250 mg) as an oil.

[0226] Preparation Example 118: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (397 mg) and 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (250 mg) dioxane (4 mL) and water (1 mL) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59.5 mg) and sodium carbonate (172 mg) under a nitrogen atmosphere, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain tert-butyl(1-{3-[6-chloro-2-(trifluoromethyl)pyridine-3-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl}-4-methylpiperidine-4-yl)carbamate (190 mg) as an oily substance.

[0227] Preparation Example 119: To a solution of tert-butyl(1-{3-[6-chloro-2-(trifluoromethyl)pyridine-3-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl}-4-methylpiperidine-4-yl) carbamate (190 mg) in MeOH (3 mL), TEA (64.5 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (23.3 mg) were added under a nitrogen atmosphere. The mixture was then degassed three times, purged with carbon monoxide, and stirred at 60°C for 16 hours under a carbon monoxide atmosphere (40 Psi). After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. To a solution of the obtained oily substance in THF (0.3 mL), 315 μL of 2 M lithium hydroxide aqueous solution was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH = 3 by adding 1 M hydrochloric acid, after which it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-6-(trifluoromethyl)pyridine-2-carboxylic acid (130 mg) as an oily substance.

[0228] Preparation Example 120: (4R)-4-hydroxy-1-[(2S)-3-methyl-2-(4-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-1,2,3-triazole-1-yl)butanoyl]-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (0.50 g) and N-(tert-butoxycarbonyl)glycine (140 mg) were mixed in DMF (3 mL). HATU (526 mg) and DIPEA (447 mg) were added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. The mixture of the obtained oily substance and 2M hydrochloric acid / dioxane solution (10 mL) was stirred at 25°C for 1 hour, and then concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[2-(4-glycylpiperazine-1-yl)ethoxy]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (500 mg) as a solid.

[0229] Preparation Example 121 A mixture of 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (4.00 g) and [2-chloro-4-(methoxycarbonyl)phenyl]boronic acid (2.47 g) dioxane (45 mL) and water (15 mL) was mixed with tripotassium phosphate (4.66 g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (448 mg). The mixture was then stirred at 80°C for 12 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 organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain methyl 3-chloro-4-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]benzoate (0.89 g) as a solid.

[0230] Preparation Example 122: A solution of 3-chloro-4-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]methyl benzoate (300 mg) was added to a solution of potassium trimethylsilanolate (123 mg) in water (1 mL), and the mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with water, neutralized to pH = 4-5 by adding a 10% aqueous citric acid solution at 25°C, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-chloro-4-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]benzoic acid (300 mg) as a solid.

[0231] Preparation Example 123: A mixture of (3-chloro-4-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]benzoic acid (195 mg) and (4R)-1-[(2S)-2-(4-{4-[2-(4-glycylpiperazine-1-yl)ethoxy]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (390 mg) in DMF (6 mL) is mixed with DIPEA (346 mg) and HATU (221 mg). After adding mg of the mixture, the mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain (4R)-1-{(2S)-2-[4-(4-{2-[4-(N-{3-chloro-4-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]benzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}L-prolineamide (310 mg) as a solid.

[0232] Preparation Example 124 A mixture of butan-1-amine (4.70 mL), hydroxylamine hydrochloride (826 mg), and copper(I) chloride (117.69 mg) was degassed three times, purged with nitrogen, and stirred under a nitrogen atmosphere at 0°C for 5 minutes. A mixture of 4-pentin-1-ol (1.00 g) in DCM (5 mL) and MeOH (5 mL) was added dropwise through a cannula over 4 minutes, followed by the addition of a mixture of (bromoethinyl)tri(propan-2-yl)silane (6.21 g) in DCM (5 mL) and MeOH (5 mL) dropwise through a cannula over 4 minutes. The reaction mixture was stirred at 0°C for 3 hours, then saturated ammonium chloride aqueous solution was added, diluted with water, and extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 7-[tri(propan-2-yl)silyl]hepta-4,6-diin-1-ol (3.10 g) as an oily substance.

[0233] Preparation Example 127: A mixture of (2R)-2-chloropropanol (0.50 g) and piperazine-1-carboxylate tert-butyl (985 mg) in DMSO (2 mL) was mixed with cesium carbonate (3.45 g), and the mixture was stirred at 100°C for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. The obtained oily substance, a mixture of 4-iodophenol (450 mg) and triphenylphosphine (537 mg) in THF (5 mL) was mixed with a solution of azodicarboxylate diisopropyl (434 mg) in THF (4 mL), and the mixture was stirred at 25°C for 16 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[1-(4-iodophenoxy)propan-2-yl]piperazine-1-carboxylate tert-butyl (700 mg) as an oily substance.

[0234] Preparation Example 129: A solution of 4-(1-{4-[(trimethylsilyl)ethynyl]phenoxy}propan-2-yl)piperazine-1-carboxylate tert-butyl (300 mg) in MeOH (4 mL) was mixed with potassium carbonate (199 mg) and stirred at 25°C for 1 hour. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain an oily substance (248 mg). The resulting oily substance (240 mg) and a mixture of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (200 mg) in THF (2 mL) and t-BuOH (1 mL) were added, to which a mixture of sodium L-ascorbate (414 mg) and copper(II) sulfate pentahydrate (174 mg) in water (1 mL) was added, and the mixture was stirred at 25°C for 16 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-{1-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]propan-2-yl}piperazine-1-carboxylate tert-butyl (230 mg) as an oily substance.

[0235] Preparation Example 130 A mixture of 4-iodophenol (931 mg), ethyl (2R)-2-hydroxypropanoate (500 mg), and triphenylphosphine (1.11 g) in THF (5 mL) was mixed with a solution of diisopropyl azodicarboxylic acid (899 mg) in THF (2 mL), and the mixture was stirred under a nitrogen atmosphere at 25°C for 16 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. To a solution of the obtained oily substance in THF (6 mL), a 1 M diisobutylaluminum hydride / toluene solution (5.20 mL) was added under a nitrogen atmosphere at -70°C, and the mixture was stirred at 0°C for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture at 0°C, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain (2S)-2-(4-iodophenoxy)propan-1-ol (430 mg) as an oily substance.

[0236] Preparation Example 131: Dess-Martin periodinane (853 mg) was added to a solution of (2S)-2-(4-iodophenoxy)propan-1-ol (430 mg) in DCM (5 mL), and the mixture was stirred at 25°C for 1.5 hours. A saturated sodium bicarbonate aqueous solution and a 2 M sodium thiosulfate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. Sodium triacetoxyboronhydride (981 mg) was added to the obtained solid and a solution of piperazine-1-carboxylate tert-butyl (287 mg) in DCM (5 mL), and the mixture was stirred at 25°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-[(2S)-2-(4-iodophenoxy)propyl]piperazine-1-carboxylate tert-butyl (550 mg) as an oily substance.

[0237] Preparation Example 134 A mixture of 4-iodophenol (1.97 g), ethyl (2S)-2-hydroxypropanoate (1.00 g), and triphenylphosphine (2.35 g) in THF (12 mL) was added dropwise to a solution of diisopropyl azodicarboxylic acid (1.90 g) in THF (4 mL), and the mixture was stirred at 25°C for 16 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (2.30 g). To a solution of the obtained oily substance (1.00 g) in THF (10 mL), 4.70 mL of 1 M diisobutylaluminum hydride-toluene solution was added under a nitrogen atmosphere at -70°C, and the mixture was stirred at 0°C for 2 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture at -70°C, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain (2R)-2-(4-iodophenoxy)propan-1-ol (300 mg) as an oily substance.

[0238] Preparation Example 138: A mixture of 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoic acid (120 mg) and L-alanine methyl hydrochloride (44.0 mg) in DMF (2 mL) was mixed with DIPEA (81.5 mg) and HATU (104 mg), and the mixture was stirred at 27°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance. To the obtained oily substance in a THF (1.5 mL) solution, a lithium hydroxide monohydrate (15.3 mg) solution in water (0.5 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water, and a 10% citric acid aqueous solution was added at 25°C to adjust the pH to 4-5, after which it was extracted with an ethyl acetate / MeOH (5 / 1) mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}-L-alanine (115 mg) as an oily substance.

[0239] Preparation Example 139: A mixture of 4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoic acid (120 mg) and D-alanine methyl hydrochloride (44.0 mg) in DMF (2 mL) was mixed with DIPEA (81.4 mg) and HATU (103 mg), and the mixture was stirred at 27°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain an oily substance. To the obtained oily substance in a THF (1.5 mL) solution, a solution of lithium hydroxide monohydrate (15.3 mg) in water (0.5 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water, and a 10% citric acid aqueous solution was added at 25°C to adjust the pH to 4-5. The mixture was then extracted with an ethyl acetate / MeOH (5 / 1) mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}-D-alanine (105 mg) as an oily substance.

[0240] Preparation Example 140: A mixed solution of L-valyl-(4R)-4-hydroxy-L-prolinemethyl hydrochloride (4.50 g) and 1H-imidazole-1-sulfonyl azide hydrochloride (3.33 g) in MeOH (50 mL) was mixed with potassium carbonate (4.43 g) and copper(II) sulfate pentahydrate (400 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with DCM. 1 M hydrochloric acid was added to the aqueous layer to adjust the pH to 3, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-L-prolinemethyl (3.70 g) as an oil.

[0241] Preparation Example 141: A mixture of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-L-prolinemethyl (4.00 g) and 4-[2-(4-ethynylphenoxy)ethyl]piperazine-1-carboxylate tert-butyl (5.00 g) in THF (60 mL) and t-BuOH (30 mL) was mixed with sodium L-ascorbate (8.80 g) and copper(II) sulfate pentahydrate (3.70 g) in water (30 mL), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-{2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (6.27 g) as a solid.

[0242] Preparation Example 142: 4-{2-[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenoxy]ethyl}piperazine-1-carboxylate tert-butyl (0.50 g) was added to a solution of DCM (6 mL) and 2 M hydrochloric acid / dioxane (4 mL), then stirred at 25°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid. The obtained solid and N-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycine (500 mg) were mixed in DMF (8 mL), to which DIPEA (412 mg) and HATU (394 mg) were added, and the mixture was stirred at 27°C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. To a solution of the obtained oily substance in THF (10 mL), a solution of lithium hydroxide monohydrate (90.6 mg) in water (2 mL) was added, and the mixture was stirred at 25°C for 4 hours. A 10% aqueous citric acid solution was added to the reaction mixture at 25°C to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: MeCN / 0.225% formic acid aqueous solution), and the fraction containing the target product was freeze-dried to obtain (4R)-1-{(2S)-2-[4-(4-{2-[4-({4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzamide}acetyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-L-proline (385 mg) as a solid.

[0243] Preparation Example 143: To a solution of ethyl acetate (diethoxyphosphinyl) (1.75 g) in THF (4 mL), sodium hydride (60%, oily, 312 mg) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 0.5 hours. A solution of 5-bromo-1,3-thiazole-4-carbaldehyde (1.00 g) in THF (2 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 25°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid. To a mixed solution of the obtained solid and sodium acetate (607 mg) in EtOH (11 mL), p-toluenesulfonyl hydrazide (2.76 g) was added, and the mixture was stirred at 90°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain ethyl 3-(5-bromo-1,3-thiazole-4-yl)propanoate (568 mg) as an oily substance.

[0244] Preparation Example 144: A mixture of tert-butyl{(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (402 mg), ethyl 3-(5-bromo-1,3-thiazole-4-yl)propanoate (235 mg), tripotassium phosphate (567 mg), dioxane (20 mL), and water (5 mL) was purged with nitrogen for 3 minutes, Pd-118 (58.0 mg) was added, and the mixture was stirred at 95°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain ethyl 3-[5-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-1,3-thiazole-4-yl]propanoate (210 mg) as an oily substance.

[0245] Preparation Example 145: To a solution of ethyl 3-[5-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-1,3-thiazole-4-yl]propanoate (100 mg) in DCM (4 mL), 1.00 mL of 1 M diisobutylaluminum hydride / toluene solution (1.00 mL) was added at -70°C under a nitrogen atmosphere, and the mixture was stirred at -60°C for 2 hours under a nitrogen atmosphere. To the reaction mixture, saturated potassium sodium tartrate aqueous solution and DCM were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes, after which it was extracted with DCM. After concentrating the organic layer under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain tert-butyl[(1S)-1-{4-[4-(3-hydroxypropyl)-1,3-thiazole-5-yl]phenyl}ethyl]carbamate (30.0 mg) as a solid.

[0246] Preparation Example 146 A mixed solution of 4-(2-chloroethyl)piperazine-1-carboxylate tert-butyl (711 mg) and 2-bromopyrimidine-5-ol (0.50 g) in DMF (5 mL) was mixed with potassium carbonate (790 mg) and stirred at 60°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-{2-[(2-bromopyrimidine-5-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (1.30 g) as an oil.

[0247] Preparation Example 149: To a solution of 4-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl (595 mg) in THF (5 mL), sodium hydride (60%, oily, 259 mg) was added and the mixture was stirred at 0°C for 0.5 hours, after which 2-bromo-5-chloropyrazine (0.50 g) was added. The reaction mixture was stirred at 60°C for 2 hours, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-{2-[(5-bromopyrazine-2-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (1.00 g) as an oil.

[0248] Preparation Example 150 A mixed solution of 4-{2-[(5-bromopyrazine-2-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (1.00 g) and ethynyltrimethylsilane (886 mg) in THF (10 mL) and TEA (2 mL) was mixed with bis(triphenylphosphine)palladium(II) dichloride (363 mg) and copper(I) iodide (98.4 mg), and the mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance (0.60 g). Potassium carbonate (205 mg) was added to a solution of the obtained oily substance (0.30 g) in MeOH (3 mL), and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-{2-[(5-ethynylpyrazine-2-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (250 mg) as an oil.

[0249] Preparation Example 151: A mixture of 4-{2-[(5-ethynylpyrazine-2-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (182 mg) and (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}L-prolineamide (250 mg) in THF (6 mL) and water (2 mL) was mixed with copper(II) sulfate pentahydrate (137 mg) and sodium L-ascorbate (325 mg), and then stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure at 45°C, and the residue was purified by silica gel column chromatography (MeOH / DCM) to obtain 4-(2-{[5-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)pyrazine-2-yl]oxy}ethyl)piperazine-1-carboxylate tert-butyl (260 mg) as an oily substance.

[0250] Preparation Example 152: To a solution of 4-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl (959 mg) in THF (10 mL), sodium hydride (60%, oily, 416 mg) was added in small increments at 0°C under a nitrogen atmosphere, and the mixture was stirred at 0°C for 0.5 hours. Then, 3-chloro-6-iodopyridazine (1.00 g) was added. The reaction mixture was stirred at 60°C for 2 hours, water was added at 25°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-{2-[(6-iodopyridazin-3-yl)oxy]ethyl}piperazine-1-carboxylate tert-butyl (1.50 g) as an oil.

[0251] Preparation Example 155: A mixture of tert-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate (500 mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (416 mg), dioxane (5 mL), and water (1 mL) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (122 mg) and potassium carbonate (460 mg), and the mixture was stirred at 100°C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid (450 mg). The mixture of the obtained solid (50 mg) and DCM (2 mL) was mixed with 2 M hydrochloric acid / dioxane (1 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure at 45°C to obtain (1S)-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethane-1-amine hydrochloride (35.0 mg) as a solid.

[0252] Preparation Example 156: A mixture of tert-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate (500 mg), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (444 mg), dioxane (5 mL), and water (1 mL) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (122 mg) and potassium carbonate (460 mg), and the mixture was stirred at 100°C for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a solid (510 mg). The mixture of the obtained solid (50 mg) and DCM (2 mL) was mixed with 2 M hydrochloric acid / dioxane (1 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure at 45°C to obtain (1S)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]ethane-1-amine hydrochloride (36.0 mg) as a solid.

[0253] Preparation Example 157 A mixture of 1,4-diiodobenzene (4.00 g), 2-(methylamino)ethane-1-ol (911 mg), potassium carbonate (3.35 g), and DMSO (60 mL) was purged with nitrogen for 3 minutes. Copper(I) iodide (231 mg) and L-proline (558 mg) were added, and the mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 2-[(4-iodophenyl)(methyl)amino]ethane-1-ol (1.09 g) as a solid.

[0254] Preparation Example 161: To a mixture of 2-bromo-5-iodopyridine (500 mg), 4-(propa-2-in-1-yl)piperazine-1-carboxylate tert-butyl (395 mg), TEA (1 mL), and THF (10.0 mL), copper(I) iodide (67.1 mg) and bis(triphenylphosphine)palladium(II) dichloride (124 mg) were added at 25°C under a nitrogen atmosphere, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an oily substance. To a solution of the resulting oily substance in ethyl acetate (10.0 mL), platinum(IV) oxide (287 mg) was added under a nitrogen atmosphere. The mixture was then purged with hydrogen after several periods of reduced pressure, and stirred under a hydrogen atmosphere (15 psi) at 25°C for 2 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain 4-[3-(6-bromopyridine-3-yl)propyl]piperazine-1-carboxylate tert-butyl (425 mg) as an oily substance.

[0255] Preparation Example 164 A mixture of methyl 3-chloro-4-[6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]benzoate (60.0 mg) and tert-butyl[(4-methylpiperidine-4-yl)methyl]carbamate (40.4 mg) in DMSO (1.5 mL) was mixed with DIPEA (57.1 mg) and stirred at 60°C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. A solution of the obtained solid in THF (2 mL) was mixed with a solution of lithium hydroxide monohydrate (10.8 mg) in water (0.5 mL) and stirred at 25°C for 2 hours. The reaction mixture was diluted with water, a 10% citric acid aqueous solution was added at 25°C to adjust the pH to 5-6, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-[6-(4-{[(tert-butoxycarbonyl)amino]methyl}-4-methylpiperidine-1-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoic acid (90.0 mg) as a solid.

[0256] Preparation Example 165: A mixture of tert-butyl{1-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (1.80 g), (2-chloro-4-hydroxyphenyl)boronic acid (686 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (243 mg), 2M sodium carbonate aqueous solution (3.32 mL), and dioxane (20 mL) was degassed three times, purged with nitrogen, and then stirred at 100°C for 3 hours under a nitrogen atmosphere. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain tert-butyl{1-[3-(2-chloro-4-hydroxyphenyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (1.56 g) as a solid.

[0257] Preparation Example 166: A mixture of tert-butyl{1-[3-(2-chloro-4-hydroxyphenyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl]-4-methylpiperidine-4-yl}carbamate (200 mg) and oxetan-2-one (106 mg) in THF (1 mL) was mixed with 1 M potassium tert-butoxide / THF solution (1.10 mL) under a nitrogen atmosphere, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH = 3 with 1 M hydrochloric acid, then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 3-{4-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorophenoxy}propanoic acid (120 mg) as an oily substance.

[0258] Preparation Example 167: A mixture of tert-butyl(1-{3-[6-chloro-2-(trifluoromethyl)pyridine-3-yl]-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl}-4-methylpiperidine-4-yl) carbamate (300 mg) and ethyl azetidine-3-carboxylate hydrochloride (108 mg) in dioxane (3 mL) was mixed with cesium carbonate (328 mg), RuPhos (94.0 mg), and RuPhos Pd G3 (84.2 mg) under a nitrogen atmosphere, and the mixture was stirred at 100°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain an oily substance. A solution of the obtained oily substance in THF (0.5 mL) was mixed with 2 M lithium hydroxide aqueous solution (349 μL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH = 3 by adding 1 M hydrochloric acid, after which it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-{5-[6-{4-[(tert-butoxycarbonyl)amino]-4-methylpiperidine-1-yl}-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-6-(trifluoromethyl)pyridine-2-yl}azetidine-3-carboxylic acid (140 mg) as an oily substance.

[0259] Preparation Example 168: A mixture of 1,4-diiodobenzene (350 mg), 4-[(azetidine-3-yl)oxy]piperidine-1-carboxylate tert-butyl (272 mg), potassium carbonate (293 mg), and DMSO (15 mL) was purged with nitrogen for 3 minutes. L-proline (48.9 mg) and copper(I) iodide (20.2 mg) were added, and the mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-{[1-(4-iodophenyl)azetidine-3-yl]oxy}piperidine-1-carboxylate tert-butyl (258 mg) as a solid.

[0260] Preparation Example 171 A mixed solution of 5-bromo-6-chloropyridine-2-carboxylic acid (500 mg) and glycine methyl hydrochloride (266 mg) in DMF (5 mL) was mixed with DIPEA (547 mg), EDCI·HCl (608 mg), and HOBt (429 mg), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was po...

Claims

1. A compound of formula (I) or a salt thereof. (In the formula, A is a group represented by the following formula (II) or formula (III), A1 is CR YN1 , A3 , A4 , , A1 , YN4 , A2 , 1 , 1-3 , YC1 , A5 , YN2 , YN3 , 1 , YN2 , A4 , A2 , 1-3 , 1-3 , YN4 , A5 , 1-3 , A3 , 1-3 , A1 , 1-3 , 1-3 , A1 or N, A2 is CR A2 or N, A3 is CR A3 or N, A4 is CR A4 or N, A5 is CR A5 or N, provided that two or more of A1 to A5 are not simultaneously N, R A1 , R A2 , R A3 , R A4 and R A5 are the same or different from each other and are H, optionally substituted C 1-3 alkyl, -O-(optionally substituted C 1-3 alkyl), halogen, cyano or a bond to A, provided that R A1 , R A2 , R A3 , R A4 and R A5 is only one bond to A, Y is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) and formula (XXV), n is the same or different from each other and is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different from each other and are 1 or 2, R YN1 is H or C 1-3 alkyl, R YN2 is H or C 1-3 alkyl, R YN3 is H or C 1-3 alkyl, R YC1 are the same or different from each other and are H or C 1-3 alkyl, X 1 is O or N(R YN4 ), R YN4 is H or C 1-3 alkyl, E 1 is CO or SO2, and also, R A1 contained in A1 and R YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 Furthermore, adjacent nitrogen atoms may unite to form a substituted 4- to 6-membered saturated heterocycle, and Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), (XIV), (XXVI), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other and may be substituted, Ar is an arylene which may be substituted, and R Z are the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, which may be the same or different from each other, and L may be bonded or substituted. 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV), (XVI), (XVII), (XVIII-1), and (XIX): k is an integer from 1 to 8, and is either the same or different from each other. 2 These are O, S, SO2, or NR X2 And R X2 H or C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, Hy1 is an optionally substituted heteroarylene, and W is one group or bond selected from the group consisting of the following formulas (XX), (XXI), and (XXII). Hy2, Hy3, and Hy4 are all heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a combination with L, where p is an integer from 1 to 3, and R a C may be substituted. 1-3 Alkyl or NR a1 2, R a1 H may be the same or different from each other, and C may be substituted. 1-3 Alkyl, or -E 2 -R a2 And R a2 C 1-3 Alkyl or aryl, E 2 is CO or SO2, R b H or C (which may be substituted) 1-3 It is an alkyl group, t is an integer from 0 to 2, and R c C may be substituted. 1-3 If it is alkyl, or if t is 2, R is bonded to a different carbon atom on the piperazine ring. c The two may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, or R a and R b These, together with the carbon atoms to which they are bonded, form a substituted or substituted 4- to 6-membered saturated heteroring or a substituted C 3-8 It may also form a cycloalkane, and EUB is given by the following formula (XXIII) or formula (XXIV): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 It is an alkyl or possibly substituted heteroaryl, where q is an integer from 1 to 3, Ar2 is an aryl or heteroaryl, and R Ar2 This includes H, halogens, and C, which may be substituted. 1-3 R7 is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8 (A cycloalkyl group, or a substituted 4- to 11-membered saturated heterocyclic group.) 2. Y is a group selected from the group consisting of the following formula (IV), formula (V), formula (VII), formula (VIII) and formula (XXV), n is the same or different from each other and is an integer from 0 to 8, m1 is 1 or 2, n1 and n2 are the same or different from each other and are 1 or 2, R YN1 is H or C 1-3 alkyl, R YN2 is H or C 1-3 alkyl, R YC1 are the same or different from each other and are H or C 1-3 alkyl, X 1 is O or N(R YN4 ) and R YN4 is H or C 1-3 alkyl, E 1 is CO or SO2, and also, R contained in A1 A1 and R contained in Y YN2 are combined so that R A1 and adjacent carbon atoms, and R YN2 and adjacent nitrogen atoms may be integrated to form an optionally substituted 4- to 6-membered saturated heterocycle, Z is a group selected from the group consisting of the following formula (IX), formula (X), formula (XI), formula (XIII), formula (XXVI) and formula (XXVII), Cy are the same or different from each other and are optionally substituted divalent groups of 4- to 11-membered saturated heterocycles, Ar is optionally substituted arylene, R Z are the same or different from each other and are H or C 1-3 alkyl, m are the same or different from each other and are integers from 0 to 8, L is a bond, optionally substituted C 1-8 alkylene, or a group selected from the group consisting of the following formula (XV) and formula (XVII), k are the same or different from each other and are integers from 1 to 8, X 2 is O, S, SO2 or NR X2 and R X2 is H or C 1-3 alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, and W is one group selected from the group consisting of the following formulas (XX) and (XXI). Hy2 and Hy3 are both heteroarylenes that may be substituted, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 H, C are the same or different from each other. 1-3 A bond with alkyl, halogen, cyano, or L, where R B1 , R B2 , R B3 , R B4 and R B5 One of these is a bond with L, and EUB is given by the following equation (XXIII): R5 may be replaced by C. 1-6 Alkyl, C may be substituted. 3-8 R6 is a cycloalkyl or optionally substituted 4- to 11-membered saturated heterocyclic group, where R6 is H or optionally substituted C 1-6 It is alkyl, Ar1 is aryl or heteroaryl, R Ar1 This includes H, halogens, and C, which may be substituted. 1-3 The compound or salt thereof according to claim 1, wherein the alkyl is an optionally substituted heteroaryl, and q is an integer from 1 to 3.

3. A is the group represented by the following formula (II): A1 is CR A1 Or N, and A2 is CR A2 Or N, and A3 is CR A3 And A4 is CR A4 And A5 is CR A5 or N, however, A1 to A5 cannot be N at two or more times, R A1 However, C may be substituted with H or halogen. 1-3 Alkyl, halogen, or cyano, R A2 However, C may be substituted with H or halogen. 1-3 Alkyl, halogen, or cyano, R A3 However, it is a bonding with A, and R A4 However, C may be substituted with H or halogen. 1-3 Alkyl, halogen, or cyano, R A5 However, C may be substituted with H or halogen. 1-3 It is alkyl, halogen, or cyano, and Y is one group selected from the group consisting of the following formulas (IV), (V), (VII), (VIII), and (XXV): n is an integer from 0 to 2, either identical or distinct from each other, m1 is 1 or 2, n1 and n2 are either identical or distinct from each other, and R YN1 H is R YN2 H is R YC1 are the same or different from each other, H or C 1-3 It is alkyl, X 1 is O or N(R YN4 ) and R YN4 H or C 1-3 It is alkyl, E 1 It is CO or SO2, and also R contained in A1. A1 and R included in Y YN2 When they combine, R A1 Also adjacent carbon atoms, and R YN2 Furthermore, adjacent nitrogen atoms may unite to form a substituted 4- to 6-membered saturated heterocycle, and Z is one group selected from the group consisting of the following formulas (IX), (XI), (XIII), (XXVI), and (XXVII). Cy is the same or different from C 1-3 A 4- to 11-membered saturated heterocyclic divalent group which may be substituted with a group selected from the group consisting of alkyl, halogen, and cyano, R Z H is H, m is the same or different from each other, 0 or 1, L is bonded, C 1-8 Alkylene, or one group selected from the group consisting of the following formulas (XV) and (XVII): k is an integer from 1 to 3, and is either the same or different from each other. 2 is O or NR X2 And R X2 C 1-3 It is alkyl, R LC1 are the same or different from each other, H or C 1-3 It is alkyl, and W is one group selected from the group consisting of the following formulas (XX) and (XXI). Hy2 is a 5- to 9-membered heteroarylene, Hy3 is a 5-membered heteroarylene, and B1 is CR B1 Or N, and B2 is CR B2 Or N, and B3 is CR B3 Or N, and B4 is CR B4 Or N, and B5 is CR B5 or N, however B1 to B5 cannot be N three or more at the same time, R B1 , R B2 , R B3 , R B4 and R B5 These are bonds with H, halogen, cyano, or L, which are identical or different from each other, except R B1 , R B2 , R B3 , R B4 and R B5 Of these, one is a bonding with L, and R a C may be substituted with NH2. 1-3 Alkyl or NR a1 2, R a1 are the same or different from each other, H or C 1-3 It is alkyl, and the C 1-3 The alkyl group may be substituted with -OMe or N(Me)2, R b H or C 1-3 It is alkyl, or R a and R b These, together with the carbon atoms to which they are bonded, form a 4- to 6-membered saturated heterocycle or C 3-8 A cycloalkane may be formed, and the 4- to 6-membered saturated heteroring and C 3-8 Cycloalkanes are composed of NH2 and C 1-3 It may be substituted with one or two groups selected from the group consisting of alkyl groups, and t is 0 or 2, and when t is 2, R c R is bonded to different carbon atoms on the piperazine ring. c The EUB may have a bridging structure composed of atoms selected from the group consisting of carbon atoms and oxygen atoms, and the EUB is given by the following formula (XXIII): R5 is C 1-6 Alkyl, C 3-8 It is a cycloalkyl group, and R6 may be substituted with H or OH. 1-6 It is alkyl, Ar1 is phenylene, R Ar1 C may be substituted with an oxo. 1-3 C is an alkyl or heteroaryl group, and the heteroaryl group may be substituted with an OH group. 1-3 The compound or salt thereof according to claim 2, which may be substituted with an alkyl group, and q is 1.

4. A is the group represented by the following formula (II): A1 is CR A1 Or N, and A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, it is H or F, and R A2 However, it is H, F, Cl, or trifluoromethyl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 is H or F, and Y is one base selected from the group consisting of the following formulas (IV-3), (IV-4), and (V-3): (Z * This indicates that it bonds with Z at this position. (The same applies below.) R YN2 H is H, and Z is a single base selected from the group consisting of the following equations (IX-11), (IX-21), (IX-3), (XI-11), (XIII-11), and (XXVI-1), (However, L * This indicates that it binds with L at this position. (The same applies below.) L is the bond, C 1-3 Alkylene, or the following formula (XV-2), (W * This indicates that it combines with W at this position. (The same applies below.) k is an integer from 2 to 3, and R LC1 is either H or methyl, and W is either the same or different from each other, and W is of the following formula (XXI-2) or formula (XXI-3): (L * This indicates that it binds with L at this position. (The same applies below.) B1 is CR B1 Or N, and B2 is CR B2 Or N, and B4 is CR B4 or N, however B1, B2 and B4 cannot all be N at the same time, and if B1, B2 or B4 is N, then B1 and B4 are both N, B2 and B4 are both N, B1 is N, or B2 is N, R B1 , R B2 and R B4 H or F are the same or different from each other, and R a C 1-3 Alkyl or NR a1 2, R a1 C may be identical or different from each other, and may be substituted with H or -OMe. 1-3 It is alkyl, R b C 1-3 It is alkyl, or R a and R b These may form a 4- to 6-membered saturated heterocycle together with the carbon atom to which they are bonded, and this 4- to 6-membered saturated heterocycle may be substituted with 1 to 2 groups selected from the group consisting of NH2 and Me, t is 0, and EUB is given by the following formula (XXIII), R5 is C 1-6 It is an alkyl group, and R6 may be substituted with an OH group. 1-6 It is alkyl, Ar1 is phenylene, R Ar1 is acetyl, or C 1-3 The compound or salt thereof according to claim 3, wherein the five-membered heteroaryl is a five-membered heteroaryl which may be substituted with an alkyl group, and the five-membered heteroaryl is one group selected from the group consisting of thiazolyl, oxazolyl, triazolyl, and pyrazolyl, and q is 1.

5. A is the group represented by the following formula (II): A1 is CR A1 Or N, and A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is H, Cl or trifluoromethyl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 H is H, and Y is a single base selected from the group consisting of the following equations (IV-3) and (V-4), Z is a single base selected from the group consisting of the following equations (IX-11), (IX-21), (XI-11), and (XIII-11): L is bond, C 1-3 Alkylene, or the following formula (XV-3), k is an integer between 2 and 3, and W is a base of 1 selected from the group consisting of the following equations: (XXI-3), (XXI-4), (XXI-5), (XXI-6), (XXI-7), and (XXI-8). R B1 is H or F, and R a , NR a1 2, R a1 H is R b C 1-3 It is alkyl, or R a and R b These may form a 4- to 6-membered saturated heterocycle together with the carbon atom to which they are bonded, and this 4- to 6-membered saturated heterocycle may be substituted with 1 to 2 groups selected from the group consisting of NH2 and Me, t is 0, and EUB is given by the following formula (XXIII), R5 is isopropyl, R6 is methyl or hydroxymethyl, Ar1 is phenylene, R Ar1 C 1-3 The compound or salt thereof according to claim 4, wherein the five-membered heteroaryl is a five-membered heteroaryl which may be substituted with an alkyl group, and the five-membered heteroaryl is one group selected from the group consisting of thiazolyl and pyrazolyl, and q is 1.

6. A is the group represented by the following formula (II): A1 is CR A1 And A2 is CR A2 And A3 is CR A3 And A4 is CR A4 And A5 is CR A5 And R A1 However, H is R A2 However, it is Cl, and R A3 However, it is a bonding with A, and R A4 However, H is R A5 H is H, and Y is a single base selected from the group consisting of the following equations (IV-3) and (V-4), Z is a single base selected from the group consisting of the following equations (IX-11), (IX-21), and (XI-11): L is given by the following equation (XV-3): k is an integer between 2 and 3, and W is given by the following equation (XXI-3) or equation (XXI-4-1): R a , NR a1 2, R a1 H is R b is Me, t is 0, and EUB is given by the following equation (XXIII): R5 is isopropyl, R6 is methyl or hydroxymethyl, Ar1 is phenylene, R Ar1 The compound or salt thereof according to claim 5, wherein is a thiazolyl which may be substituted with Me, and q is 1.

7. A is the group represented by the following formula (II), Y is a base selected from the group consisting of the following equations (IV), (V), (VI), and (VIII): n are integers from 0 to 8, either identical or distinct from each other, m1 is 1 or 2, R YN1 H or C 1-3 It is alkyl, R YN2 H or C 1-3 It is alkyl, R YN3 H or C 1-3 It is alkyl, R YC1 are the same or different from each other, H or C 1-3 It is an alkyl group, where Z is one group selected from the group consisting of the following formulas (IX), (X), (XI), (XII), (XIII), and (XXVII). Cy is a 4- to 11-membered saturated heterocycle divalent group which may be identical or different from each other, Ar is an arylene which may be substituted, and R Z However, they are the same or different from each other, H or C 1-3 It is an alkyl group, m is an integer from 0 to 8, either the same or different from each other, and L is given by the following formula (XVIII-1): k is 1 or 2, W is a bond, R a However, NR a1 2, R a1 However, C may be identical or different from each other, and may be H or substituted. 1-3 It is alkyl, R b However, C may be substituted. 1-3 It is alkyl, or R a and R b These are 4- to 6-membered saturated heterocycles, which may be substituted together with the carbon atoms to which they are bonded, or substituted C 3-8 It may also form a cycloalkane, where EUB is given by the following formula (XXIV): Ar2 is aryl or heteroaryl, R Ar2 However, H, halogen, and C may be substituted. 1-3 It is an alkyl or optionally substituted heteroaryl, where r is an integer from 1 to 3, Ar3 is an optionally substituted aryl or optionally substituted heteroaryl, and R7 is an optionally substituted C 1-6 Alkyl, C may be substituted. 3-8 The compound or salt thereof according to claim 1, which is a cycloalkyl or a substituted 4- to 11-membered saturated heterocycle.

8. The compound is (4R)-1-[(2S)-2-{4-[3-(2-{[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]oxy}ethoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-(2-{[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]oxy}ethoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(3-{2-[1-(3-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}-3-oxopropanoyl)piperidine-4-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-(3-{4-[{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chloroanilino}(oxo)acetyl]piperazine-1-yl}propoxy)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-N-[(1S)-1-(4-acetylphenyl)ethyl]-1-{(2S)-2-[4-(4-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{3-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]propoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{3-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]propyl}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(5-{2-[4-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperazine-1-yl]ethoxy}pyridine-2-yl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-{(2S)-2-[4-(3-{2-[1-(N-{4-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-3-chlorobenzoyl}glycyl)piperidine-4-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, and, The compound according to claim 1 or a salt thereof, which is a compound selected from the group consisting of (4R)-1-{(2S)-2-[4-(4-{2-[4-({5-[6-(4-amino-4-methylpiperidine-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl]-4-chloro-1-oxo-1,3-dihydro-2H-isoindole-2-yl}acetyl)piperazine-1-yl]ethoxy}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide.

9. A pharmaceutical composition comprising the compound or a salt thereof described in claim 1, and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for the treatment of cancer.

11. Use of the compound or salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for the treatment of cancer.

12. The compound or salt thereof according to claim 1 for use in the treatment of cancer.

13. Use of the compound or salt thereof according to claim 1 for the treatment of cancer.

14. A method for treating cancer comprising administering an effective amount of the compound or salt thereof described in claim 1 to a target.

Images