Hydroxy Pyrrolidine Derivatives and Their Pharmaceutical Uses

Abstract

The present invention provides a target protein degradation inducing compound which is a bifunctional compound having, at one terminal, a portion that binds to VHL which is a substrate recognition protein of a ubiquitin ligase complex and, at the other terminal, a portion that binds to a target protein. Specifically, the present invention provides a compound represented by structural formula (I) (in the formula, each symbol is as defined in the description) or a pharmacologically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to a target protein degradation-inducing compound which is a bifunctional compound having a portion that binds to Von-Hippel-Lindau, which is a substrate recognition protein of a ubiquitin ligase complex composed of a low molecular weight compound, at one end (hereinafter sometimes referred to as a VHL-binding ligand), and a portion or a binding portion capable of binding to a target protein at the other end (hereinafter sometimes referred to as a target-directed ligand), and is useful in the field of medicine.

Background Art

[0002] The ubiquitin-proteasome system is a system that degrades and removes unnecessary proteins in cells via ubiquitination of target proteins by the proteasome in an ATP-dependent manner, and plays an important role in cell growth, survival, and maintenance of homeostasis. The ubiquitin-proteasome system involves multiple enzymes called ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3), and ubiquitination of target proteins is achieved by their continuous function. In particular, target proteins that have undergone so-called polyubiquitination, in which ubiquitin chains are linked via the 48th lysine residue of ubiquitin, are efficiently recognized by the proteasome and degraded. It has been reported that humans have two types of ubiquitin-activating enzymes, approximately 40 types of ubiquitin-conjugating enzymes, and approximately 600 types of ubiquitin ligases, and it is known that substrate recognition by ubiquitin ligases is strictly regulated. There are ubiquitin ligases that function alone and those that function by forming a complex. In particular, in the latter case, the substrate recognition protein has a complex structure in which it binds to the scaffold protein via an adapter protein, and this substrate recognition protein determines the substrate protein to be ubiquitinated. In recent years, it has been reported that by chemically linking a compound that binds to several proteins (target-directed ligand) and a compound that binds to the substrate recognition protein, it is possible to induce the degradation of a protein that is not originally a substrate of the ubiquitin ligase. To date, research on selective protein degradation induction (chemical knockdown) via ubiquitin ligase using small-molecule compounds has been underway.

[0003] In recent years, a technology that forms an artificial complex of E3 and a target protein in cells using a compound in which a ligand of E3 [VHL, Cereblon (CRBN), Cellular Inhibitor of Apoptosis Protein1 (cIAP1)] having ubiquitin ligase activity and an inhibitor of the target protein are linked, and induces the degradation of the target protein by utilizing the ubiquitin-proteasome system, which is an intracellular proteolytic mechanism, has attracted attention as a new drug discovery technology (Non-Patent Document 1).

[0004] Patent Document 1 discloses a bifunctional compound having a VHL ligand that binds to VHL, which is a substrate recognition protein of ubiquitin ligase, at one end and a moiety that binds to a target protein at the other end.

[0005] Patent Document 2 discloses a bifunctional compound having a CRBN ligand that binds to CRBN, which is a substrate recognition protein of ubiquitin ligase, at one end and a moiety that binds to a target protein at the other end.

[0006] Patent Document 3 discloses a bifunctional compound having a proline compound as a ligand for the substrate recognition protein IAP of the ubiquitin ligase complex.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0008]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0009] As described above, the induction of selective degradation of target proteins by bifunctional compounds has been studied, but the range of applicable target proteins and the effect of degradation induction have not necessarily been sufficient. Therefore, research and development of bifunctional compounds utilizing more effective low-molecular-weight compounds have been desired.

Means for Solving the Problems

[0010] As a result of intensive studies to solve the above problems, the present inventors have completed the present invention. The present invention is as follows.

[0011] [1] The following structural formula (I):

[0012] [Chemical formula]

[0013] (In the formula, L is bonded to either W or X; E represents a bond, -CO-, -SO-, or -SO 2 -; X represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; W represents an optionally substituted aryl group, an optionally substituted condensed heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 6 to 10 ring-constituting atoms, an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms, an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a heterocyclic group, a cyano group, or a hydrogen atom; L represents a bond or a chemical linker; and A represents a target-directed ligand.) A compound represented by the formula (hereinafter sometimes referred to as compound (I)) or a pharmacologically acceptable salt thereof. [2] The compound represented by the structural formula (I) is the compound represented by the following structural formula (Ia) or (Ib), the compound according to the above [1], or a pharmacologically acceptable salt thereof.

[0014]

Chemical formula

[0015] (In the formula, E, X, W, L, and A have the same meanings as described above, and X 1 and W 1 each represent a divalent group derived from X and W, respectively.)

[0016] [3] The compound according to the above [1] or [2], or a pharmacologically acceptable salt thereof, wherein W is an optionally substituted condensed heterocyclic group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and having 6 to 10 ring-constituting atoms. [4] W is a group of the formula:

[0017]

Chemical formula

[0018] [In the formula, group A is an optionally substituted heteroaryl group having 5 ring-constituting atoms, and two A 1 are each independently a group or atom selected from CR Z1 , N, NR Z2 , O, and S, two A 2 each independently represent C or N; and ring Q is an aromatic hydrocarbon ring, an aromatic heterocyclic ring optionally containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, a non-aromatic hydrocarbon ring, or represents a heterocyclic ring which may contain 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the ring has 5 to 7 ring-constituting atoms and, at substitutable positions, a halogen atom, a hydroxy group, a cyano group, a hydroxycarbonyl group, an oxo group, a thioxo group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, -CO―N(R 7a )(R 7b ), -N(R 7a )(R 7b ), -N(R 7c )―CO―R 7d , and -CO―R 7e , may be substituted with a group selected from. (In the above formulas, R Z1 and R Z2 each independently represent a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an optionally substituted alkyl group; an optionally substituted cycloalkyl group; an optionally substituted alkoxy group; an optionally substituted alkoxycarbonyl group; -CO―N(R 7a )(R 7b ); -N(R 7a )(R 7b ); -N(R 7c )―CO―R 7d ; an aryl group; or an optionally substituted heteroaryl group containing 1 to 3 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and having 5 to 6 ring-constituting atoms (provided that R Z2 represents a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; -N(R 7a)(R 7b ) or -N(R 7c )-CO-R 7d is not); R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group, or R 7a and R 7b may be bonded to each other to form, together with the adjacent nitrogen atom, a heterocycle which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; R 7c and R 7d each independently represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; and R 7e represents an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, or a heteroaryl group which may be substituted.)] The compound or a pharmacologically acceptable salt thereof according to any one of [1] to [3] above, which is a group represented by. [5] W is a group of the formula:

[0019] [Chemical formula]

[0020] [wherein, A x1 is a group or atom selected from -NR Z2 -, -O- and -S-, ring Q is a non-aromatic hydrocarbon ring having 5 or 6 ring-constituting atoms; or a heterocycle having 5 or 6 ring-constituting atoms, which may contain 1 to 4 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and wherein the ring is, at a substitutable position, a halogen atom, an alkyl group having 1 to 6 carbon atoms, and -CO-R7e It may be substituted by a substituent selected from the following. (In the formula, R z2 and R 7e have the same meanings as described above.)] The compound according to any one of [1] to [4] above or a pharmacologically acceptable salt thereof, which is a group represented by

[0021] [6] The compound according to [1] above or a pharmacologically acceptable salt thereof, wherein W is an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the number of ring-constituting atoms is 3 to 10. [7] W is a group represented by the formula:

[0022]

Chemical formula

[0023] [In the formula, group A' is a heteroaryl group having 5 ring-constituting atoms, and A 3a , A 3b , A 3c and A 3d are each independently an atom selected from a nitrogen atom, an oxygen atom, a carbon atom and a sulfur atom, and when A 3a , A 3b , and A 3c are nitrogen atoms or carbon atoms, they each have R a1 , R a2 and R a3 . Here, R a1 is (1) a hydrogen atom, (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted aryl group, (5) an optionally substituted heteroaryl group, or (6) an optionally substituted heterocyclic group. is shown, and R a2 and R a3 are each independently (1) a hydrogen atom, (2) -CN, (3) a halogen atom, (4) an optionally substituted alkyl group, (5) an optionally substituted cycloalkyl group, (6) an optionally substituted aryl group, (7) an optionally substituted heteroaryl group, (8) an optionally substituted heterocyclic group, (9) -V a3a -(optionally substituted alkyl), (10) -V a3a -(optionally substituted cycloalkyl), (11) -V a3a -(optionally substituted aryl), (12) -V a3a -(optionally substituted heteroaryl), or (13) -V a3a -(optionally substituted heterocyclic group) (In the above formula, V a3a is 1) -CO-, 2) -NR Va3 -[[]] (wherein R Va3 is (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (c) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms .), 3) -O-, 4) -S-, 5) -SO-, or 6) -SO 2 -[[]] .), or (14) -V a3b -NR Na3 R Na3’ (wherein V a3b is 1) -CO- 2) -SO-, or 3) -SO 2 - represents, R Na3 and R Na3’ are each independently, 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) an optionally substituted cycloalkyl group, 4) an optionally substituted aryl group, 5) an optionally substituted heteroaryl group, or 6) an optionally substituted heterocyclic group represents.) represents.] The compound or a pharmaceutically acceptable salt thereof according to the above [1] or [6], which is a group represented by. [8] The compound or a pharmaceutically acceptable salt thereof according to the above [7], wherein the group A' is an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, an isothiadiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a triazolyl group, or a tetrazolyl group. [9] The compound or a pharmaceutically acceptable salt thereof according to the above [8], wherein the group A' is a group selected from an imidazolyl group, a thiazolyl group, and an oxazolyl group.

[10] W is of the formula:

[0024] [Chemical formula]

[0025] [wherein, A 6 is -O-, -S-, or -NR 6a1 - (wherein R 6a1 is, (1) a hydrogen atom, (2) an optionally substituted alkyl group, (3) An optionally substituted cycloalkyl group, (4) An optionally substituted aryl group, (5) An optionally substituted heteroaryl group, or (6) An optionally substituted heterocyclic group .) ; R 6a2 is (1) A hydrogen atom, (2) CN, (3) A halogen atom, (4) An optionally substituted alkyl group having 1 to 4 carbon atoms, (5) An optionally substituted cyclopropyl group, (6) An optionally substituted oxetanyl group, (7) An optionally substituted azetidinyl group, (8) An optionally substituted aryl group having 6 to 10 carbon atoms, or (9) -CO-NR a2N6 R a2N6’ (In the formula, R a2N6 and R a2N6’ are each independently 1) A hydrogen atom, 2) An optionally substituted alkyl group having 1 to 4 carbon atoms, 3) An optionally substituted cyclopropyl group, 4) An optionally substituted oxetanyl group, or 5) An optionally substituted azetidinyl group. .) ; and R 6a3 is (1) A hydrogen atom, (2) -CN, (3) A halogen atom, (4) An optionally substituted alkyl group, (5) An optionally substituted cycloalkyl group, (6) An optionally substituted aryl group, (7) An optionally substituted heteroaryl group, (8)A heterocyclic group which may be substituted, (9) -CO-(a heterocyclic group which may be substituted), or (10) -CO-NR a3N6 R a3N6’ (wherein R a3N6 and R a3N6’ are each independently 1) a hydrogen atom, 2) an alkyl group which may be substituted, 3) a cycloalkyl group which may be substituted, 4) an aryl group which may be substituted, 5) a heteroaryl group which may be substituted, or 6) a heterocyclic group which may be substituted .) .] The compound or a pharmaceutically acceptable salt thereof according to [1], [6] to [9] above, which is a group represented by .

[11] W is a group of the formula:

[0026] [Chemical formula]

[0027] [wherein A 6 is -S- or -NR 6a1 - (wherein R 6a1 is (1) a hydrogen atom, or (2) an alkyl group which may be substituted), .) ; R 6a2 is (1) a hydrogen atom, (2) an alkyl group having 1 to 4 carbon atoms which may be substituted, (3) an aryl group having 6 to 10 carbon atoms which may be substituted, or (4) -CO-NR a2N6 R a2N6’ (In the formula, R a2N6 and R a2N6’ each independently represent an optionally substituted alkyl group having 1 to 4 carbon atoms.) and; and R 6a3 is (1) a hydrogen atom, (2) an optionally substituted alkyl group, (3) an optionally substituted aryl group, (4) -CO-(optionally substituted heterocyclic group), or (5) -CO-NR a3N6 R a3N6’ (In the formula, R a3N6 and R a3N6’ each independently represent 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) an optionally substituted cycloalkyl group, or 4) an optionally substituted heterocyclic group .) .] The compound or a pharmaceutically acceptable salt thereof according to the above [1], [6] to

[10] , which is a group represented by .

[0028]

[12] R 6a1 is a hydrogen atom, and R 6a3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, the compound or a pharmaceutically acceptable salt thereof according to

[10] or

[11] .

[13] A 6 is -S- or -NH-, and R 6a2 is hydrogen, the compound or a pharmaceutically acceptable salt thereof according to the above

[12] .

[0029]

[14] R 6a1 is a hydrogen atom, and R 6a3 is (1) -Y 6a -W6a (In the formula, Y 6a is 1) a bond, 2) -(CR Y1 R Y1’ ) ny6a -A Y6a -(CR Y2 R Y2’ ) ny6b - (In the formula, R Y1 , R Y1’ , R Y2 and R Y2’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted alkyl having 1 to 6 carbon atoms), (d) -O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), (e) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (f) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms or, (g) R Y1 and R Y1’ , and R Y2 and R Y2’ are each independently bonded to each other to form, together with adjacent carbon atoms, an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or an optionally substituted heterocycle having 3 to 10 ring-constituting atoms and containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms, ny6a represents an integer of 1 to 6, A Y6a is (a) a bond, (b) -CO-, (c) -O-, (d) -SO-, (e) -SO 2 -, (f) -NR NY6a (In the formula, R NY6a is​ (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (v) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (vi) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) is shown.), or (g) -V Y6b -NR NY6b - or -NR NY6b -V Y6b - (In the formula, V Y6b is (i) -CO-, (ii) -SO-, or (iii) -SO 2 - is shown, R NY6b is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms is shown.) is shown, ny6b represents an integer from 0 to 6, and W 6a is 1) a hydrogen atom, 2) a halogen atom, 3) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, 4) an optionally substituted aryl group having 6 to 10 carbon atoms, 5) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, or 6) Optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 3 to 10 ring-constituting atoms is shown.) The compound or its pharmacologically acceptable salt according to the above

[10] or

[11] , which is shown by .

[15] A 6 is -S- or -NR 6a1 -, R 6a1 is a hydrogen atom, and R 6a3 is (1) -Y 6a -W 6a (In the formula, Y 6a is 1) A bond, 2) -(CR Y1 R Y1’ ) ny6a -A Y6a -(CR Y2 R Y2’ ) ny6b - (In the formula, R Y1 , R Y1’ , R Y2 and R Y2’ are each independently (a) A hydrogen atom, ny6a represents an integer of 1 to 6, A Y6a is (a) A bond, (b) -O-, (c) -NR NY6a -, (In the formula, R NY6a is Optionally substituted alkyl group having 1 to 6 carbon atoms, is shown.), or (d) -V Y6b -NR NY6b - or -NR NY6b -V Y6b - (In the formula, V Y6b is -CO-, represents, R NY6b is, an alkyl group having 1 to 6 carbon atoms which may be substituted, represents, ny6b represents an integer from 0 to 6, and W 6a is, 1) a hydrogen atom, 2) a cycloalkyl group having 3 to 10 carbon atoms which may be substituted, 3) an aryl group having 6 to 10 carbon atoms which may be substituted, or represents.) The compound according to the above

[14] or a pharmacologically acceptable salt thereof, which represents.

[16] A 6 is -S- or -NR 6a1 -, R 6a1 is a hydrogen atom, and R 6a3 is, (1) -Y 6a -W 6a (wherein, Y 6a is, 1) a bond, 2) -(CR Y1 R Y1’ ) ny6a -A Y6a -(CR Y2 R Y2’ ) ny6b - (wherein, R Y1 , R Y1’ , R Y2 and R Y2’ are each independently, a hydrogen atom, ny6a represents an integer from 1 to 6, A Y6a is, (a) a bond (b) -O-, (c) -NR NY6a (wherein R (wherein, R NY6a is, An alkyl group having 1 to 6 carbon atoms which may be substituted by a substituent selected from a cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms, is shown.), or (d)-V Y6b -NR NY6b - or -NR NY6b -V Y6b - (In the formula, V Y6b is -CO-, is shown, R NY6b is An alkyl group having 1 to 6 carbon atoms which may be substituted by a group selected from a cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms, is shown, ny6b represents an integer of 0 to 6, and W 6a is 1) A hydrogen atom, 2) A cycloalkyl group having 3 to 10 carbon atoms, or 3) An aryl group having 6 to 10 carbon atoms, is shown.) is shown, the compound according to the above

[14] or

[15] or a pharmacologically acceptable salt thereof.

[17] W 6a is -W 6a’ -(CR Y3 R Y3’ ) ny6c -A Y6b -(CR Y4 R Y4’ ) ny6d -W 6b [In the formula, W 6a’ is (1) An optionally substituted divalent cycloalkyl group having 3 to 10 carbon atoms, (2) An optionally substituted divalent aryl group having 6 to 10 carbon atoms, (3) An optionally substituted divalent heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, or (4) A divalent heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 3 to 10 ring-constituting atoms. is shown as R Y3 , R Y3’ , R Y4 and R Y4’ are each independently (1) A hydrogen atom, (2) A halogen atom, (3) -O-(optionally substituted alkyl having 1 to 6 carbon atoms), (4) -O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), (5) An optionally substituted alkyl group having 1 to 6 carbon atoms, (6) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown, or (7) R Y3 and R Y3’ and R Y4 and R Y4’ are each independently bonded to each other to form, together with adjacent carbon atoms, an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or an optionally substituted heterocycle containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and having 3 to 10 ring-constituting atoms, A Y6b is (1) A bond, (2) -O-, (3) -SO-, (4) -SO 2 -, (5) -NR NY6c (wherein R NY6c is 1) A hydrogen atom, 2) An optionally substituted alkyl group having 1 to 6 carbon atoms, 3) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms, 4) An optionally substituted heterocyclic group having 3 to 6 carbon atoms, ​5) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or 6) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) is shown.), or (6) -V Y6d -NR NY6d - or -NR NY6d -V Y6d -[[]]END]] (In the formula, V Y6d is (a) -CO-, (b) -SO-, or (c) -SO 2 -[[]]END]] is shown.), and R NY6d is 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or 4) an optionally substituted heterocyclic group having 3 to 6 carbon atoms is shown.) is shown, ny6c and ny6d each independently represent an integer from 0 to 6, W 6b is (1) a hydrogen atom, (2) a halogen atom, (3) an optionally substituted aryl group having 6 to 10 carbon atoms, (4) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, (5) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (6) an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms, (7) -CO-(an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms), (8) -CONRNW6 R NW6’ (wherein, R NW6 and R NW6’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, or 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms .), or (9) -NR NW6’’ R NW6’’’ (wherein, R NW6’’ and R NW6’’’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, 4) an optionally substituted heterocyclic group having 3 to 6 carbon atoms, 5) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or 6) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) .) .] represents the compound described in the above

[14] to

[16] or a pharmaceutically acceptable salt thereof.

[18] W 6a is -W 6a’ -(CR Y3 R Y3’ ) ny6c -A Y6b -(CR Y4 R Y4’ ) ny6d -W 6b [wherein, W 6a’ is (1) an optionally substituted divalent cycloalkyl group having 3 to 10 carbon atoms, (2) an optionally substituted divalent aryl group having 6 to 10 carbon atoms, and R Y3 , RY3’ , R Y4 and R Y4’ are each independently (1) a hydrogen atom, or (2) a halogen atom, A Y6b is (1) a bond, (2) -O-, or (3) -V Y6d -NR NY6d - (wherein V Y6d is (a) -CO-, is shown. ) is shown, and R NY6d is an optionally substituted alkyl group having 1 to 6 carbon atoms, is shown. ) and ny6c and ny6d are each independently an integer from 0 to 6, W 6b is (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted heteroaryl group having 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, is shown. ] is shown, the compound according to

[14] to

[17] above or a pharmacologically acceptable salt thereof.

[19] W 6a is -W 6a’ -(CR Y3 R Y3’ ) ny6c -A Y6b -(CR Y4 R Y4’ ) ny6d -W 6b [wherein, W 6a’ is (1) a cycloalkyl divalent group having 3 to 10 carbon atoms, (2) an aryl divalent group having 6 to 10 carbon atoms, is shown, R Y3 、R Y3’ 、R Y4 and R Y4’ each independently represents (1) a hydrogen atom, or (2) a halogen atom, A Y6b represents (1) a bond, (2) -O-, or (3) -V Y6d -NR NY6d - (wherein V Y6d represents -CO-, ). And R NY6d represents an alkyl group having 1 to 6 carbon atoms, ).) represents, ny6c and ny6d each independently represent an integer from 0 to 6, W 6b represents (1) a hydrogen atom, (2) a halogen atom, or (3) a heteroaryl group which may be substituted by an alkyl group having 1 to 6 carbon atoms and contains 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms and has 5 to 6 ring-constituting atoms, ).] represents the compound according to

[14] to

[18] above or a pharmaceutically acceptable salt thereof.

[20] wherein ny6c and ny6d both represent 0, and A Y6b represents a bond, the compound according to

[17] to

[19] above or a pharmaceutically acceptable salt thereof.

[0030]

[21] R 6a1 represents (1) a hydrogen atom, or (2) an optionally substituted alkyl group and R 6a2 represents (1) A hydrogen atom, (2) CN, (3) A halogen atom, (4) An optionally substituted alkyl group having 1 to 4 carbon atoms, (5) An optionally substituted cyclopropyl group, (6) An optionally substituted oxetanyl group, (7) An optionally substituted azetidinyl group, or (8) An optionally substituted aryl group having 6 to 10 carbon atoms and R 6a3 is of the formula: -CO-R 9a -W 9a -Y 9b -W 9b [In the formula, R 9a is (1) The formula:

[0031]

Chemical formula

[0032] (In the formula,

[0033]

Chemical formula

[0034] is a Y which contains a nitrogen atom and may further contain 1 to 5 identical or different atoms selected from nitrogen, oxygen and sulfur atoms, and has 3 to 10 ring-constituting atoms, 9a and in addition, an optionally further substituted heterocyclic group, and Y 9a is 1)-(CR Y5 R Y5’ ) ny9a -A Y9a -(CR Y6 R Y6’ ) ny9b - (In the formula, R Y5, R Y5’ , R Y6 and R Y6’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted C1-C6 alkyl), (d) -O-(optionally substituted C3-C6 cycloalkyl), (e) an optionally substituted C1-C6 alkyl group, (f) an optionally substituted C3-C6 cycloalkyl group or (g) R Y5 and R Y5’ and R Y6 and R Y6’ are each independently bonded to each other to form, together with adjacent carbon atoms, an optionally substituted C3-C10 cycloalkyl group, or an optionally substituted heterocyclic ring having 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms; ny9a and ny9b each independently represent an integer from 0 to 6; A Y9a is (a) a bond, (b) -O-, (c) -SO-, (d) -SO 2 -, (e) -NR NY9c - (wherein R NY9c is (i) a hydrogen atom, (ii) an optionally substituted C1-C6 alkyl group, (iii) an optionally substituted C3-C6 cycloalkyl group, (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (v) -CO-(optionally substituted C1-C6 alkyl), or (vi) -CO-(optionally substituted C3-C6 cycloalkyl) is shown.) (f)-V Y9d -NR NY9d - or -NR NY9d -V Y9d - (In the formula, V Y9d is (i)-CO- (ii)-SO-, or (iii)-SO 2 - is shown, and R NY9d is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms.) is shown.) is shown.] a group represented by, or (2) Formula: -NR N9 -,-NR N9 -(CR Y7 R Y7’ ) n9 - -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -(CR Y8 R Y8’ ) m9 - -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -NR N9’ -(CR Y8 R Y8’ ) m9 - -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’ -V 9 -(CR Y8 R Y8’ ) m9 - -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’’ -(CR Y8 R Y8’ ) m9 -、 -NR N9 -(CR Y7 R Y7’ ) o9 -O-(CR Y8 R Y8’ ) m9 -、 or -NR N9 -(CR Y7 R Y7’ ) o9 -S-(CR Y8 R Y8’ ) m9 - [In the above formula, R N9 is 1) a hydrogen atom, 2)-(CR N9a R N9a’ ) nN9a -Y N9 -W N9 (wherein R N9a and R N9a’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c)-O-(optionally substituted C1-C6 alkyl), (d)-O-(optionally substituted C3-C6 cycloalkyl), (e) an optionally substituted C1-C6 alkyl group, (f) an optionally substituted C3-C6 cycloalkyl group or (g) R N9a and R N9a’ are bonded to each other and, together with the adjacent carbon atoms, form an optionally substituted C3-C10 cycloalkyl group, or It may form an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 3 to 10 ring-constituting atoms; nN9a represents an integer from 1 to 6; Y N9 is (a) a bond -, (b) -O-, (c) -SO-, (d) -SO 2 -, (e) -NR N9b - (wherein R N9b is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (v) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (vi) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms is shown. ), or (f) -V N9c -NR N9c - or -NR N9c -V N9c - (wherein V N9c is (i) -CO-, (ii) -SO-, or (iii) -SO 2 - is shown, R N9c is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown. ) is shown, W N9 is (a) a hydrogen atom, (b) An optionally substituted alkyl group having 1 to 6 carbon atoms, (c) An optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (d) An optionally substituted aryl group having 6 to 10 carbon atoms, (e) An optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, and having 3 to 10 ring-constituting atoms, or (f) A halogen atom is shown.) is shown; R Y7 、R Y7’ 、R Y8 and R Y8’ are each independently 1) A hydrogen atom, 2) A halogen atom, 3) -O-(optionally substituted alkyl having 1 to 6 carbon atoms), 4) -O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), 5) An optionally substituted alkyl group having 1 to 6 carbon atoms, 6) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown, or 7) R Y7 and R Y7’ and R Y8 and R Y8’ may each independently bond to each other to form, together with adjacent carbon atoms, an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or an optionally substituted heterocycle containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms; n9 represents an integer of 1 to 6; V 9 is 1) -CO-, 2) -SO-, 3) -SO 2 -, or 4) An optionally substituted divalent heterocyclic group having 3 to 6 ring-constituting atoms is shown; m9 represents an integer of 0 to 6; R N9’ represents 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or 4) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms ; o9 represents an integer of 2 to 6; R N9’’ represents 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, 4) an optionally substituted heterocyclic group having 3 to 6 carbon atoms, 5) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or 6) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) . A group represented by; W 9a represents (1) an optionally substituted alkylene group having 1 to 6 carbon atoms, (2) an optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) an optionally substituted heteroaryl divalent group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 to 10 ring-constituting atoms, (4) an optionally substituted cycloalkyl divalent group having 3 to 10 carbon atoms, or (5) an optionally substituted heterocyclic divalent group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3 to 10 ring-constituting atoms, Y 9b represents (1) -(CR Y9 R Y9’ )ny9c-A Y9b -(CR Y10 R Y10’ )ny9d- (wherein, R​​​​​​​Y9 , R Y9’ , R Y10 and R Y10’ are each independently 1) a hydrogen atom, 2) a halogen atom, 3) -O-(optionally substituted alkyl having 1 to 6 carbon atoms), 4) -O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), 5) optionally substituted alkyl having 1 to 6 carbon atoms, or 6) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or 7) R Y9 and R Y9’ as well as R Y10 and R Y10’ are each independently bonded to each other to form, together with adjacent carbon atoms, an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom and having 3 to 10 ring-constituting atoms, ny9c and ny9d each independently represent an integer of 0 to 6, A Y9b is 1) a bond, 2) -O-, 3) -SO-, 4) -SO 2 -, 5) -NR NY9e -, (wherein R NY9e is (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (d) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (e) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), (f) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) .), or 6)-V Y9f -NR NY9f - or -NR NY9f -V Y9f - (wherein, V Y9f is (i) -CO-, (ii) -SO-, or (iii) -SO 2 - represents, R NY9f is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms ).) represents, W 9b is (1) a hydrogen atom, (2) a halogen atom, (3) an optionally substituted aryl group having 6 to 10 carbon atoms, (4) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, (5) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (6) an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, or (7) -CONR NW9 R NW9’ (wherein, R NW9 and R NW9’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, or 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms ).), or 4) -NRNW9’’ R NW9’’’ (wherein R NW9’’ and R NW9’’’ are each independently (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (d) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (e) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (f) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) .) .] A compound or a pharmaceutically acceptable salt thereof according to

[10] or

[11] , which is a group represented by .

[22] R 6a1 is (1) a hydrogen atom, or (2) an optionally substituted alkyl group .

[0035] R 6a2 is (1) a hydrogen atom, (2) an optionally substituted alkyl group having 1 to 4 carbon atoms, or (3) an optionally substituted aryl group having 6 to 10 carbon atoms .

[0036] R 6a3 is of the formula: -CO-R 9a -W 9a -Y 9b -W 9b [wherein R 9a is (1) the formula:

[0037]

Chemical formula

[0038] (wherein,

[0039] [Chemical formula]

[0040] is Y which contains a nitrogen atom and may further contain 1 to 5 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and has 3 to 10 ring constituent atoms 9a represents a heterocyclic group which may be further substituted in addition to Y 9a is 1)-(CR Y5 R Y5’ ) ny9a -A Y9a -(CR Y6 R Y6’ ) ny9b - (wherein, R Y5 、R Y5’ 、R Y6 and R Y6’ each independently represent a hydrogen atom, ny9a and ny9b each independently represent an integer from 0 to 6, A Y9a is (a) a bond, (b) -O-, (c) -NR NY9c - (wherein, R NY9c is (i) represents a hydrogen atom), or (d) -V Y9d -NR NY9d - or -NR NY9d -V Y9d - (wherein, V Y9d is (i) -CO- represents, and R NY9d is (i) a hydrogen atom, or (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, is shown.] a group represented by, or

[0041] (2) Formula: -NR N9 -, -NR N9 -(CR Y7 R Y7’ ) n9 -, -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -NR N9’ -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’ -V 9 -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’’ -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) o9 -O-(CR Y8 R Y8’ ) m9 -, or [In the above formula, R N9 is 1) a hydrogen atom, 2)-(CR N9a R N9a’ )nN9a -Y N9 -W N9 (wherein, R N9a and R N9a’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (d) R N9a and R N9a’ may be bonded to each other to form, together with adjacent carbon atoms, an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or an optionally substituted heterocyclic group having 3 to 10 ring-constituting atoms, containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms; nN9a represents an integer from 1 to 6; Y N9 is (a) a bond, (b) -O-, or (c) -NR N9c -V N9c - (wherein, V N9c is (i) -CO-, and R N9c is (i) a hydrogen atom, or (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, .) represents, W N9 is (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (d) an optionally substituted aryl group having 6 to 10 carbon atoms, or (e) a halogen atom .) represents; R Y7 , R Y7’ , R Y8 and RY8’ independently represents 1) a hydrogen atom, or 2) an optionally substituted alkyl group having 1 to 6 carbon atoms ; n9 represents an integer from 1 to 6; V 9 represents 1) -CO-, or 2) an optionally substituted divalent heterocyclic group having 3 to 6 ring-constituting atoms m9 represents an integer from 0 to 6; R N9’ represents 1) a hydrogen atom, or 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, ; o9 represents an integer from 2 to 6; R N9’’ represents 1) a hydrogen atom, ;] a group represented by;

[0042] W 9a represents (1) an optionally substituted alkylene group having 1 to 6 carbon atoms, (2) an optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) an optionally substituted heteroaryl divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, or (4) an optionally substituted cycloalkyl divalent group having 3 to 10 carbon atoms, or an optionally substituted divalent heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms,

[0043] Y 9b represents (1) -(CR Y9 R Y9’ )ny9c-A Y9b -(CR Y10 R Y10’ )ny9d- (wherein, R Y9 , R Y9’ , R Y10 and R Y10’ are each independently 1) a hydrogen atom, or 2) a halogen atom, ny9c and ny9d each independently represent an integer from 0 to 6, A Y9b is 1) a bond, or 2) -O-, ).) represents, and

[0044] W 9b is (1) a hydrogen atom, (2) a halogen atom, (3) an aryl group having 6 to 10 carbon atoms, (4) a heteroaryl group which may be substituted and contains 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and has 5 to 10 ring-constituting atoms, (5) -CONR NW9 R NW9’ (wherein, R NW9 and R NW9’ are each independently 1) a hydrogen atom, or 2) a optionally substituted alkyl group having 1 to 6 carbon atoms).) .) The compound according to

[21] above or a pharmaceutically acceptable salt thereof, which is a group represented by

[23] R 6a1 is (1) a hydrogen atom, or (2) an optionally substituted alkyl group substituted by an optionally substituted aryl group having 6 to 10 carbon atoms and

[0045] R 6a2 is (1) a hydrogen atom, (2) an alkyl group having 1 to 4 carbon atoms, or (3) An aryl group having 6 to 10 carbon atoms which may be substituted by a group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and a halogen and

[0046] R 6a3 is of the formula: -CO-R 9a -W 9a -Y 9b -W 9b [wherein, R 9a is (1) The formula:

[0047]

Chemical formula

[0048] (wherein,

[0049]

Chemical formula

[0050] is Y which contains a nitrogen atom and may further contain 1 to 5 identical or different atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and has 3 to 10 ring-constituting atoms 9a represents a heterocyclic group which may be further substituted in addition to Y 9a is 1)-(CR Y5 R Y5’ ) ny9a -A Y9a -(CR Y6 R Y6’ ) ny9b - (wherein R Y5 , R Y5’ , R Y6 and R Y6’ each independently represent (a) a hydrogen atom, ny9a and ny9b each independently represent an integer of 0 to 6; AY9a is (a) bond, (b) -O-, (c) -NR NY9c - (wherein R NY9c is (i) represents a hydrogen atom), or (d) -V Y9d -NR NY9d - or -NR NY9d -V Y9d - (wherein V Y9d is (i) -CO-, represents) represents, and R NY9d is (i) a hydrogen atom, or (ii) an alkyl group having 1 to 6 carbon atoms, represents.) represents.] a group represented by, or (2) formula: -NR N9 -, -NR N9 -(CR Y7 R Y7’ ) n9 (wherein R -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -(CR Y8 R Y8’ ) m9 -(wherein R -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -NR N9’ -(CR Y8 R Y8’ ) m9 -(wherein R -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’ -V 9 -(CR Y8 R Y8’ ) m9 -(wherein R -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’’ -(CR Y8 R Y8’ ) m9 -、-NR N9 -(CR Y7 R Y7’ ) o9 -O-(CR Y8 R Y8’ ) m9 -、 or -NR N9 -(CR Y7 R Y7’ ) o9 -S-(CR Y8 R Y8’ ) m9 - [In the above formula, R N9 is 1) a hydrogen atom, or 2)-(CR N9a R N9a’ ) nN9a -Y N9 -W N9 (wherein R N9a and R N9a’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (d) R N9a and R N9a’ may be bonded to each other to form, together with adjacent carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a heterocyclic group containing 1 to 2 oxygen atoms and having 5 to 6 ring-constituting atoms; nN9a represents an integer from 1 to 6; Y N9 is (a) a bond, (b) -O-, or (c) -NR N9c -V N9c - (wherein V N9c is (i) represents -CO- and R N9c is (i) a hydrogen atom, or (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, .) represents W N9 is (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 6 carbon atoms, (d) an aryl group having 6 to 10 carbon atoms, or (e) a halogen atom . R Y7 , R Y7’ , R Y8 and R Y8’ are each independently 1) a hydrogen atom, or 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, n9 represents an integer from 1 to 6; V 9 is 1) -CO-, 2) an optionally substituted divalent heterocyclic group having 3 to 6 ring-constituting atoms; m9 represents an integer from 0 to 6; R N9’ is 1) a hydrogen atom, or 2) an alkyl group having 1 to 6 carbon atoms, . o9 represents an integer from 2 to 6; R N9’’ is 1) a hydrogen atom .] a group represented by;

[0051] W 9a is (1) an optionally substituted alkylene group having 1 to 6 carbon atoms, (2) an optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) A heteroaryl divalent group which may be substituted, containing 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms, and having 5 to 6 ring-constituting atoms, or (4) A hetero ring divalent group which may be substituted, containing 1 to 4 nitrogen atoms and having 5 to 6 ring-constituting atoms,

[0052] Y 9b is (1)-(CR Y9 R Y9’ )ny9c-A Y9b -(CR Y10 R Y10’ )ny9d- (In the formula, R Y9 , R Y9’ , R Y10 and R Y10’ are each independently 1) a hydrogen atom, or 2) a halogen atom, ny9c and ny9d each independently represent an integer of 0 to 6, A Y9b is 1) a bond, or 2) -O-, ).) represents

[0053] W 9b is (1) a hydrogen atom, (2) a halogen atom, (3) an aryl group having 6 to 10 carbon atoms which may be substituted by a halogen, (4) a heteroaryl group which may be substituted by an alkyl group having 1 to 6 carbon atoms, containing 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms, and having 5 to 6 ring-constituting atoms, (8) -CONR NW9 R NW9’ (In the formula, R NW9 and R NW9’ are each independently 1) a hydrogen atom, or 2) an alkyl group having 1 to 6 carbon atoms is shown.) is shown.] a group represented by, a compound described in

[21] or

[22] or a pharmaceutically acceptable salt thereof.

[0054]

[24] R 9a is of the formula: (1) -NR N9 -, (2) -NR N9 -(CR Y7 R Y7’ ) n9 -, (3) -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -(CR Y8 R Y8’ ) m9 -, (4) -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -NR N9’ -(CR Y8 R Y8’ ) m9 -, (5) -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’ -V 9 -(CR Y8 R Y8’ ) m9 -, (6) -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’’ -(CR Y8 R Y8’ ) m9 -, (7) -NR N9 -(CR Y7 R Y7’ ) o9 -O-(CR Y8 R Y8’ ) m9 - or (8)-NR N9 -(CR Y7 R Y7’ ) o9 -S-(CR Y8 R Y8’ ) m9 - (In the above formula, the definitions of the respective symbols are the same as those described above.) The compound described in the above

[21] or a pharmacologically acceptable salt thereof, which is a group represented by

[25] W 9a is (1) An optionally substituted alkylene group having 1 to 6 carbon atoms, (2) An optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) An optionally substituted heteroaryl divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, or (4) An optionally substituted heterocyclic divalent group containing 1 to 4 nitrogen atoms and having 5 to 6 ring-constituting atoms The compound described in the above

[24] or a pharmacologically acceptable salt thereof, which represents

[26] W 9a is (1) An optionally substituted alkylene group having 1 to 6 carbon atoms, (2) An optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) An optionally substituted heteroaryl divalent group containing 1 to 4 identical or different atoms selected from nitrogen and sulfur atoms and having 5 to 6 ring-constituting atoms or (4) An optionally substituted heterocyclic divalent group containing 1 to 4 nitrogen atoms and having 5 to 6 ring-constituting atoms The compound described in the above

[25] or a pharmacologically acceptable salt thereof, which represents

[27] ny9c and ny9d are both 0, and A Y9b is a bond. The compound described in

[25] or

[26] or a pharmacologically acceptable salt thereof.

[28] W9a is (1) an optionally substituted alkylene group having 1 to 6 carbon atoms, (2) an optionally substituted phenylene group, (3) an optionally substituted pyridine-diyl group, (4) an optionally substituted thiazole-diyl group, or (5) an optionally substituted piperidine-diyl group as described in the above

[25] to

[27] , or a pharmacologically acceptable salt thereof.

[0055]

[29] R 9a is of the formula:

[0056]

Chemical formula

[0057] (wherein,

[0058]

Chemical formula

[0059] and Y 9a are as defined above.) is a group represented by the above formula, or a pharmacologically acceptable salt thereof as described in the above

[21] .

[30] wherein ny9c and ny9d are both 0 and A Y9b is a bond, or a pharmacologically acceptable salt thereof as described in the above

[29] .

[31] W 9b is a hydrogen atom, or a pharmacologically acceptable salt thereof as described in the above

[29] or

[30] .

[32] The formula:

[0060]

Chemical formula

[0061] The group represented by is each Y 9a In addition to, it may further be substituted with an oxo group or a halogen atom, and is an azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, tetrahydronaphthyridinyl group, tetrahydrothiazolopyridyl group or tetrahydroisoquinolyl group. The compound described in the above

[21] ,

[22] ,

[23] ,

[29] ,

[30] or

[31] or a pharmaceutically acceptable salt thereof.

[0062]

[33] A 6 is -NR 6a1 -, R 6a1 is (1) -Y 10a -W 10a -Y 10b -W 10b [In the formula, Y 10a is 1) a bond, 2) -(CR Y11 R Y11’ ) n10 -, 3) -(CR Y11 R Y11’ ) n10 -V 10 -(CR Y12 R Y12’ ) m10 -, 4) -(CR Y11 R Y11’ ) n10 -V 10 -NR N10’ -(CR Y12 R Y12’ ) m10 -, 5) -(CR Y11 R Y11’ ) o10 -NR N10’ -V 10 -(CR Y12 R Y12’ ) m10 -, 6) -(CR Y11 R Y11’ ) o10 -NR N10’’ -(CRY12 R Y12’ ) m10 -, 7)-(CR Y11 R Y11’ ) o10 -O-(CR Y12 R Y12’ ) m10 - or 8)-(CR Y11 R Y11’ ) o10 -S-(CR Y12 R Y12’ ) m10 - (wherein R Y11 , R Y11’ , R Y12 and R Y12’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted C1-C6 alkyl), (d) -O-(optionally substituted C3-C6 cycloalkyl), (e) an optionally substituted C1-C6 alkyl group, (f) an optionally substituted C3-C6 cycloalkyl group or, (g) R Y11 and R Y11’ and R Y12 and R Y12’ are each independently bonded to form an optionally substituted cycloalkyl having 3 to 10 carbon atoms, or an optionally substituted heterocycle having 3 to 10 ring atoms and containing 1 to 6 atoms selected from nitrogen, oxygen or sulfur atoms, n10 represents an integer of 1 to 6, V 10 is (a) -CO-, (b) -SO-, or (c) -SO 2 - and m10 represents an integer of 0 to 6, R N10’ is (a) a hydrogen atom, (b) Optionally substituted alkyl group having 1 to 6 carbon atoms, (c) Optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (d) Optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms represents, o10 represents an integer of 2 to 6, R N10’’ is (a) a hydrogen atom, (b) Optionally substituted alkyl group having 1 to 6 carbon atoms, (c) Optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (d) Optionally substituted heterocyclic group having 3 to 6 carbon atoms, (e) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (f) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) (wherein, R represents, W 10a is 1) Optionally substituted alkylene group having 1 to 6 carbon atoms, 2) Optionally substituted aryl divalent group having 6 to 10 carbon atoms, 3) Optionally substituted heteroaryl divalent group containing 1 to 6 atoms selected from nitrogen atom, oxygen atom or sulfur atom and having 5 to 10 ring-constituting atoms, 4) Optionally substituted cycloalkyl divalent group having 3 to 10 carbon atoms, or 5) Optionally substituted heterocyclic divalent group containing 1 to 6 atoms selected from nitrogen atom, oxygen atom or sulfur atom and having 3 to 10 ring-constituting atoms represents, Y 10b is 1)-(CR Y13 R Y13’ ) ny10c -A Y10b -(CR Y14 R Y14’ ) ny10d - (wherein, R Y13 、R Y13’ 、RY14 and R Y14’ each independently is (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted C1-C6 alkyl), (d) -O-(optionally substituted C3-C6 cycloalkyl), (e) an optionally substituted C1-C6 alkyl group, (f) an optionally substituted C3-C6 cycloalkyl group or, (g) R Y13 R and Y13’ R and Y14 R and Y14’ each independently bond to each other and, together with adjacent carbon atoms, form an optionally substituted monocyclic or fused cycloalkane having 3 to 10 carbon atoms, or an optionally substituted heterocycle having 3 to 10 ring-constituting atoms and containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, ny10c and ny10d each independently represent an integer of 0 to 6, A Y10b is (a) a bond, (b) -O-, (c) -SO-, (d) -SO 2 -, (e) -NR NY10e - (wherein R NY10e is (i) a hydrogen atom, (ii) an optionally substituted C1-C6 alkyl group, (iii) an optionally substituted C3-C6 cycloalkyl group, (iv) an optionally substituted C3-C6 heterocyclic group, (v) -CO-(optionally substituted C1-C6 alkyl), (vi) -CO-(optionally substituted C3-C6 cycloalkyl)), or (f) -V Y10f-NR NY10f - or NR NY10f -V Y10f - (In the formula, V Y10f represents -CO-, -SO- or -SO 2 -, and R NY10f represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or an optionally substituted heterocyclic group having 3 to 6 carbon atoms.) represents and W 10b represents 1) a hydrogen atom, 2) a halogen atom, 3) an optionally substituted aryl group having 6 to 10 carbon atoms, 4) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, 5) an optionally substituted monocyclic or fused cycloalkyl having 3 to 10 carbon atoms, 6) an optionally substituted heterocyclic group containing 1 to 6 atoms selected from nitrogen, oxygen, or sulfur atoms and having 3 to 10 ring-constituting atoms, 7) -CONR NW10 R NW10’ (In the formula, R NW10 and R NW10’ may be the same or different and each independently represents (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (c) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms.), or 8) -NR 8) -NR NW10’’ R NW10’’’ (In the formula, RNW10’’ and R NW10’’’ may be the same or different and each independently (a) a hydrogen atom, (b) unsubstituted or substituted C1-C6 alkyl, (c) optionally substituted C3-C6 cycloalkyl, (d) optionally substituted heterocyclic group having 3 to 6 ring constituent atoms, (e) -CO-(optionally substituted C1-C6 alkyl), or (f) -CO-(optionally substituted C3-C6 cycloalkyl) .) .] The compound or a pharmacologically acceptable salt thereof according to

[10] or

[11] which is

[34] A 6 is -NR 6a1 -, R 6a1 is (1) -Y 10a -W 10a -Y 10b -W 10b [wherein Y 10a is 1) -(CR Y11 R Y11’ ) n10 -, or 2) -(CR Y11 R Y11’ ) n10 -V 10 -NR N10’ -(CR Y12 R Y12’ ) m10 - (wherein R Y11 , R Y11’ , R Y12 and R Y12’ each independently represent (a) a hydrogen atom, n10 represents an integer of 1 to 6, V 10 is (a) -CO-, .) m10 represents an integer from 0 to 6, R N10’ represents (a) a hydrogen atom, .) represents W 10a represents 1) an aryl divalent group having 6 to 10 carbon atoms, or 2) a heteroaryl divalent group containing 1 to 4 identical or different atoms selected from nitrogen atoms and oxygen atoms and having 5 to 6 ring constituent atoms, represents Y 10b represents 1)-(CR Y13 R Y13’ ) ny10c -A Y10b -(CR Y14 R Y14’ ) ny10d - (wherein R Y13 , R Y13’ , R Y14 and R Y14’ are each independently (a) a hydrogen atom, or (b) a halogen atom, ny10c and ny10d each independently represent an integer from 0 to 6, A Y10b represents (a) a bond, or (b) -O-, .) represents W 10b represents 1) a hydrogen atom, 2) an aryl group having 6 to 10 carbon atoms which may be substituted by a group selected from an alkyl group having 1 to 6 carbon atoms which may be substituted by a halogen and a halogen, or 3) a heteroaryl group containing 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms and having 5 to 6 ring constituent atoms, which may be substituted by an alkyl group having 1 to 6 carbon atoms, .) represents.] The compound described in the above

[33] or a pharmacologically acceptable salt thereof.

[35] Y 10a is (1) a bond, (2)-(CR Y11 R Y11’ ) n10 - or (3)-(CR Y11 R Y11’ ) o10 -O-(CR Y12 R Y12’ ) m10 - (wherein each symbol has the same meaning as described above) The compound described in the above

[33] or

[34] or a pharmacologically acceptable salt thereof.

[36] W 10a is (1) an optionally substituted divalent aryl group having 6 to 10 carbon atoms, (2) an optionally substituted divalent heteroaryl group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 to 10 ring-constituting atoms, (3) an optionally substituted divalent heterocyclic group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3 to 10 ring-constituting atoms, or (4) an optionally substituted alkylene group having 1 to 6 carbon atoms, The compound described in the above

[33] to

[35] or a pharmacologically acceptable salt thereof.

[37] ny10c and ny10d are both 0, A Y10b is a bond, the compound described in the above

[33] to

[36] or a pharmacologically acceptable salt thereof.

[38] W 10a is (1) a phenylene group, (2) a pyridine-diyl group, (3) Optionally substituted monocyclic heterocyclic divalent group containing 1 to 2 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 4 to 7 ring-constituting atoms, or (4) Optionally substituted alkylene group having 1 to 6 carbon atoms, The compound or its pharmacologically acceptable salt as described in the above

[33] to

[37] .

[39] W 10b is (1) Optionally substituted aryl group having 6 to 10 carbon atoms, or (2) Optionally substituted heteroaryl containing 1 to 6 atoms selected from nitrogen atom, oxygen atom and sulfur atom and having 5 to 10 ring-constituting atoms, the compound or its pharmacologically acceptable salt as described in the above

[33] to

[38] .

[0063]

[40] E is (1) A bond (2) -CO-, (3) -SO-, or (4) -SO 2 - and X is (1) Optionally substituted alkyl group having 1 to 6 carbon atoms, (2) Optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (3) Optionally substituted aryl group having 6 to 10 carbon atoms, (4) Optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom or sulfur atom and having 3 to 10 ring-constituting atoms, or (5) Optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom and having 5 to 10 ring-constituting atoms, The compound or its pharmacologically acceptable salt as described in any of the above [1] to

[39] .

[41] The compound or its pharmacologically acceptable salt as described in any of the above [1] to

[40] , wherein E is -CO-.

[42] X is -CHR m -X 1 -X 2 [wherein R m is (1) an optionally substituted alkyl group having 1 to 10 carbon atoms, (2) an optionally substituted aryl group, (3) an optionally substituted heteroaryl group, (4) an optionally substituted heterocyclic group, or (5) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms represents, X 1 is (1) a bond, (2) an optionally substituted arylene group having 6 to 10 carbon atoms, (3) an optionally substituted heteroarylene group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, (4) an optionally substituted cycloalkylene group having 3 to 10 carbon atoms, (5) an optionally substituted heterocyclene group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, or (6) -NR 1X - (wherein R 1X is 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, or 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms .) represents, X 2 is (1) a hydrogen atom, (2) an optionally substituted alkyl group, (3) an optionally substituted aryl group having 6 to 10 carbon atoms, (4) Optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 5 to 10 ring-constituting atoms, (5) Optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (6) Optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 3 to 10 ring-constituting atoms, (7) -CO-, (8) -CO-(optionally substituted alkyl), (9) -CO-(optionally substituted aryl having 6 to 10 carbon atoms), (10) -CO-(optionally substituted heteroaryl containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 5 to 10 ring-constituting atoms), (11) -CO-(optionally substituted cycloalkyl having 3 to 10 carbon atoms), (12) -CO-(optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 3 to 10 ring-constituting atoms), (13) -CO-(optionally substituted alkylene having 1 to 6 carbon atoms)-(O-optionally substituted alkylene having 1 to 6 carbon atoms) r - (In the formula, r represents an integer of 1 to 6.) (14) -CO-(optionally substituted alkylene having 1 to 6 carbon atoms)-O-(optionally substituted alkylene having 1 to 6 carbon atoms)-CONH-(optionally substituted alkylene having 1 to 6 carbon atoms)-, (15) -CO-(optionally substituted alkylene having 1 to 6 carbon atoms)-CONH-(optionally substituted alkylene having 1 to 6 carbon atoms)-, or (16) -OR 2X or -NR 2X R 2X’ (In the formula, R 2X and R 2X’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, or 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms .) . (However, when X 1 is NR 1x , X 2 is not -OR 2X or -NR 2X R 2X’ .)] is the compound according to the above [1] to

[41] or a pharmacologically acceptable salt thereof.

[43] X 1 is -NR 1X - (wherein R 1X is as defined above.) is the compound according to the above

[42] or a pharmacologically acceptable salt thereof.

[44] X 2 is (1) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), (2) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), (3) -CO-(optionally substituted alkylene having 1 to 6 carbon atoms)-(O-optionally substituted alkylene having 1 to 6 carbon atoms) r - (wherein r represents an integer of 1 to 6), (4) -CO-(optionally substituted alkylene having 1 to 6 carbon atoms)-O-(optionally substituted alkylene having 1 to 6 carbon atoms)-CONH-(optionally substituted alkylene having 1 to 6 carbon atoms)-, or (5) -CO-(optionally substituted alkylene having 1 to 6 carbon atoms)-CONH-(optionally substituted alkylene having 1 to 6 carbon atoms)- is the compound according to the above

[43] or a pharmacologically acceptable salt thereof.

[45] X 1 is (1) An optionally substituted arylene divalent group having 6 to 10 carbon atoms, or (2) An optionally substituted heteroarylene divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, and having 5 to 10 ring-constituting atoms is the compound according to the above

[42] or a pharmaceutically acceptable salt thereof.

[46] X 1 is (1) An optionally substituted heteroarylene divalent group containing 1 to 4 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, and having 5 or 6 ring-constituting atoms is the compound according to the above

[45] or a pharmaceutically acceptable salt thereof.

[47] X 1 is (1) An optionally substituted heteroarylene divalent group containing 1 to 4 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, and having 5 ring-constituting atoms is the compound according to the above

[46] or a pharmaceutically acceptable salt thereof.

[0064]

[48] L is -(L a ) q - [In the formula, q represents an integer from 1 to 100, and q Ls a are each independently (1) A bond, (2) CR L1 R L1’ , (3) O, (4) S, (5) CO, (6) SO, (7) SO 2 , (8) NR L1 , (9) CONR L1 (10) NR L1 CO, (11) NR L1 CONR L1’ 、 (12) SONR L1 、 (13) NR L1 SO、 (14) SO 2 NR L1 、 (15) NR L1 SO 2 、 (16) NR L1 SO 2 NR L1’ (17) CR L1 =CR L1’ 、 (18) C≡C、 (19) SiR L1 R L1’ 、 (20) P(O)R L1 、 (21) P(O)OR L1 、 (22) NR L1 C(=NCN)NR L1’ 、 (23) -NR L1 C(=NCN)-、 (24) An optionally substituted cycloalkyl divalent group, (25) An optionally substituted heterocyclic divalent group, (26) An optionally substituted aryl divalent group, or (27) An optionally substituted heteroaryl divalent group (In the above formula, R L1 and R L1’ are each independently, 1) A hydrogen atom 2) A halogen atom, 3) -CN, 4) -NO 2 、 5) -SF 5 、 6) -CO 2 H, 7) -N(R L2 R L2’ )、 8) -AL2 R L2 9) an alkyl group which may be substituted, 10) a cycloalkyl group which may be substituted, 11) a heterocyclic group which may be substituted, 12) an aryl group which may be substituted, 13) a heteroaryl group which may be substituted, 14) -SO 2 R L2 , 15) -P(O)(OR L2 )OR L2’ , 16) -C≡CR L2 , 17) -C(R L2 )=C(R L2’ R L2’’ ), 18) -COR L2 , 19) -CON(R L2 R L2’ ), 20) -SO 2 N(R L2 R L2’ ), 21) -N(R L2 )CON(R L2’ R L2’’ ), and 22) -N(R L2 )SO 2 N(R L2’ R L2’’ ) (In the above formula, A L2 represents an oxygen atom or a sulfur atom, R L2 , R L2’ , and R L2’’ are each independently a) a hydrogen atom, b) an alkyl group of C 1 -C 8 which may be substituted, or c) a cycloalkyl group of C 3 -C 8 which may be substituted. ).) The compound according to any one of the above [1] to

[47] or a pharmacologically acceptable salt thereof.

[49] The compound according to the above

[48] or a pharmacologically acceptable salt thereof, wherein q is an integer of 1 to 50.

[50] L is ―L 1 -L 2 -L 3 - [wherein L 1 and L 3 are each independently (1) a bond, (2) CR L1 R L1’ 、 (3) O, (4) S, (5) SO, (6) SO 2 、 (7) NR L1 、 (8) SO 2 NR L1 、 (9) NR L1 SO 2 (10) SONR L1 、 (11) NR L1 SO、 (12) CONR L1 、 (13) NR L1 CO、 (14) NR L1 CONR L1’ 、 (15) NR L1 SO 2 NR L1’ 、or (16) CO, and L 2 is (CH 2 ) p1a -O-(CH 2 -CH 2 -O) p2a -(CH 2 ) p3a (wherein, p1a and p3a are adjacent L 1 or L 3 When the directly bonding atoms are carbon atoms or bonds, it represents an integer from 0 to 10; when they are other atoms, it represents an integer from 2 to 10, and p2a represents an integer from 0 to 10.) is shown.] is the compound or its pharmacologically acceptable salt described in the above

[48] or "49".

[51] When L is -L b1 -L b2 -L b3 - [In the formula, L b1 and L b3 are each independently (1) a bond, (2) CR L1 R L1’ , (3) O, (4) S, (5) SO, (6) SO 2 , (7) NR L1 , (8) SO 2 NR L1 , (9) NR L1 SO 2 , (10) SONR L1 , (11) NR L1 SO, (12) CONR L1 , (13) NR L1 CO, (14) NR L1 CONR L1’ , (15) NR L1 SO 2 NR L1’ , or (16) CO, and L b2 is (1) a bond, (2) (CH 2 )1-10 , (3)(CH 2 ) 0-6 -O-(CH 2 ) 0-6 , (4)(CH 2 ) 0-6 -CONH-(CH 2 ) 0-6 , (5)(CH 2 ) 0-6 -NHCO-(CH 2 ) 0-6 , (6)(CH 2 ) 0-6 -NH-(CH 2 ) 0-6 , (7)(CH 2 ) 0-6 -NHSO 2 -(CH 2 ) 0-6 、 or (8)(CH 2 ) 0-6 -SO 2 NH-(CH 2 ) 0-6 is shown. (In the formula, R L1 and R L1’ are as defined above.) is the compound or a pharmaceutically acceptable salt thereof according to the above

[48] or

[49] .

[0065]

[52] The compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to

[51] , wherein A is a moiety capable of binding to a target protein or a group having a binding moiety.

[53] The compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to

[52] , wherein the target protein to which A binds is a protein having a biological function selected from the group consisting of structure, control, hormone, enzyme, gene regulation, immunity, contraction, storage, transport, and signal transduction.

[54] The target protein to which A binds is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, and proteins related to the integrated functions of cells, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (assimilation and dissimilation), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecular activity, binding activity (protein, lipid, glycoprotein), receptor activity, cell motility, membrane fusion, intercellular communication, regulation of biological processes, development, cell differentiation, stimulus response, cell adhesion, cell death, transport (protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity), pathogenicity, viral envelope, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, epigenetic regulation, aggregation, extracellular organization, biological viability, or translational regulator activity. The compound according to any one of [1] to

[52] above or a pharmaceutically acceptable salt thereof.

[55] The target protein to which A binds is selected from the group consisting of proteins related to cancer-related proteins, autoimmune disease-related proteins, inflammatory disease-related proteins, neurodegenerative disease-related proteins, muscle disease-related proteins, sensory organ system disease-related proteins, cardiovascular disease-related proteins, metabolic disease-related proteins, and genetic disease-related proteins. The compound according to any one of [1] to

[52] above or a pharmaceutically acceptable salt thereof.

[0066]

[56] A pharmaceutical containing, as an active ingredient, the compound according to [1] above or a pharmaceutically acceptable salt thereof.

[57] The pharmaceutical according to

[56] above, which is a prophylactic or therapeutic agent for diseases caused by dysregulation of protein activity.

[58] A pharmaceutical composition containing, as an active ingredient, the compound according to [1] above or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[59] Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for producing a prophylactic or therapeutic agent for a disease caused by dysregulation of protein activity.

[60] A method for regulating the protein activity of a target protein in a mammal, comprising administering an effective amount of the compound according to [1] above or a pharmaceutically acceptable salt thereof to the mammal.

[61] A method for preventing or treating a disease caused by dysregulation of protein activity, comprising administering a prophylactically or therapeutically effective amount of the compound according to [1] above or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

[62] The compound according to [1] above or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease caused by dysregulation of protein activity.

Effect of the Invention

[0067] The present invention relates to a target protein degradation-inducing compound, which is a bifunctional compound having a portion that binds to VHL, a substrate recognition protein of the ubiquitin ligase complex, at one end and a portion that binds to a target protein at the other end. The target protein degradation-inducing compound of the present invention can exhibit a wide range of pharmacological activities by regulating the ubiquitination of the target protein and inducing the degradation of the target protein.

Brief Description of the Drawings

[0068]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0069] [Regarding the Target Protein Degradation-Inducing Compound of the Present Invention] The present invention will be described in detail below.

[0070] (Definition of each group used in this specification) Hereinafter, the definition of each group used in this specification will be described in detail. Unless otherwise specified, each group has the following definition. In this specification, when indicating the number of carbon atoms constituting a certain group, instead of the notation "carbon number 1 to 6", it may be denoted as "C 1 -C 6 ". Also, when indicating the number of atoms constituting a certain ring, instead of the notation "the number of ring-constituting atoms 3 to 10", it may be denoted as "3- to 10-membered".

[0071] When compound (I) has an acidic functional group and / or a basic functional group in the compound, it can form a salt. Examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc.

[0072] In this specification, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.

[0073] In this specification, the "alkyl group" (including the case where it is the "alkyl" part in the definition) includes alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, 3-methyloctyl, nonyl, and decyl. Here, a more preferred embodiment is an alkyl group having 1 to 8 carbon atoms. Another preferred embodiment is an alkyl group having 1 to 6 carbon atoms. Still another embodiment is an alkyl group having 1 to 4 carbon atoms.

[0074] In this specification, the "alkenyl group" (including the case where it is the "alkenyl" part in the definition) includes alkenyl groups having 2 to 6 carbon atoms. For example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl may be mentioned.

[0075] In this specification, the "alkynyl group" (including the case where it is the "alkynyl" part in the definition) includes alkynyl groups having 2 to 6 carbon atoms. For example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl may be mentioned.

[0076] In this specification, the "alkylene group" (including the case where it is the "alkylene" part in the definition) includes alkylene groups having 1 to 6 carbon atoms. For example, -CH 2 -,-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-(CH 2 ) 6 -,-CH(CH 3 )-,-C(CH 3 ) 2 -,-CH(C 2 H 5 )-,-CH(C 3 H 7 )-,-CH(CH(CH 3 ) 2 )-,-(CH(CH 3 )) 2 -,-CH 2 -CH(CH 3 )-,-CH(CH 3 )-CH2 -, -CH 2 -CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -CH 2 -CH 2 - are included.

[0077] In this specification, examples of the "alkenylene group" (including the case where it is the "alkenylene" part in the definition) include alkenylene groups having 2 to 6 carbon atoms, such as -CH=CH-, -CH 2 -CH=CH-, -CH=CH-CH 2 -, -C(CH 3 ) 2 -CH=CH-, -CH=CH-C(CH 3 ) 2 -, -CH 2 -CH=CH-CH 2 -, -CH 2 -CH 2 -CH=CH-, -CH=CH-CH 2 -CH 2 -, -CH=CH-CH=CH-, -CH=CH-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH=CH- are included.

[0078] In this specification, examples of the "alkynylene group" (including the case where it is the "alkynylene" part in the definition) include alkynylene groups having 2 to 6 carbon atoms, such as -C≡C-, -CH 2 -C≡C-, -C≡C-CH 2 -, -C(CH 3 ) 2-C≡C-, -C≡C-C(CH 3 ) 2 -, -CH 2 -C≡C-CH 2 -, -CH 2 -CH 2 -C≡C-, -C≡C-CH 2 -CH 2 -, -C≡C-C≡C-, -C≡C-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -C≡C- are included.

[0079] In this specification, the "alkoxy group" (including the case where it is the "alkoxy" part in the definition) includes alkoxy groups having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy. Here, a more preferred embodiment is an alkoxy group having 1 to 4 carbon atoms.

[0080] In this specification, the "alkoxycarbonyl group" includes (alkoxy having 1 to 6 carbon atoms)-carbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl.

[0081] In this specification, the "cycloalkyl group" (including the case where it is the "cycloalkyl" part in the definition) includes monocyclic or fused cycloalkyl groups having 3 to 10 (preferably 3 to 8) carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl. Here, a more preferred embodiment is a cycloalkyl group having 3 to 6 carbon atoms.

[0082] In this specification, the "cycloalkyl divalent group" (which may be referred to as the "cycloalkan-diyl group") (including the case of the "cycloalkyl divalent group" part in the definition) includes a divalent group formed by the above-described "cycloalkyl group having 3 to 10 carbon atoms" having one more bonding hand, and for example, 1,3-cyclopropanediyl is included. Here, a more preferred embodiment is a cycloalkyl divalent group having 3 to 6 carbon atoms.

[0083] In this specification, the "cycloalkyloxy group" includes a (cycloalkyl having 3 to 10 carbon atoms)-oxy group, and for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy are included.

[0084] In this specification, the "aryl group" (including the case of the "aryl" part in the definition) includes a monocyclic or condensed aryl group having 6 to 14 carbon atoms, and for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl are included. Here, a more preferred embodiment is an aryl group having 6 to 10 carbon atoms.

[0085] In this specification, "C 7-16 aralkyl group" (including the case of the "C 7-16 aralkyl" part in the definition) includes, for example, benzyl, phenethyl, naphthylmethyl, phenylpropyl.

[0086] In this specification, the "aryl divalent group" (including the case where it is the "aryl divalent group" part in the definition) (which may be referred to as the "arylene group") includes a divalent group formed by the above-described "aryl group" having yet another bonding hand, and examples thereof include an aryl divalent group having 6 to 14 carbon atoms (preferably an aryl divalent group having 6 to 10 carbon atoms), such as phenylene.

[0087] In this specification, the "heterocyclic group" (including the case where it is the "heterocycle" part in the definition) (which may be referred to as the "non-aromatic heterocyclic group") includes, for example, a monocyclic or condensed heterocyclic group (non-aromatic heterocyclic group) containing 1 to 6 (preferably 1 to 4) identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms in addition to carbon atoms as ring-constituting atoms, and having 3 to 14 (preferably 3 to 10) ring-constituting atoms. Preferable examples of the "heterocyclic group" (the "non-aromatic heterocyclic group") include monocyclic heterocyclic groups (non-aromatic heterocyclic groups) having 3 to 8 ring-constituting atoms such as aziridinyl, oxiranyl, thiaranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, etc.; Condensed polycyclic (preferably bicyclic or tricyclic) heterocyclic groups (non-aromatic heterocyclic groups) having 9 to 14 ring-constituting atoms, such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl, etc. are included.

[0088] In this specification, the "heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms or sulfur atoms and having 3 to 10 ring-constituting atoms" refers to those among the "heterocyclic groups" described above that contain 1 to 6 heteroatoms as ring-constituting atoms and have 3 to 10 ring-constituting atoms. In this specification, the "condensed heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and having 6 to 10 ring-constituting atoms" refers to those among the "heterocyclic groups" described above that are condensed polycyclic and contain 1 to 6 heteroatoms as ring-constituting atoms and have 6 to 10 ring-constituting atoms. In this specification, the "heterocyclic group having 3 to 6 ring-constituting atoms" refers to those among the "heterocyclic groups" described above that have 3 to 6 ring-constituting atoms. In this specification, the "heterocyclic group having 3 to 10 ring-constituting atoms, containing a nitrogen atom and optionally 1 to 5 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms" refers to, among the "heterocyclic groups" described above, those having 1 to 6 heteroatoms as ring-constituting atoms, containing at least one nitrogen atom as a ring-constituting atom, and having 3 to 10 ring-constituting atoms. In this specification, the "heterocyclic group containing 1 to 2 oxygen atoms and having 5 to 6 ring-constituting atoms" refers to, among the "heterocyclic groups" described above, those containing 1 to 2 oxygen atoms and having 5 to 6 ring-constituting atoms.

[0089] In this specification, the "heterocyclic divalent group" (including the case where it is the "heterocyclic divalent group" part in the definition) includes a divalent group formed by the "heterocyclic group" described above having an additional bond, for example, piperazine-diyl. In this specification, the "heterocyclic divalent group having 3 to 6 ring-constituting atoms" refers to, among the "heterocyclic divalent groups" described above, those having 3 to 6 ring-constituting atoms. In this specification, the "heterocyclic divalent group having 3 to 10 ring-constituting atoms and containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms" refers to, among the "heterocyclic divalent groups" described above, those having 1 to 6 heteroatoms as ring-constituting atoms and having 3 to 10 ring-constituting atoms. In this specification, the "heterocyclic divalent group containing 1 to 4 nitrogen atoms and having 5 to 6 ring-constituting atoms" refers to, among the "heterocyclic divalent groups" described above, those containing 1 to 4 nitrogen atoms and having 5 to 6 ring-constituting atoms. In this specification, the "monocyclic heterocyclic divalent group having 4 to 7 ring-constituting atoms and containing 1 to 2 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms" refers to, among the "heterocyclic divalent groups" described above, a monocyclic heterocyclic divalent group containing 1 to 2 heteroatoms and having 4 to 7 ring-constituting atoms.

[0090] In this specification, the "heteroaryl group" (including the case where it is the "heteroaryl" part in the definition, and may be referred to as the "aromatic heterocyclic group") includes, for example, a monocyclic or fused heteroaryl group (aromatic heterocyclic group) having 1 to 6 (preferably 1 to 4) identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms in addition to carbon atoms as ring-constituting atoms, and having 5 to 14 (preferably 5 to 10) ring-constituting atoms. Preferable examples of the "heteroaryl group" (aromatic heterocyclic group) include monocyclic heteroaryl groups (aromatic heterocyclic groups) having 5 to 6 ring-constituting atoms such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; condensed polycyclic (preferably bicyclic or tricyclic) heteroaryl groups (aromatic heterocyclic groups) having 8 to 14 ring-constituting atoms such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0091] In this specification, the "heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms and having 5 to 10 ring-constituting atoms" refers to, among the "heteroaryl groups" described above, those containing 1 to 6 heteroatoms as ring-constituting atoms and having 5 to 10 ring-constituting atoms. In this specification, the "heteroaryl group having 5 ring-constituting atoms" refers to, among the "heteroaryl groups" described above, those having 5 ring-constituting atoms. In this specification, the "heteroaryl group containing 1 to 4 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms and having 5 to 6 ring-constituting atoms" refers to, among the "heteroaryl groups" described above, those containing 1 to 4 heteroatoms as ring-constituting atoms and having 5 to 6 ring-constituting atoms.

[0092] In this specification, examples of the "heteroaryl divalent group" (including the case of the "heteroaryl divalent group" part in the definition) include divalent groups formed by the "heteroaryl group" described above having one more bond, such as pyridine-diyl. In this specification, the "heteroaryl divalent group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms and having 5 to 10 ring-constituting atoms" refers to, among the "heteroaryl divalent groups" described above, those containing 1 to 6 heteroatoms as ring-constituting atoms and having 5 to 10 ring-constituting atoms. In this specification, the "heteroaryl divalent group containing 1 to 4 identical or different atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms and having 5 to 6 ring-constituting atoms" refers to, among the "heteroaryl divalent groups" described above, those containing 1 to 4 heteroatoms and having 5 to 6 ring-constituting atoms.

[0093] In this specification, examples of the "aromatic hydrocarbon ring" include aromatic hydrocarbon rings having 6 to 14 carbon atoms (preferably 6 to 10 carbon atoms), such as benzene and naphthalene.

[0094] In this specification, examples of the "non-aromatic hydrocarbon ring" include saturated or partially unsaturated cyclic hydrocarbon rings, such as cycloalkanes and cycloalkenes. In this specification, examples of the "cycloalkane" include "C 3-10 cycloalkane", such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. In this specification, examples of the "cycloalkene" include "C 3-10 cycloalkene", such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, and cyclodecene. In this specification, the "non-aromatic hydrocarbon ring having 5 or 6 ring-constituting atoms" refers to those among the "non-aromatic hydrocarbon rings" described above that have 5 or 6 ring-constituting atoms.

[0095] In this specification, examples of the "aromatic heterocyclic ring" include aromatic heterocyclic rings containing 1 to 6 (preferably 1 to 4) heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms in addition to carbon atoms as ring-constituting atoms, and having 5 to 14 (preferably 5 to 10) ring-constituting atoms. Preferred examples of the "aromatic heterocyclic ring" include monocyclic aromatic heterocyclic rings having 5 to 6 (5- or 6-membered) ring-constituting atoms such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine, etc.; Examples of the condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic rings having 8 to 14 ring-constituting atoms (8- to 14-membered rings) include benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine. In the present specification, the "aromatic heterocyclic ring containing a nitrogen atom and optionally containing 1 to 5 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms" refers to those among the "aromatic heterocyclic rings" described above that contain 1 to 6 heteroatoms as ring-constituting atoms and contain at least one nitrogen atom as a ring-constituting atom.

[0096] In this specification, the "heterocyclic ring" includes, for example, non-aromatic heterocyclic rings containing 1 to 6 (preferably 1 to 4) heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms in addition to carbon atoms as ring-constituting atoms, and having 3 to 14 (preferably 3 to 10) ring-constituting atoms. Preferred examples of the "heterocyclic ring" (the "non-aromatic heterocyclic ring") include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepan, diazepan, azepine, azocane, diazocane, oxepane, etc., monocyclic non-aromatic heterocyclic rings having 3 to 8 (3- to 8-membered) ring-constituting atoms; dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline, etc., condensed polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic rings having 9 to 14 (9- to 14-membered) ring-constituting atoms. In this specification, the "heterocyclic ring containing a nitrogen atom and optionally containing 1 to 5 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms" refers to, among the "heterocyclic rings" described above, those containing 1 to 6 heteroatoms as ring-constituting atoms and containing at least one nitrogen atom as a ring-constituting atom. In this specification, the "heterocyclic ring having 5 or 6 ring-constituting atoms, containing a nitrogen atom and optionally containing 1 to 3 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms" refers to, among the "heterocyclic rings" described above, those containing 1 to 4 heteroatoms as ring-constituting atoms, containing at least one nitrogen atom as a ring-constituting atom, and having 5 or 6 ring-constituting atoms. In this specification, the "heterocyclic ring containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and having 3 to 10 ring-constituting atoms" refers to, among the "heterocyclic rings" described above, those containing 1 to 6 heteroatoms as ring-constituting atoms and having 3 to 10 ring-constituting atoms.

[0097] In this specification, examples of the "substituent" in the definitions of the "optionally substituted alkyl group", "optionally substituted cycloalkyl group", "optionally substituted aryl group", "optionally substituted heterocyclic group", "optionally substituted heteroaryl group", "optionally substituted fused heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and having 6 to 10 ring-constituting atoms", "optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and having 5 to 10 ring-constituting atoms", and other compound (I) include substituents selected from the following [substituent group]. The "substituent" may be present in 1 to 5 (preferably 1 to 3) positions where substitution is possible, and when there are 2 or more substituents, each substituent may be the same or different. In addition, for each group or ring, etc., when there is a special explanation for the "substituent", it shall follow that explanation.

[0098] [Group of substituents] (1) A halogen atom, (2) A nitro group, (3) A cyano group, (4) An oxo group, (5) A hydroxy group, (6) An optionally halogenated C 1 -C 6 alkoxy group (e.g., methoxy, chloromethoxy, trifluoroethoxy), (7) C 6 -C 14 aryloxy group (e.g., phenoxy, naphthoxy), (8) C 7 -C 16 aralkyloxy group (e.g., benzyloxy), (9) C 1 -C 6 alkyl-carbonyl-oxy group (e.g., acetoxy, propanoyloxy), (10) C 6 -C 14 aryl-carbonyl-oxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (11) C 1 -C 6 alkoxy-carbonyl-oxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (12) A 5- to 14-membered aromatic heterocyclic group, (13) A 3- to 14-membered non-aromatic heterocyclic group, (14) A formyl group, (15) A carboxy group, (16) An optionally halogenated C 1 -C 6 alkyl-carbonyl group (e.g., acetyl, chloroacetyl, trifluoroacetyl), (17) C 6 -C 14 aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl), (18) C 1 -C 6An alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl), (19) A carbamoyl group, (20) An amino group, (21) Mono- or di-C 1 -C 6 An alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (22) Mono- or di-C 6 -C 14 An arylamino group (e.g., phenylamino), (23) A formylamino group, (24) C 1 -C 6 An alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (25) C 1 -C 6 An alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (26) Optionally halogenated C 1 -C 6 An alkyl group (e.g., methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl), (27) C 2 -C 6 An alkenyl group (e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl), (28) C 2 -C 6 An alkynyl group (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl), (29) C 3 -C 10A cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl), (30)C 3 -C 10 A cycloalkenyl group (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), and (31)C 6 -C 14 An aryl group (e.g., phenyl, naphthyl).

[0099] In the present specification, the "chemical linker" can be appropriately determined by those skilled in the art according to the selection of the target protein. Details will be described later.

[0100] In the present specification, the "target-directed ligand" includes a group having a moiety capable of binding to the "target protein" or a moiety that binds. Details will be described later.

[0101] The compound of the present invention is a compound (I) represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof.

[0102]

Chemical formula

[0103] (In the formula, L is bonded to either W or X; E represents a bond, -CO-, -SO-, or -SO 2 -; X represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group; W represents an optionally substituted aryl group, A condensed heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 6 to 10 ring-constituting atoms, A heteroaryl group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 3 to 10 ring-constituting atoms, An alkyl group which may be substituted with a group selected from halogen atoms, hydroxy groups, alkoxy groups, and heterocyclic groups, A cyano group, or represents a hydrogen atom; L represents a bond or a chemical linker; and A represents a target-directed ligand.)

[0104] In compound (I), L is bonded to either W or X. Therefore, compound (I) can structurally take the following two modes. Both of these modes are included within the scope of the present invention.

[0105]

Chemical formula

[0106] (In the formula, E, X, W, L, and A have the same meanings as described above, and X 1 and W 1 each represent a divalent group derived from X and W, respectively.)

[0107] Hereinafter, each symbol of compound (I) will be described in detail. [Regarding E] E represents a bond, -CO-, -SO- or -SO 2 -, preferably a bond or -CO-, more preferably -CO-.

[0108] [Regarding X] X is an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, A heterocyclic group which may be substituted, or A heteroaryl group which may be substituted, is shown, preferably An optionally substituted alkyl group having 1 to 6 carbon atoms, An optionally substituted cycloalkyl group having 3 to 10 carbon atoms, An optionally substituted aryl group having 6 to 10 carbon atoms, An optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom and having 3 to 10 ring constituent atoms (more preferably, an optionally substituted heterocyclic group containing 1 to 4 identical or different atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom and having 5 to 6 ring constituent atoms), or An optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 to 10 ring constituent atoms (more preferably, an optionally substituted heteroaryl group containing 1 to 4 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 to 6 ring constituent atoms), is shown.

[0109] In another preferred embodiment, X is a group represented by -CHR m -X 1 -X 2 wherein, in the formula, R m is (1) An optionally substituted alkyl group having 1 to 10 carbon atoms (preferably, an optionally substituted alkyl group having 1 to 6 carbon atoms), (2) An optionally substituted aryl group (preferably, an optionally substituted aryl group having 6 to 10 carbon atoms), (3) An optionally substituted heteroaryl group (preferably, an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 to 10 ring constituent atoms), (4) An optionally substituted heterocyclic group (preferably an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms) (5) An optionally substituted cycloalkyl group having 3 to 10 carbon atoms represents X 1 is (1) A bond (2) An optionally substituted aryl divalent group having 6 to 10 carbon atoms (3) An optionally substituted heteroaryl divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms Preferably, an optionally substituted heteroaryl divalent group containing 1 to 4 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 6 ring-constituting atoms and optionally substituted with an alkyl group having 1 to 6 carbon atoms (for example, pyridine-diyl, pyrimidine-diyl, pyrazole-diyl, imidazole-diyl, triazole-diyl, tetrazole-diyl, isoxazole-diyl, oxadiazole-diyl, etc.) (4) An optionally substituted cycloalkyl divalent group having 3 to 10 carbon atoms (5) An optionally substituted heterocyclic divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms, or (6) -NR 1X -[[]]END]] (wherein R 1X is 1) A hydrogen atom 2) An optionally substituted alkyl group having 1 to 6 carbon atoms, or 3) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown.). represents X 2 is (1) A hydrogen atom (2) An optionally substituted alkyl group (preferably an optionally substituted alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms), (3) An optionally substituted aryl group having 6 to 10 carbon atoms, (4) An optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, Preferably, a heteroaryl group (e.g., pyridyl, isoxazolyl, etc.) containing 1 to 4 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 6 ring-constituting atoms, which may be substituted with 1 to 3 substituents selected from an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, (5) An optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (6) An optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, (7) -CO-, (8) -CO-(optionally substituted alkyl), Preferably, -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), More preferably, -CO-(alkyl having 1 to 6 carbon atoms which may be substituted with an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms), Even more preferably, -CO-(alkyl having 1 to 6 carbon atoms which may be substituted with a heteroaryl group (e.g., isoxazolyl, etc.) containing 1 to 4 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 6 ring-constituting atoms and which may be substituted with an alkyl group having 1 to 6 carbon atoms), (9) -CO-(optionally substituted aryl having 6 to 10 carbon atoms), (10) -CO-(a heteroaryl group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 5 to 10 ring-constituting atoms), (11) -CO-(a cycloalkyl group having 3 to 10 carbon atoms which may be substituted), Preferably, -CO-(a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a halogen (e.g., cyclopropyl)), (12) -CO-(a heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 3 to 10 ring-constituting atoms), (13) -CO-(an alkylene group having 1 to 6 carbon atoms which may be substituted)-(O- an alkylene group having 1 to 6 carbon atoms which may be substituted) r - (wherein r represents an integer of 1 to 6). Preferably, -CO-(an alkylene group having 1 to 6 carbon atoms)-(O- an alkylene group having 1 to 6 carbon atoms) r - (wherein r represents an integer of 1 to 6). (14) -CO-(an alkylene group having 1 to 6 carbon atoms which may be substituted)-O-(an alkylene group having 1 to 6 carbon atoms which may be substituted)-CONH-(an alkylene group having 1 to 6 carbon atoms which may be substituted)-, Preferably, -CO-(an alkylene group having 1 to 6 carbon atoms)-O-(an alkylene group having 1 to 6 carbon atoms)-CONH-(an alkylene group having 1 to 6 carbon atoms)-, More preferably, -CO-(an alkylene group having 1 to 6 carbon atoms)-O-(an alkylene group having 1 to 6 carbon atoms)-CONH-(an alkylene group having 1 to 6 carbon atoms)-, (15) -CO-(an alkylene group having 1 to 6 carbon atoms which may be substituted)-CONH-(an alkylene group having 1 to 6 carbon atoms which may be substituted)-, Preferably, -CO-(an alkylene group having 1 to 6 carbon atoms)-CONH-(an alkylene group having 1 to 6 carbon atoms)-, or (16) -OR 2X or -NR 2X R 2X’ (wherein, R 2X and R 2X’ each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms (preferably an alkyl group having 1 to 6 carbon atoms), or 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown.) is as follows.

[0110] [Regarding W] W is (W1) an optionally substituted aryl group, (W2) an optionally substituted fused heterocyclic group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 6 to 10 ring-constituting atoms, (W3) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3 to 10 ring-constituting atoms, (W4) an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a heterocyclic group, (W5) a cyano group, or (W6) a hydrogen atom. Hereinafter, the groups (W1) to (W4) in W will be described in detail.

[0111] Group (W1): an optionally substituted aryl group The "aryl group" in the "optionally substituted aryl group" is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms. The aryl group may be substituted at a substitutable position with 1 to 3 identical or different substituents selected from the "substituent group" described in the above "definition of each group used in the present specification".

[0112] Group (W2): an optionally substituted fused heterocyclic group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 6 to 10 ring-constituting atoms The meaning of the "fused heterocyclic group" in the "optionally substituted fused heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 6 to 10 ring-constituting atoms" can be referred to the above-mentioned "definitions of each group used in the present specification", but preferably includes both a mode in which two 6-membered rings are fused and a mode in which a 5-membered ring and a 6-membered ring are fused. The said "fused heterocyclic group" may be substituted at a substitutable position with 1 to 3 identical or different substituents selected from the "substituent group" described in the above-mentioned "definitions of each group used in the present specification". The former includes, for example, tetrahydroquinoline, tetrahydroquinazoline, and the like.

[0113] Hereinafter, the latter will be described more specifically. The latter preferably has the formula (W2a):

[0114]

Chemical formula

[0115] [In the formula, Group A is an optionally substituted heteroaryl group having 5 ring-constituting atoms, and two As 1 are each independently a group or atom selected from CR Z1 , N, NR Z2 , O, and S, Two As 2 each independently represent C or N; and Ring Q is an aromatic hydrocarbon ring, an aromatic heterocyclic ring which may contain 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, a non-aromatic hydrocarbon ring, or a heterocyclic ring which may contain 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, and here, the ring has 5 to 7 ring-constituting atoms and, at substitutable positions, A halogen atom, a hydroxy group, a cyano group, a hydroxycarbonyl group, an oxo group, a thioxo group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, -CO―N(R 7a )(R 7b ), -N(R 7a )(R 7b ), -N(R 7c )―CO―R 7d , and -CO―R 7e , may be substituted with a group selected from (In the above formulas, R Z1 and R Z2 are each independently a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an optionally substituted alkyl group; an optionally substituted cycloalkyl group; an optionally substituted alkoxy group; an optionally substituted alkoxycarbonyl group; -CO―N(R 7a )(R 7b ); -N(R 7a )(R 7b ); -N(R 7c )―CO―R 7d ; an aryl group; an optionally substituted heteroaryl group containing 1 to 3 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 6 ring-constituting atoms; a group selected from (provided that R Z2 is not a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; -N(R 7a )(R 7b ) or -N(R 7c )―CO―R 7d ); R 7a and R 7beach independently represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group, or R 7a and R 7b may be bonded to each other to form, together with the adjacent nitrogen atom, a heterocycle which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; R 7c and R 7d each independently represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; and R 7e represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.)] is a group represented by.

[0116] Examples of the group A's "optionally substituted heteroaryl group having 5 ring constituent atoms, wherein two A 1 each independently represents =CR Z1 -, =N-, -NR Z2 -, -O- and -S-, or an atom, and two A 2 each independently represents a carbon atom or a nitrogen atom" include, for example, pyrrolyl, imidazolyl, thienyl, furyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl and the like.

[0117] For the meanings of the groups of "aromatic hydrocarbon ring", "aromatic heterocyclic ring which may contain 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom", "non-aromatic hydrocarbon ring", and "heterocyclic ring which may contain 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom" in ring Q, reference can be made to the above-mentioned "definitions of each group used in the present specification".

[0118] The "halogen atom", "optionally substituted alkyl group", "optionally substituted cycloalkyl group", "optionally substituted alkoxy group", "optionally substituted cycloalkyloxy group", "-CO-N(R 7a )(R 7b )", "-N(R 7a )(R 7b )", "-N(R 7c )-CO-R 7d " and "-CO-R 7e ", which are substituents by which the above-mentioned "aromatic hydrocarbon ring" etc. of the ring Q may be substituted, for the meanings of each group, reference may also be made to the "definitions of each group used in this specification" described above.

[0119] Group (W2) is more preferably of formula (W2b):

[0120]

Chemical formula

[0121] [In the formula, A x1 is a group or atom selected from -NR Z2 -, -O- and -S- (more preferably, a group or atom selected from -NR - and -S-); Z2 ; ring Q is a non-aromatic hydrocarbon ring having 5 or 6 ring-constituting atoms (for example, tetrahydrobenzene); or a heterocyclic ring having 5 or 6 ring-constituting atoms, which may contain 1 to 3 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (more preferably, a heterocyclic ring having 6 ring-constituting atoms, which may contain 1 to 3 identical or different atoms selected from a nitrogen atom and an oxygen atom), where the ring may be substituted at a substitutable position by a substituent selected from -CO-R 7e , a halogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms and an optionally substituted cycloalkyl group having 3 to 4 carbon atoms. (In the formula, R z2 and R 7eis synonymous with the above.)] is a group represented by

[0122] Group (W3): A heteroaryl group which may be substituted, containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 10 ring-constituting atoms For the meaning of "a heteroaryl group containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, having 3 to 10 ring-constituting atoms" in Group (W3) and the "substituent" by which the heteroaryl group may be substituted, reference may be made to the above-mentioned "definitions of each group used in the present specification".

[0123] Group (W3) is preferably the following formula (W3a):

[0124] [Chemical formula]

[0125] [In the formula, Group A' is a heteroaryl group having 5 ring-constituting atoms, A 3a , A 3b , A 3c and A 3d are each independently an atom selected from a nitrogen atom, an oxygen atom, a carbon atom and a sulfur atom, and when A 3a , A 3b , and A 3c are a nitrogen atom or a carbon atom, they each have R a1 , R a2 and R a3 . Here, R a1 is (1) a hydrogen atom, (2) an alkyl group which may be substituted, (3) a cycloalkyl group which may be substituted, (4) an aryl group which may be substituted, (5) a heteroaryl group which may be substituted, or (6) A heterocyclic group which may be substituted, is shown, and R a2 and R a3 are each independently (1) A hydrogen atom, (2) CN, (3) A halogen atom, (4) An alkyl group which may be substituted, (5) A cycloalkyl group which may be substituted, (6) An aryl group which may be substituted, (7) A heteroaryl group which may be substituted, (8) A heterocyclic group which may be substituted, (9) -V a3a -(An alkyl which may be substituted), (10) -V a3a -(A cycloalkyl which may be substituted), (11) -V a3a -(An aryl which may be substituted), (12) -V a3a -(A heteroaryl which may be substituted), or (13) -V a3a -(A heterocyclic group which may be substituted) (In the above formula, V a3a is 1) -CO-, 2) -NR Va3 -[[]] (In the formula, R Va3 is (a) A hydrogen atom, (b) An alkyl group having 1 to 6 carbon atoms which may be substituted, or (c) A cycloalkyl group having 3 to 6 carbon atoms which may be substituted .), 3) -O-, 4) -S-, 5) -SO-, or 6) -SO 2 -[[]] .), or (14) -V a3b -NR Na3 R Na3’ (wherein, V a3b is 1) -CO- 2) -SO-, or 3) -SO 2 - represents, R Na3 and R Na3’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) an optionally substituted cycloalkyl group, 4) an optionally substituted aryl group, 5) an optionally substituted heteroaryl group, or 6) an optionally substituted heterocyclic group, more preferably, R a1 is (1) a hydrogen atom, (2) an optionally substituted alkyl group, represents, and R a2 and R a3 are each independently (1) a hydrogen atom, (4) an optionally substituted alkyl group, (6) an optionally substituted aryl group, (13) -V a3a -(optionally substituted heterocyclic group) (In the above formula, V a3a is 1) -CO-, represents.) or (14) -V a3b -NR Na3 R Na3’ (wherein, V a3b is 1) -CO- represents, R Na3 and R Na3’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) An optionally substituted cycloalkyl group, or 6) An optionally substituted heterocyclic group is shown.] is a group represented by.

[0126] In the group represented by formula (W3a), "group A'" is preferably a group selected from an imidazolyl group, a pyrazolyl group, a thiazolyl group (e.g., 1,2-thiazolyl, 1,3-thiazolyl), an isothiazolyl group, a thiadiazolyl group, an isothiadiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a triazolyl group (1,2,3-triazolyl, 1,2,4-triazolyl), and a tetrazolyl group, and more preferably a group selected from an imidazolyl group, a thiazolyl group, and an oxazolyl group.

[0127] Regarding R a1 , R a2 and R a3 in the group represented by formula (W3a), the meanings can be referred to the "definitions of each group used in the present specification" described above.

[0128] Group (W3) is more preferably the following formulas (W3b) and (W3c):

[0129]

Chemical formula

[0130] [In the formula, A 6 is -O-, -S-, or -NR 6a1 - (in the formula, R 6a1 is (1) a hydrogen atom, (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted aryl group, (5) an optionally substituted heteroaryl group, or (6) an optionally substituted heterocyclic group is shown.) is; R 6a2 is (1) a hydrogen atom, (2) CN, (3) a halogen atom, (4) an optionally substituted alkyl group having 1 to 4 carbon atoms, (5) an optionally substituted cyclopropyl group, (6) an optionally substituted oxetanyl group, (7) an optionally substituted azetidinyl group, (8) an optionally substituted aryl group having 6 to 10 carbon atoms, or (9) -CO-NR a2N6 R a2N6’ (wherein R a2N6 and R a2N6’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 4 carbon atoms, 3) an optionally substituted cyclopropyl group, 4) an optionally substituted oxetanyl group, or 5) an optionally substituted azetidinyl group, is shown.) is; and R 6a3 is (1) a hydrogen atom, (2) CN, (3) a halogen atom, (4) an optionally substituted alkyl group, (5) an optionally substituted cycloalkyl group, (6) an optionally substituted aryl group, (7) an optionally substituted heteroaryl group, (8) an optionally substituted heterocyclic group, (9) -CO-(an optionally substituted heterocyclic group), or (10) -CO-NR a3N6 R a3N6’ (wherein Ra3N6 and R a3N6’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) an optionally substituted cycloalkyl group, 4) an optionally substituted aryl group, 5) an optionally substituted heteroaryl group, or 6) an optionally substituted heterocyclic group .) .] is a group represented by

[0131] Hereinafter, R 6a1 , R 6a2 and R 6a3 in the above formula will be described in detail.

[0132] R 6a1 is (1) a hydrogen atom, (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted aryl group, (5) an optionally substituted heteroaryl group, or (6) an optionally substituted heterocyclic group , and preferably (1) a hydrogen atom, (2) an optionally substituted alkyl group having 1 to 6 carbon atoms, (3) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (4) an optionally substituted aryl group having 6 to 14 carbon atoms, (5) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, or (6) an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms . More preferably, R 6a1 is (1) hydrogen, (2) an alkyl group having 1 to 6 carbon atoms, or (3) -Y 10a -W 10a -Y 10b -W 10b [In the formula, Y 10a is 1) a bond, 2) -(CR Y11 R Y11’ ) n10 -, 3) -(CR Y11 R Y11’ ) n10 -V 10 -(CR Y12 R Y12’ ) m10 -、4)-(CR Y11 R Y11’ ) n10 -V 10 -NR N10’ -(CR Y12 R Y12’ ) m10 -、 5)-(CR Y11 R Y11’ ) o10 -NR N10’ -V 10 -(CR Y12 R Y12’ ) m10 -、 6)-(CR Y11 R Y11’ ) o10 -NR N10’’ -(CR Y12 R Y12’ ) m10 -、 7)-(CR Y11 R Y11’ ) o10 -O-(CR Y12 R Y12’ ) m10 - or 8)-(CR Y11 R Y11’ ) o10 -S-(CR Y12 R Y12’ ) m10 - (wherein, R Y11 , R Y11’ , R Y12 and R Y12’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted C1-C6 alkyl), (d) -O-(optionally substituted C3-C6 cycloalkyl), (e) an optionally substituted C1-C6 alkyl group, or (f) an optionally substituted C3-C6 cycloalkyl group or, (g) R Y11 and R Y11’ and R Y12 and R Y12’ are each independently bonded to form an optionally substituted cycloalkyl having 3 to 10 carbon atoms, or an optionally substituted heterocycle containing 1 to 6 atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom and having 3 to 10 ring constituent atoms, n10 represents an integer of 1 to 6, V 10 is (a) -CO-, (b) -SO- or (c) -SO2- and m10 represents an integer of 0 to 6, R N10’ is (a) a hydrogen atom, (b) an optionally substituted C1-C6 alkyl group, (c) an optionally substituted C3-C6 cycloalkyl group, or (d) an optionally substituted heterocyclic group having 3 to 6 ring constituent atoms and o10 represents an integer of 2 to 6, R N10’’ is (a) a hydrogen atom, (b) an optionally substituted C1-C6 alkyl group, (c) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (d) An optionally substituted heterocyclic group having 3 to 6 carbon atoms, (e) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (f) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) .) represents, W 10a is 1) An optionally substituted alkylene group having 1 to 6 carbon atoms, 2) An optionally substituted aryl divalent group having 6 to 10 carbon atoms, 3) An optionally substituted heteroaryl divalent group containing 1 to 6 atoms selected from nitrogen, oxygen or sulfur atoms and having 5 to 10 ring constituent atoms, 4) An optionally substituted cycloalkyl divalent group having 3 to 10 carbon atoms, or 5) An optionally substituted heterocyclic divalent group containing 1 to 6 atoms selected from nitrogen, oxygen or sulfur atoms and having 3 to 10 ring constituent atoms Y 10b is 1) -(CR Y13 R Y13’ ) ny10c -A Y10b -(CR Y14 R Y14’ ) ny10d - (wherein R Y13 , R Y13’ , R Y14 and R Y14’ are each independently (a) A hydrogen atom, (b) A halogen atom, (c) -O-(optionally substituted alkyl having 1 to 6 carbon atoms), (d) -O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), (e) An optionally substituted alkyl group having 1 to 6 carbon atoms, or (f) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms or, (g)R Y13 and R Y13’ and R Y14 and R Y14’ may each independently be bonded to each other to form, together with adjacent carbon atoms, an optionally substituted monocyclic or fused cycloalkane having 3 to 10 carbon atoms, or an optionally substituted heterocycle having 3 to 10 ring-constituting atoms and containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms, ny10c and ny10d each independently represent an integer of 0 to 6, A Y10b is (a) a bond, (b) -O-, (c) -SO-, (d) -SO2-, (e) -NR NY10e - (wherein R NY10e is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (iv) an optionally substituted heterocyclic group having 3 to 6 carbon atoms, (v) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (vi) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms).), or (f) -V Y10f -NR NY10f - or NR NY10f -V Y10f - (wherein V Y10f is -CO-, -SO- or -SO 2 - represents, R NY10f is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, An optionally substituted cycloalkyl group having 3 to 6 carbon atoms or an optionally substituted heterocyclic group having 3 to 6 carbon atoms is shown.) is shown, W 10b is 1) a hydrogen atom, 2) a halogen atom, 3) an optionally substituted aryl group having 6 to 10 carbon atoms, 4) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, 5) an optionally substituted monocyclic or condensed cycloalkyl having 3 to 10 carbon atoms, 6) an optionally substituted heterocyclic group containing 1 to 6 atoms selected from nitrogen, oxygen or sulfur atoms and having 3 to 10 ring-constituting atoms, 7) -CONR NW10 R NW10’ (In the formula, R NW10 and R NW10’ may be the same or different and are each independently (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (c) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms .), 8) -NR NW10’’ R NW10’’’ (In the formula, R NW10’’ and R NW10’’’ may be the same or different and are each independently (a) a hydrogen atom, (b) unsubstituted or substituted alkyl having 1 to 6 carbon atoms, (c) an optionally substituted cycloalkyl having 3 to 6 carbon atoms, (d) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (e) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (f)-CO-(optionally substituted C3-C6 cycloalkyl) is shown.) is shown.], (4) an optionally substituted C3-C10 cycloalkyl group, (5) an optionally substituted C6-C14 aryl group, (6) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, or (7) an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, is. More preferably, R 6a1 is (1) hydrogen, (2) a C1-C6 alkyl group, or (3) -Y 10a -W 10a -Y 10b -W 10b [In the formula, Y 10a is 1)-(CR Y11 R Y11’ ) n10 -, 2)-(CR Y11 R Y11’ ) n10 -V 10 -NR N10’ -(CR Y12 R Y12’ ) m10 (wherein R , R Y11 , R Y11’ and R Y12 and R Y12’ are each independently (a) represents a hydrogen atom, n10 represents an integer of 1 to 6, V 10 is (a) -CO-, is shown, m10 represents an integer of 0 to 6, RN10’ represents (a) a hydrogen atom, .) represents, W 10a represents 1) an arylene divalent group having 6 to 10 carbon atoms, 2) a heteroarylene divalent group containing 1 to 4 identical or different atoms selected from nitrogen atoms and oxygen atoms and having 5 to 6 ring-constituting atoms, represents, Y 10b represents 1)-(CR Y13 R Y13’ ) ny10c -A Y10b -(CR Y14 R Y14’ ) ny10d - (wherein R Y13 , R Y13’ , R Y14 and R Y14’ are each independently (a) a hydrogen atom, (b) a halogen atom), ny10c and ny10d each independently represent an integer of 0 to 6, A Y10b represents (a) a bond, (b)-O-, .) represents, W 10b represents 1) a hydrogen atom, 2) a group selected from an alkyl group having 1 to 6 carbon atoms which may be substituted by a halogen and an aryl group having 6 to 10 carbon atoms which may be substituted by a group selected from a halogen, 3) a heteroaryl group containing 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms and having 5 to 6 ring-constituting atoms, which may be substituted by an alkyl group having 1 to 6 carbon atoms, .) represents.]、 (4) a cycloalkyl group having 3 to 10 carbon atoms which may be substituted, (5) An aryl group having 6 to 14 carbon atoms which may be substituted, (6) A heteroaryl group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 3 to 10 ring-constituting atoms, or (7) A heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and having 3 to 10 ring-constituting atoms, is. Here, the meaning of each group can be referred to the "definition of each group used in this specification" described above.

[0133] R 6a2 is (1) A hydrogen atom, (2) CN, (3) A halogen atom, (4) An alkyl group which may be substituted, (5) A cycloalkyl group which may be substituted, (6) An aryl group which may be substituted, (7) A heteroaryl group which may be substituted, (8) A heterocyclic group which may be substituted, (9) -V a3a -(an alkyl group which may be substituted), (10) -V a3a -(a cycloalkyl group which may be substituted), (11) -V a3a -(an aryl group which may be substituted), (12) -V a3a -(a heteroaryl group which may be substituted), or (13) -V a3a -(a heterocyclic group which may be substituted) (In the above formula, V a3a is 1) -CO-, 2) -NR Va3 -[[]] (wherein R Va3 is (a) A hydrogen atom, (b) An alkyl group having 1 to 6 carbon atoms which may be substituted, or (c) A cycloalkyl group having 3 to 6 carbon atoms which may be substituted is shown. ), 3) -O-, 4) -S-, 5) -SO-, or 6) -SO 2 - is shown. ), or (14) -V a3b -NR Na3 R Na3’ (In the formula, V a3b is 1) -CO- 2) -SO-, or 3) -SO 2 - is shown, R Na3 and R Na3’ are each independently 1) A hydrogen atom, 2) An alkyl group which may be substituted, 3) A cycloalkyl group which may be substituted, 4) An aryl group which may be substituted, 5) A heteroaryl group which may be substituted, or 6) A heterocyclic group which may be substituted is shown. ). and preferably (1) A hydrogen atom, (2) CN, (3) A halogen atom, (4) An alkyl group having 1 to 4 carbon atoms which may be substituted, (5) A cyclopropyl group which may be substituted, (6) An oxetanyl group which may be substituted, (7) An azetidinyl group which may be substituted, (8) An aryl group having 6 to 10 carbon atoms which may be substituted, or (9) -CO-NR a2N6 R a2N6’ (In the formula, Ra2N6 and R a2N6’ each independently represents 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 4 carbon atoms, 3) an optionally substituted cyclopropyl group, 4) an optionally substituted oxetanyl group, or 5) an optionally substituted azetidinyl group, .) and more preferably (1) a hydrogen atom, (2) CN, (3) a halogen atom, (4) an alkyl group having 1 to 4 carbon atoms, (5) an optionally substituted cyclopropyl group, (6) an optionally substituted oxetanyl group, (7) an optionally substituted azetidinyl group, (8) an aryl group having 6 to 10 carbon atoms optionally substituted with an alkoxy group having 1 to 6 carbon atoms, or (9) -CO-NR a2N6 R a2N6’ (wherein R a2N6 and R a2N6’ each independently represents 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 4 carbon atoms, 3) an optionally substituted cyclopropyl group, 4) an optionally substituted oxetanyl group, or 5) an optionally substituted azetidinyl group, .) is. Here, the meaning of each group can be referred to the "definition of each group used in this specification" described above.

[0134] R 6a3 represents (1) a hydrogen atom, (2) CN, (3) a halogen atom, (4) An optionally substituted alkyl group, (5) An optionally substituted cycloalkyl group, (6) An optionally substituted aryl group, (7) An optionally substituted heteroaryl group, (8) An optionally substituted heterocyclic group, (9) -V a3a -(Optionally substituted alkyl), (10) -V a3a -(Optionally substituted cycloalkyl), (11) -V a3a -(Optionally substituted aryl), (12) -V a3a -(Optionally substituted heteroaryl), or (13) -V a3a -(Optionally substituted heterocyclic group) (In the above formula, V a3a is 1) -CO-, 2) -NR Va3 -[[]] (wherein R Va3 is (a) A hydrogen atom, (b) An optionally substituted alkyl group having 1 to 6 carbon atoms, or (c) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms .), 3) -O-, 4) -S-, 5) -SO-, or 6) -SO 2 -[[]] .), or (14) -V a3b -NR Na3 R Na3’ (wherein V a3b is 1) -CO- 2) -SO-, or 3) -SO 2 -[[]] .), and R Na3 and R Na3’are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) an optionally substituted cycloalkyl group, 4) an optionally substituted aryl group, 5) an optionally substituted heteroaryl group, or 6) Optionally substituted heterocyclic group Indicates. ) Indicates. ] Preferably, (1) a hydrogen atom, (2) CN, (3) a halogen atom, (4) an optionally substituted alkyl group, (5) an optionally substituted cycloalkyl group, (6) an optionally substituted aryl group, (7) an optionally substituted heteroaryl group, (8) an optionally substituted heterocyclic group, (9) -CO- (an optionally substituted heterocyclic group), or (10)-CO-NR a3N6 R a3N6’ (In the formula, R a3N6 and R a3N6’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group, 3) an optionally substituted cycloalkyl group, 4) an optionally substituted aryl group, 5) an optionally substituted heteroaryl group, or 6) Optionally substituted heterocyclic group (Indicates and more preferably (1) a hydrogen atom, (2) CN, (3) a halogen atom, (4) an optionally substituted alkyl group having 1 to 6 carbon atoms, (5) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (6) An aryl group having 6 to 14 carbon atoms which may be substituted, (7) A heteroaryl group which may be substituted, containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 10 ring constituent atoms, (8) A heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 10 ring constituent atoms, (9) -CO-(a heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 10 ring constituent atoms), or (10) -CO-NR a3N6 R a3N6’ (In the formula, R a3N6 and R a3N6’ each independently represent 1) A hydrogen atom, 2) An alkyl group having 1 to 6 carbon atoms which may be substituted, 3) A cycloalkyl group having 3 to 10 carbon atoms which may be substituted, 4) An aryl group having 6 to 14 carbon atoms which may be substituted, 5) A heteroaryl group which may be substituted, containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 10 ring constituent atoms, or 6) A heterocyclic group which may be substituted, containing 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 10 ring constituent atoms. )(It is shown.) It is. More preferably, R 6a3 is (First group) A hydrogen atom or an alkyl group having 1 to 6 carbon atoms (Second group) -Y 6a -W 6a (In the formula, Y 6a is 1) A bond, 2) -(CR Y1R Y1’ ) ny6a -A Y6a -(CR Y2 R Y2’ ) ny6b - (wherein R Y1 、R Y1’ 、R Y2 and R Y2’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted C1-C6 alkyl), (d) -O-(optionally substituted C3-C6 cycloalkyl), (e) an optionally substituted C1-C6 alkyl group, or (f) an optionally substituted C3-C6 cycloalkyl group or, (g) R Y1 and R Y1’ , and R Y2 and R Y2’ are each independently bonded to each other to form, together with the adjacent carbon atoms, an optionally substituted C3-C10 cycloalkyl group or an optionally substituted heterocycle having 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, ny6a represents an integer of 1 to 6, A Y6a is (a) a bond, (b) -CO-, (c) -O-, (d) -SO-, (e) -SO 2 -, (f) -NR NY6a -, (wherein R NY6a is (i) a hydrogen atom, (ii) an optionally substituted C1-C6 alkyl group, (iii) an optionally substituted C3-C6 cycloalkyl group, (iv) A heterocyclic group having 3 to 6 ring-constituting atoms, which may be substituted, (v) -CO-(an optionally substituted alkyl having 1 to 6 carbon atoms), or (vi) -CO-(an optionally substituted cycloalkyl having 3 to 6 carbon atoms) is shown. ), or (g) -V Y6b -NR NY6b - or -NR NY6b -V Y6b - (In the formula, V Y6b is (i) -CO-, (ii) -SO-, or (iii) -SO 2 - is shown, R NY6b is (i) A hydrogen atom, (ii) An optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (iv) An optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms is shown. ) is shown, ny6b represents an integer from 0 to 6, and W 6a is 1) A hydrogen atom, 2) A halogen atom, 3) An optionally substituted cycloalkyl group having 3 to 10 carbon atoms, 4) An optionally substituted aryl group having 6 to 10 carbon atoms, 5) An optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, or 6) An optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, is shown. ) The group represented by (The third group) Formula: -CO-R 9a -W 9a -Y 9b -W 9b [In the formula, R 9a is (1) formula:

[0135] [Chemical formula]

[0136] (In the formula,

[0137] [Chemical formula]

[0138] is Y which contains a nitrogen atom and may further contain 1 to 5 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and has 3 to 10 ring-constituting atoms 9a and may be further substituted with a heterocyclic group (For example, an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a tetrahydronaphthyridinyl group, a tetrahydrothiazolopyridyl group or a tetrahydroisoquinolyl group, each of which may be further substituted with an oxo group or a halogen atom in addition to Y 9a ) represents, and Y 9a is 1)-(CR Y5 R Y5’ ) ny9a -A Y9a -(CR Y6 R Y6’ ) ny9b - (In the formula, R Y5 , R Y5’ , R Y6 and R Y6’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) -O-(optionally substituted C1-C6 alkyl), (d) -O-(optionally substituted C3-C6 cycloalkyl), (e) optionally substituted C1-C6 alkyl group, or (f) optionally substituted C3-C6 cycloalkyl group represents, or (g) R Y5 and R Y5’ as well as R Y6 and R Y6’ may each independently bond to each other to form, together with adjacent carbon atoms, an optionally substituted C3-C10 cycloalkyl group, or an optionally substituted heterocycle containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms; ny9a and ny9b each independently represent an integer from 0 to 6; A Y9a is (a) a bond, (b) -O-, (c) -SO-, (d) -SO 2 -, (e) -NR NY9c - (wherein R NY9c is (i) a hydrogen atom, (ii) an optionally substituted C1-C6 alkyl group, (iii) an optionally substituted C3-C6 cycloalkyl group, (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (v) -CO-(optionally substituted C1-C6 alkyl), or (vi) -CO-(optionally substituted C3-C6 cycloalkyl) represents.) (f) -V Y9d -NR NY9d - or -NR NY9d -V Y9d - (wherein V Y9drepresents (i) -CO-, (ii) -SO-, or (iii) -SO 2 - and R NY9d represents (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms.) represents.) represents.] a group represented by, or

[0139] (2) Formula: -NR N9 -, -NR N9 -(CR Y7 R Y7’ ) n9 (ii) -SO -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -NR N9’ -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’ -V 9 -(CR Y8 R Y8’ ) m9 -, -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’’-(CR Y8 R Y8’ ) m9 -、 -NR N9 -(CR Y7 R Y7’ ) o9 -O-(CR Y8 R Y8’ ) m9 -、 or -NR N9 -(CR Y7 R Y7’ ) o9 -S-(CR Y8 R Y8’ ) m9 - [In the above formula, R N9 is 1) a hydrogen atom, 2)-(CR N9a R N9a’ ) nN9a -Y N9 -W N9 (In the formula, R N9a and R N9a’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c)-O-(optionally substituted alkyl having 1 to 6 carbon atoms), (d)-O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), (e) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (f) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms or, (g) R N9a and R N9a’ are bonded to each other and, together with the adjacent carbon atoms, form an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or (h) may form an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms; nN9a represents an integer from 1 to 6; Y N9 is (a) Bond -, (b) -O-, (c) -SO-, (d) -SO 2 -, (e) -NR N9b - (In the formula, R N9b is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (v) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (vi) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms is shown. ), or (f) -V N9c -NR N9c - or -NR N9c -V N9c - (In the formula, V N9c is (i) -CO-, (ii) -SO-, or (iii) -SO 2 - is shown, R N9c is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown. ) is shown, W N9 is (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (d) an optionally substituted aryl group having 6 to 10 carbon atoms, (e) Optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 3 to 10 ring-constituting atoms, or (f) halogen atom is shown. ) is shown; R Y7 , R Y7’ , R Y8 and R Y8’ are each independently 1) hydrogen atom, 2) halogen atom, 3) -O-(optionally substituted alkyl having 1 to 6 carbon atoms), 4) -O-(optionally substituted cycloalkyl having 3 to 6 carbon atoms), 5) optionally substituted alkyl group having 1 to 6 carbon atoms, or 6) optionally substituted cycloalkyl group having 3 to 6 carbon atoms is shown, or, 7) R Y7 and R Y7’ and R Y8 and R Y8’ are each independently bonded to each other to form, together with adjacent carbon atoms, an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, or an optionally substituted heterocycle containing 1 to 6 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom and having 3 to 10 ring-constituting atoms; n9 represents an integer of 1 to 6; V 9 is 1) -CO-, 2) -SO-, 3) -SO 2 -, or 4) optionally substituted divalent heterocyclic group having 3 to 6 ring-constituting atoms is shown; m9 represents an integer of 0 to 6; R N9’ is 1) hydrogen atom, 2) optionally substituted alkyl group having 1 to 6 carbon atoms, 3) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or 4) An optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms is shown; o9 represents an integer of 2 to 6; R N9’’ is 1) A hydrogen atom, 2) An optionally substituted alkyl group having 1 to 6 carbon atoms, 3) An optionally substituted cycloalkyl group having 3 to 6 carbon atoms, 4) An optionally substituted heterocyclic group having 3 to 6 carbon atoms, 5) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or 6) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) is shown.] The group represented by;

[0140] W 9a is (1) An optionally substituted alkylene group having 1 to 6 carbon atoms, (2) An optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) An optionally substituted heteroaryl divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms, (4) An optionally substituted cycloalkyl divalent group having 3 to 10 carbon atoms, or (5) An optionally substituted heterocyclic divalent group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 3 to 10 ring-constituting atoms is shown,

[0141] Y 9b is (1)-(CR Y9 R Y9’ )ny9c-A Y9b -(CR Y10 R Y10’ )ny9d- (In the formula, R Y9 , R Y9’ , R Y10 and RY10’ each independently, 1) a hydrogen atom, 2) a halogen atom, 3) -O-(optionally substituted C1-C6 alkyl), 4) -O-(optionally substituted C3-C6 cycloalkyl), 5) optionally substituted C1-C6 alkyl or 6) optionally substituted C3-C6 cycloalkyl group, or 7) R Y9 and R Y9’ and R Y10 and R Y10’ may each independently bond to each other to form, together with adjacent carbon atoms, an optionally substituted C3-C10 cycloalkyl group, or an optionally substituted heterocyclic group having 1 to 6 identical or different atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom and having 3 to 10 ring-constituting atoms, ny9c and ny9d each independently represent an integer of 0 to 6, A Y9b is 1) a bond, 2) -O-, 3) -SO-, 4) -SO 2 -, 5) -NR NY9e -, (wherein R NY9e is (a) a hydrogen atom, (b) an optionally substituted C1-C6 alkyl group, (c) an optionally substituted C3-C6 cycloalkyl group, (d) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (e) -CO-(optionally substituted C1-C6 alkyl), (f) -CO-(optionally substituted C3-C6 cycloalkyl) .), or 6) -V Y9f -NR NY9f - or -NRNY9f -V Y9f - (wherein V Y9f is (i) -CO-, (ii) -SO-, or (iii) -SO 2 - represents, R NY9f is (i) a hydrogen atom, (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, (iii) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, or (iv) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms .) represents,

[0142] W 9b is (1) a hydrogen atom, (2) a halogen atom, (3) an optionally substituted aryl group having 6 to 10 carbon atoms, (4) an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 5 to 10 ring-constituting atoms, (5) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, (6) an optionally substituted heterocyclic group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen and sulfur atoms and having 3 to 10 ring-constituting atoms, (7) -CONR NW9 R NW9’ (wherein R NW9 and R NW9’ are each independently 1) a hydrogen atom, 2) an optionally substituted alkyl group having 1 to 6 carbon atoms, or 3) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms .), or 4) -NR NW9’’ R NW9’’’ ​​ (wherein, R NW9’’ and R NW9’’’ each independently represents (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, (d) an optionally substituted heterocyclic group having 3 to 6 ring-constituting atoms, (e) -CO-(optionally substituted alkyl having 1 to 6 carbon atoms), or (f) -CO-(optionally substituted cycloalkyl having 3 to 6 carbon atoms) .) .] (is). More preferably, R 6a3 is (Group 1) a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (Group 2) -Y 6a -W 6a (wherein, Y 6a is 1) a bond, 2) -(CR Y1 R Y1’ ) ny6a -A Y6a -(CR Y2 R Y2’ ) ny6b - (wherein, R Y1 , R Y1’ , R Y2 and R Y2’ each independently represent a hydrogen atom, ny6a represents an integer of 1 to 6, A Y6a is (a) a bond (b) -O-, (c) -NR NY6a -, (wherein, R NY6a is An alkyl group having 1 to 6 carbon atoms which may be substituted by a substituent selected from a cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms, is shown. ), or (d)-V Y6b -NR NY6b - or -NR NY6b -V Y6b - (In the formula, V Y6b is -CO-, is shown, R NY6b is An alkyl group having 1 to 6 carbon atoms which may be substituted by a group selected from a cycloalkyl group having 3 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms, is shown, ny6b represents an integer from 0 to 6, and W 6a is 1) A hydrogen atom, 2) A cycloalkyl group having 3 to 10 carbon atoms, 3) An aryl group having 6 to 10 carbon atoms, 4) -W 6a’ -(CR Y3 R Y3’ ) ny6c -A Y6b -(CR Y4 R Y4’ ) ny6d -W 6b [In the formula, W 6a’ is (1) A cycloalkyl divalent group having 3 to 10 carbon atoms, (2) An aryl divalent group having 6 to 10 carbon atoms, is shown, R Y3 , R Y3’ , R Y4 and R Y4’ are each independently (1) A hydrogen atom, (2) A halogen atom, A Y6b is (1) A bond, (2) -O-, or (3) -VY6d -NR NY6d - (wherein, V Y6d is -CO- and (), and R NY6d is an alkyl group having 1 to 6 carbon atoms ).) represents ny6c and ny6d each independently represent an integer from 0 to 6 W 6b is (1) a hydrogen atom (2) a halogen atom (4) a heteroaryl group which may be substituted by an alkyl group having 1 to 6 carbon atoms and contains 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms and has 5 to 6 ring-constituting atoms (Group 3) Formula: -CO-R 9a -W 9a -Y 9b -W 9b [wherein, R 9a is (1) Formula:

[0143]

Chemical formula

[0144] (wherein,

[0145]

Chemical formula

[0146] is a hetero ring group which contains a nitrogen atom and may further contain 1 to 5 identical or different atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and has 3 to 10 ring-constituting atoms and may be further substituted in addition to Y 9a (for example, each being Y (e.g., each being Y9a An azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, tetrahydro naphthyridinyl group, tetrahydro thiazolopyridyl group or tetrahydroisoquinolyl group, which may be further substituted with an oxo group or a halogen atom in addition to those described above) is shown as Y 9a is 1)-(CR Y5 R Y5’ ) ny9a -A Y9a -(CR Y6 R Y6’ ) ny9b - (wherein R Y5 , R Y5’ , R Y6 and R Y6’ are each independently (a) represents a hydrogen atom ny9a and ny9b each independently represent an integer from 0 to 6; A Y9a is (a) a bond (b) -O- (e) -NR NY9c - (wherein R NY9c is (i) a hydrogen atom (f) -V Y9d -NR NY9d - or -NR NY9d -V Y9d - (wherein V Y9d is (i) -CO- is shown, and R NY9d is (i) a hydrogen atom (ii) an alkyl group having 1 to 6 carbon atoms is shown.] a group represented by, or (2) formula: -NR N9 -, -NR N9 -(CR Y7 R Y7’ ) n9 -, -NRN9 -(CR Y7 R Y7’ ) n9 -V 9 -(CR Y8 R Y8’ ) m9 -、 -NR N9 -(CR Y7 R Y7’ ) n9 -V 9 -NR N9’ -(CR Y8 R Y8’ ) m9 -、 -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’ -V 9 -(CR Y8 R Y8’ ) m9 -、 -NR N9 -(CR Y7 R Y7’ ) o9 -NR N9’’ -(CR Y8 R Y8’ ) m9 -、-NR N9 -(CR Y7 R Y7’ ) o9 -O-(CR Y8 R Y8’ ) m9 -、 or [In the above formula, R N9 is 1) a hydrogen atom, 2)-(CR N9a R N9a’ ) nN9a -Y N9 -W N9 (In the formula, R N9a and R N9a’ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) an optionally substituted alkyl group having 1 to 6 carbon atoms, or (d) R N9aand R N9a’ may be bonded to each other to form, together with the adjacent carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a heterocyclic group containing 1 to 2 oxygen atoms and having 5 to 6 ring-constituting atoms; nN9a represents an integer from 1 to 6; Y N9 is (a) a bond, (b) -O-, (c) -NR N9c -V N9c - (wherein V N9c is (i) represents -CO-). R N9c is (i) a hydrogen atom, or (ii) an optionally substituted alkyl group having 1 to 6 carbon atoms, .) represents W N9 is (a) a hydrogen atom, (b) an optionally substituted alkyl group having 1 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 6 carbon atoms, (d) an aryl group having 6 to 10 carbon atoms, or (f) a halogen atom .) represents; R Y7 、R Y7’ 、R Y8 and R Y8’ are each independently 1) a hydrogen atom 2) represents an optionally substituted alkyl group having 1 to 6 carbon atoms, n9 represents an integer from 1 to 6; V 9 is 1) -CO-, 2) represents an optionally substituted divalent heterocyclic group having 3 to 6 ring-constituting atoms; m9 represents an integer from 0 to 6; R N9’ is 1) a hydrogen atom, 2) An alkyl group having 1 to 6 carbon atoms, is shown; o9 represents an integer from 2 to 6; R N9’’ is 1) A hydrogen atom, is shown. ] A group represented by;

[0147] W 9a is (1) An optionally substituted alkylene group having 1 to 6 carbon atoms, (2) An optionally substituted aryl divalent group having 6 to 10 carbon atoms, (3) An optionally substituted heteroaryl divalent group containing 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms and having 5 to 6 ring-constituting atoms, or (5) An optionally substituted heterocyclic divalent group containing 1 to 4 nitrogen atoms and having 5 to 6 ring-constituting atoms, is shown,

[0148] Y 9b is (1)-(CR Y9 R Y9’ )ny9c-A Y9b -(CR Y10 R Y10’ )ny9d- (In the formula, R Y9 , R Y9’ , R Y10 and R Y10’ are each independently 1) A hydrogen atom, or 2) A halogen atom, is shown, ny9c and ny9d each independently represent an integer from 0 to 6, A Y9b is 1) A bond, 2)-O-, is shown, is shown,

[0149] W 9b is (1) A hydrogen atom, (2) A halogen atom, (3) An aryl group having 6 to 10 carbon atoms which may be substituted by a halogen, (4) A heteroaryl group having 1 to 4 identical or different atoms selected from nitrogen atoms and sulfur atoms, having 5 to 6 ring-constituting atoms, and which may be substituted by an alkyl group having 1 to 6 carbon atoms, (5) -CONR NW9 R NW9’ (In the formula, R NW9 and R NW9’ are each independently 1) A hydrogen atom, 2) An alkyl group having 1 to 6 carbon atoms, or as shown.] is a group represented by.

[0150] Group (W4): An alkyl group which may be substituted by a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a heterocyclic group Group (W4) is preferably 1) a halogen atom, 2) a hydroxy group, 3) an alkoxy group having 1 to 6 carbon atoms, and 4) an alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 groups selected from substituted heterocyclic groups having 1 to 6 atoms selected from nitrogen atoms, oxygen atoms or sulfur atoms and having 3 to 10 ring-constituting atoms.

[0151] [Regarding L] L represents a bond or a chemical linker, and preferably, formula (L-I): -(L a ) q - [wherein q represents an integer from 1 to 100 (more preferably, an integer from 1 to 50), and q Ls a are each independently (1) A bond, (2) CR L1 R L1’ , (3) O, (4) S, (5) CO, (6) SO, (7) SO 2 , (8) NR L1 , (9) CONR L1 , (10) NR L1 CO, (11) NR L1 CONR L1’ , (12) SONRL1 , (13) NR L1 SO, (14) SO 2 NR L1 , (15) NR L1 SO 2 , (16) NR L1 SO 2 NR L1’ , (17) CR L1 =CR L1’ , (18) C≡C, (19) SiR L1 R L1’ , (20) P(O)R L1 , (21) P(O)OR L1 , (22) NR L1 C(=NCN)NR L1’ , (23) NR L1 C(=NCN), (24) optionally substituted cycloalkyl divalent group, (25) optionally substituted heterocyclic divalent group, (26) optionally substituted aryl divalent group, or (27) optionally substituted heteroaryl divalent group (In the above formula, R L1 and R L1’ are each independently 1) hydrogen atom, 2) halogen atom, 3) -CN, 4) -NO 2 , 5) -SF 5 , 6) -CO 2 H, 7) -N(R L2 R L2’ ), 8) -A L2 R L2 , 9) optionally substituted alkyl group, 10) optionally substituted cycloalkyl group, 11) optionally substituted heterocyclic divalent group, 12) optionally substituted aryl group, 13) optionally substituted heteroaryl group, 14) -SO 2 R L2 , 15) -P(O)(OR L2 )OR L2’ , 16) -C≡CR L2 , 17) -C(R L2 )=C(R L2’ R L2’’ ), 18) -COR L2 , 19) -CON(R L2 R L2’ ), 20) -SO 2 N(RL2 R L2’ )、21)-N(R L2 )CON(R L2’ R L2’’ )、 or 22)-N(R L2 )SO 2 N(R L2’ R L2’’ ) (In the above formula, A L2 represents an oxygen atom or a sulfur atom, and R L2 , R L2’ , and R L2’’ each independently represent a group selected from a) a hydrogen atom, b) an optionally substituted C 1 -C 8 alkyl group, or c) an optionally substituted C 3 -C 8 cycloalkyl group.).] is a group represented by.

[0152] L is more preferably of the formula (L-II): ―L b1 -L b2 -L b3 - [wherein L b1 and L b3 each independently represent (1) a bond, (2) CR L1 R L1’ , (3) O, (4) S, (5) SO, (6) SO 2 , (7) NR L1 , (8) SO 2 NR L1 , (9) NR L1 SO 2 , (10) SONR L1 , (11) NR L1 SO, (12) CONR L1 , (13) NR L1 CO, (14) NR L1 CONR L1’ , (15) NR L1 SO 2 NR L1’ , or (16) CO, and L b2 is (1) a bond, (2) (CH 2 )1-10 , (3)(CH 2 ) 0-6 -O-(CH 2 ) 0-6 , (4)(CH 2 ) 0-6 -CONH-(CH 2 ) 0-6 , (5)(CH 2 ) 0-6 -NHCO-(CH 2 ) 0-6 , (6)(CH 2 ) 0-6 -NH-(CH 2 ) 0-6 , (7)(CH 2 ) 0-6 -NHSO 2 -(CH 2 ) 0-6 , or (8)(CH 2 ) 0-6 -SO 2 NH-(CH 2 ) 0-6 represents. (In the formula, R L1 and R L1’ have the same meanings as described above.)] It is a group represented by.

[0153] L is more preferably of the formula (L-III): ―L 1 -L 2 -L 3 - [In the formula, L 1 and L 3 are each independently (1) a bond, (2) CR L1 R L1’ , (3) O, (4) S, (5) SO, (6) SO 2 , (7) NR L1 , (8) SO 2 NR L1 , (9) NR L1 SO 2 , (10) SONR L1 , (11) NR L1 SO, (12) CONR L1 , (13) NR L1 CO, (14) NR L1 CONR L1’, (15) NR L1 SO 2 NR L1’ or (16) CO, and L 2 is (CH 2 ) p1a -O-(CH 2 -CH 2 -O) p2a -(CH 2 ) p3a (wherein p1a and p3a are integers from 0 to 10 when the directly bonding atoms of adjacent L 1 or L 3 are carbon atoms or a bond, and are integers from 2 to 10 for other atoms, and p2a is an integer from 0 to 10.) is shown.] is a group represented by

[0154] L is particularly preferably -L b1 -L b2 -L b3 - [wherein L b1 and L b3 are each independently (1) a bond, (2) CR L1 R L1’ , (3) O, (4) S, (5) SO, (6) SO 2 , (7) NR L1 , (8) SO 2 NR L1 , (9) NR L1 SO 2 , (10) SONR L1 , (11) NR L1 SO, (12) CONR L1 , (13) NR L1 CO, (14) NR L1 CONR L1’ , (15) NR L1 SO 2 NR L1’ , or (16) CO, and L b2 is (1) a bond, (2) (CH 2 )1-10 、(3)(CH 2 ) 0-6 -O-(CH 2 ) 0-6 、(4)(CH 2 ) 0-6 -CONH-(CH 2 ) 0-6 、(5)(CH 2 ) 0-6 -NHCO-(CH 2 ) 0-6 、(6)(CH 2 ) 0-6 -NH-(CH 2 ) 0-6 、(7)(CH 2 ) 0-6 -NHSO 2 -(CH 2 ) 0-6 、 or (8)(CH 2 ) 0-6 -SO 2 NH-(CH 2 ) 0-6 represents. (In the formula, R L1 and R L1’ have the same meaning as described above.)] It is a group represented by.

[0155] Among the above definitions, the meanings of each group of "optionally substituted cycloalkyl divalent group", "optionally substituted heterocyclic divalent group", "optionally substituted aryl divalent group", "optionally substituted heteroaryl divalent group", "halogen atom", "optionally substituted alkyl group", "optionally substituted cycloalkyl group", "optionally substituted aryl group", "optionally substituted heteroaryl group", "optionally substituted C 1 -C 8 alkyl group", and "optionally substituted C 3 -C 8 cycloalkyl group" can be referred to the above-mentioned "definitions of each group used in this specification".

[0156] [Regarding A] A represents a target-directed ligand. More specifically, it may be a group having a portion capable of binding to or a binding portion for a target protein. For example, specific examples of preferred target-directed ligands include compounds that bind to the following target proteins. However, the "target-directed ligand" of the present invention is not limited thereto. A person skilled in the art can appropriately select or design a target-directed ligand according to the target protein of interest and use it. For example, those described in Examples 163 to 165 below can be cited as an example.

[0157] In the present invention, the target protein to which A binds is preferably a protein having a biological function selected from the group consisting of structure, control, hormone, enzyme, gene regulation, immunity, contraction, storage, transport, and signal transduction. The protein is more preferably selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, and proteins related to the integrated functions of cells, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (assimilation and dissimilation), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid, glycoprotein), receptor activity, cell motility, membrane fusion, intercellular communication, control of biological processes, development, cell differentiation, stimulus response, cell adhesion, cell death, transport (protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity), pathogenicity, virus outer shell, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, epigenetic control, aggregation, extracellular organization, biological activity, or translation regulator activity.

[0158] In the present invention, it is preferable that the target protein to which A binds is selected from the group consisting of proteins related to cancer-related proteins, autoimmune disease-related proteins, inflammatory disease-related proteins, neurodegenerative disease-related proteins, muscle disease-related proteins, sensory organ system disease-related proteins, cardiovascular disease-related proteins, metabolic disease-related proteins, and genetic disease-related proteins.

[0159] When compound (I) contains optical isomers (enantiomers, diastereomers), stereoisomers, positional isomers, or rotational isomers, these are also included as compound (I), and each can be obtained as a single product by known synthetic methods and separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0160] Compound (I) may be appropriately converted into a prodrug, and such an embodiment is also included within the scope of the present invention (hereinafter, compound (I) and its prodrug may be collectively referred to as "the compound of the present invention" in some cases). The prodrug may be one that changes into compound (I) under physiological conditions, as described on pages 163 to 198 of Volume 7, Molecular Design, of "Drug Development" published by Hirokawa Shoten in 1990.

[0161] Compound (I) may be any of a hydrate, an anhydrate, a solvate, or a non-solvate. Also, compound (I) may be a compound labeled or substituted with an isotope (e.g., 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.). A compound labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and may be useful in the field of medical diagnosis and the like. 1 H to 2 The deuterium-converted product obtained by converting H to

[0162] Tautomers are also included in compound (I).

[0163] [Method for Producing Target Proteolytic Inducing Compound of the Present Invention] Hereinafter, the method for producing compound (I) will be described.

[0164] (General Synthetic Approach)

[0165] The compounds of the present invention can be produced by the following methods A to X. These methods and steps may be combined with each other, but the production method is not limited thereto.

[0166] Formula (I) of the present invention:

[0167] [Chemical Formula]

[0168] (In the formula, each symbol has the same meaning as described above.)

[0169] Formula (1) of the intermediate of the present invention:

[0170] [Chemical Formula]

[0171] (In the formula, PG 1 means a protecting group for an amine, PG 2 means a protecting group for a hydroxy group, and the other symbols have the same meaning as described above.) Examples of the protecting group represented by PG 1 include, for example, carbamate-based protecting groups. Examples of the protecting group represented by PG 2 include, for example, silyl-based protecting groups. When PG 1 is, for example, a Boc group, deprotection can be carried out in a suitable solvent in the presence of an acid. When PG 2 is, for example, a TBS group, deprotection can be carried out in a suitable solvent in the presence of an acid or a base or fluoride ions.

[0172] Synthesis method A The production method described herein is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is an imidazolyl group, that is, the following compound [A-2].

[0173]

Chemical formula

[0174] (In the formula, each symbol has the same meaning as described above.) The general formula [A-2] can be derived from the general formula [A-1] according to a known method (for example, BIOORGANIC & Medicinal Chemistry Letters, 26(21), 5354-5360; 2016).

[0175] Synthesis method B The production method described herein is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is an imidazolyl group and R a2 , R a3 is substituted, that is, the following compound [B-2].

[0176]

Chemical formula

[0177] (In the formula, each symbol has the same meaning as described above.) The general formula [B-2] can be derived from the general formula [B-1] according to a known method (for example, WO2006099060).

[0178] Synthesis method C The production method described herein is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is an imidazolyl group, R a1 , R a2 is a hydrogen atom, and R a3 is substituted with a carboxylic acid, that is, the following compound [C-4].

[0179]

Chem.

[0180] (wherein, R C O[M C represents an alkali metal alkoxide, and each symbol has the same meaning as described above.) General formula [C-1] can be derived from compound [A-1] according to a known method (for example, Journal of Medicinal Chemistry, 33(1), 317-27; 1990). General formula [C-2] is obtained by decomposition of the trifluoro group with the base of general formula [C-1]. The reaction proceeds using an alkali metal alkoxide in a suitable alcohol solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 5 minutes to 12 hours. Examples of the base having an alkoxy group include alkali metal alkoxides such as sodium methoxide, specifically potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Examples of the solvent include methanol, ethanol, tert-butanol, etc. General formula [C-3] is obtained by decomposition of general formula [C-2] under acidic conditions. The reaction proceeds using an acid in a suitable solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction time used, but the reaction usually proceeds for 1 hour to 24 hours. Examples of the acid include trifluoroacetic acid, hydrochloric acid, etc. Examples of the solvent include dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethyl acetate, toluene, 1,4-dioxane, etc. General formula [C-4] can be obtained by subjecting general formula [C-3] to basic conditions or acidic conditions. The reaction proceeds in a suitable solvent using a base or an acid, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but usually the reaction proceeds in 1 hour to 48 hours. When using a base, examples include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. When using an acid, examples include trifluoroacetic acid, hydrochloric acid, etc. As the solvent, when using a base, for example, methanol, ethanol, tetrahydrofuran, water can be mentioned. When using an acid, dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethyl acetate, toluene, 1,4-dioxane, water, etc. can be mentioned.

[0181] Synthesis method D The production method described herein is suitable for producing an intermediate in which W in the compound represented by general formula (I) is represented by a thiazolyl group and is substituted with R a2 、R a3 , that is, the following compound [D-4].

[0182]

Chemical formula

[0183] (In the formula, X A is a halogen atom, and each symbol has the same meaning as described above. The halogen atom means a chlorine atom, a bromine atom, or an iodine atom.) General formula [D-2] can be obtained by thioamidating general formula [D-1]. The thioamidation reaction proceeds in a suitable solvent using a sulfurizing agent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but usually it is 0.5 hour to 24 hours. Examples of the sulfurizing agent include Lawesson's reagent and phosphorus pentasulfide, etc. Examples of the solvent include 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, etc. The general formula [D-4] can be derived from the general formula [D-2] and the general formula [D-3] according to known methods (for example, ChemBioChem, 12(15), 2284-2288; 2011, WO2009098448, WO2010060952).

[0184] Synthesis method E The production method described here is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is represented by an oxadiazolyl group and is substituted with R a3 , that is, the following compound [E-3].

[0185]

Chemical formula

[0186] (In the formula, each symbol has the same meaning as described above.) The general formula [E-3] can be derived from the general formula [E-1] and the general formula [E-2] according to known methods (for example, WO2016044386).

[0187] Synthesis method F The production method described here is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is represented by a triazolyl group and is substituted with R a1 , R a3 , that is, the following compound [F-3].

[0188]

Chemical formula

[0189] (In the formula, each symbol has the same meaning as described above.) The general formula [F-1] can be derived from the general formula [D-1] according to known methods (for example, Tetrahedron Letters, 45(52), 9557-9559; 2004). The general formula [F-3] can be derived from the general formula [F-1] and the general formula [F-2] according to known methods (for example, US20120264735).

[0190] Synthesis method G The production method described herein is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is a tetrazolyl group, that is, the following compound [G-2].

[0191]

Chemical formula

[0192] (In the formula, each symbol has the same meaning as described above.) The general formula [G-2] can be derived from the general formula [G-1] according to a known method (for example, Synthesis, 46(15), 2065-2070; 2014 or WO2011035900).

[0193] Synthesis method H The production method described herein is suitable for producing an intermediate in which W in the compound represented by the general formula (I) is a triazolyl group and is substituted by R a2 , that is, the following compound [H-3].

[0194]

Chemical formula

[0195] (In the formula, each symbol has the same meaning as described above.) The general formula [H-1] can be derived from the general formula [A-1] according to a known method (for example, Bioorganic & Medicinal Chemistry Letters, 26(5), 1419-1427; 2016). The general formula [H-3] can be derived from the general formula [H-1] and the general formula [H-2] according to a known method (for example, Organometallics, 30(5), 1021-1029; 2011).

[0196] Synthesis method I The manufacturing method described herein is suitable for manufacturing an intermediate in which W in the compound represented by the general formula (I) is represented by a pyrazolyl group and is substituted with R a2 , R a3 , that is, the following compound (I-3).

[0197]

Chemical formula

[0198] (In the formula, each symbol has the same meaning as described above.) The general formula [I-3] can be derived from the general formula [I-1] and the general formula [I-2] according to a known method (for example, WO2002034716).

[0199] Synthesis method J The manufacturing method described herein is suitable for manufacturing an intermediate in which W in the compound represented by the general formula (I) is represented by an oxazolyl group and is substituted with R a2 , R a3 , that is, the following compound [J-2].

[0200]

Chemical formula

[0201] (In the formula, each symbol has the same meaning as described above.) The general formula [J-2] can be derived from the general formula [J-1] according to a known method (for example, WO2009080226).

[0202] Synthesis method K The manufacturing method described herein is suitable for manufacturing an intermediate in which W in the compound represented by the general formula (I) is represented by a pyridyl group, that is, the following compound [K-2].

[0203]

Chemical formula

[0204] (In the formula, each symbol has the same meaning as described above.)

[0205] General formula [K-2] can be derived from general formula [K-1] according to a known method (for example, WO2013061977).

[0206] Synthesis method L The production method described herein is suitable for producing an intermediate substituted by X, that is, the following compound [L-5], wherein W in the compound represented by the general formula (I) is an alkyl group which may be substituted by a group selected from hetero ring groups. 2aL

[0207]

Chemical formula

[0208] (In the formula, X 2aL represents carbon or an oxygen atom. Each symbol has the same meaning as described above.)

[0209] General formula [L-2] can be obtained from the following two steps. Method 1 General formula [L-2] can be obtained by a reduction reaction from general formula [L-1]. The reaction proceeds using a reducing agent in a suitable solvent, usually from -78°C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvents, and reaction time used, but usually the reaction proceeds in 10 minutes to 24 hours. When using a reducing agent, , Li lithium aluminum hydride, DIBAL-H, etc. can be mentioned. Examples of the solvent include methylene chloride, diethyl ether, tetrahydrofuran, and toluene. Method 2 General formula [L-2] can be obtained by a reduction reaction from general formula [E-1]. The reaction proceeds using a reducing agent in a suitable solvent, usually from -78°C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvents, and reaction time used, but usually the reaction proceeds in 10 minutes to 24 hours. When using a reducing agent, , Li lithium aluminum hydride, BH3·THF, etc. can be mentioned. Examples of the solvent include diethyl ether and tetrahydrofuran. General formula [L-3] is obtained by halogenating general formula [L-2]. The reaction proceeds using a halogenating agent in a suitable solvent, usually from 0 °C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but usually the reaction proceeds within 10 minutes to 24 hours. Examples of the halogenating agent include iodine and triphenylphosphine, or carbon tetrabromide and triphenylphosphine. In the case of iodine and triphenylphosphine, imidazole or the like is used as the base. Examples of the solvent include diethyl ether, tetrahydrofuran, and dichloromethane. General formula [L-5] is obtained by an alkylation reaction of general formula [L-3] and general formula [L-4]. The alkylation reaction proceeds using a base and an alkylating agent such as alkyl halide in a suitable solvent, usually from 0 °C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but usually it is from 30 minutes to 24 hours. Examples of the base include inorganic bases such as sodium hydride, potassium hydroxide, cesium carbonate, and potassium carbonate, and alkoxides such as potassium tert-butoxide and sodium methoxide. Examples of the solvent include N,N-dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide.

[0210] Synthesis method M The production method described here is suitable for producing an intermediate, namely the following compound [M-4], among the compounds represented by general formula (I), where W is a heteroaryl group having 5 ring-constituting atoms and A 3c is represented by a carbon atom, and R a1 , R a2 is substituted, and further R a3 is an aryl group which may be substituted, or a heteroaryl group which may be substituted.

[0211]

Chemical formula

[0212] (In the formula, B 1represents boric acid or a boronic acid ester which may have a substituent, and each of the other symbols has the same meaning as described above. Here, B in the formula 1 The boronic acid ester which may have a substituent of means pinacolato boron, neopentyl glycolato boron, etc. )

[0213] General formula [M-2] is obtained from general formula [M-1] by a halogenation reaction. The reaction proceeds at 0 °C to the reflux temperature of the solvent in a suitable solvent in the presence of a halogenating agent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 1 hour to 24 hours. Examples of the halogenating agent include bromine, iodine, NCS, NBS, NIS, etc. Examples of the solvent include acetonitrile, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, etc. General formula [M-4] is obtained by the coupling reaction of general formula [M-2] and boronic acid derivative [M-3]. The reaction preferably proceeds in a suitable solvent at 0 °C to heating, especially from room temperature to the boiling point of the solvent, in the presence of a palladium catalyst, a phosphine ligand and a base. The reaction time varies depending on the raw materials, solvent and reaction temperature used, but is usually from 1 hour to 24 hours. Examples of the palladium catalyst include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0) or its chloroform adduct. Examples of the phosphine ligand include triphenylphosphine, 2-(dicyclohexylphosphino)-2’,4’,6’-triisopropyl-1,1’-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl, 2-(dicyclohexylphosphino)-2,6-diisopropoxy-1,1’-biphenyl, 2-di-tert-butylphosphino-2’-4’-6’-triisopropylbiphenyl, 2-dicyclohexylphosphino-2’-6’-dimethoxybiphenyl, 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl, tri-o-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-(di-tert-butylphosphino)-1,1-binaphthyl, tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, and the like.A reagent in which a palladium catalyst and a phosphine ligand form a complex may be used. For example, tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), bis(tri-tert-butylphosphine)palladium(0), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, etc. may be mentioned. Examples of the base include sodium tert-butoxide, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, etc. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, alcohol solvents such as methanol, ethanol, propanol, butanol, N,N-dimethylformamide, NMP, or a mixed solvent of these organic solvents and water, etc.

[0214] Synthesis method N In the production method described herein, among the compounds represented by the general formula (I), W represents an imidazolyl group, or a thiazolyl group, or an oxazolyl group, and R 6a2 is substituted, and R 6a3 is -CO-NR a3N6 Ra3N6’ or -CO-(a hetero ring group which contains a nitrogen atom, may further contain 1 to 5 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, has 3 to 10 ring constituent atoms, and may be further substituted in addition to Y) 9a is suitable for producing an intermediate represented by, that is, the following compound [N-4] or [N-5].

[0215] [Chemical formula]

[0216] (In the formula, each symbol has the same meaning as described above.)

[0217] As a method for obtaining the general formula [N-4] or [N-5], for example, any of the following three methods is used. Method 1 The general formula [N-4] or [N-5] is obtained by a condensation reaction of the general formula [N-1] and the general formula [N-2] or the general formula [N-3]. The reaction proceeds in a suitable solvent at 0 °C to the reflux temperature of the solvent in the presence of a suitable base using a condensing agent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 30 minutes to 24 hours. Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM), 2-chloro-1-methylpyridinium iodide, and the like. Examples of the solvent include methanol, N,N-dimethylformamide, chloroform, dichloromethane, tetrahydrofuran, and the like. In addition, the reaction may be promoted by adding 1-hydroxybenzotriazole (HOBt). Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, and the like. Method 2 General formula [N-4] or [N-5] can be obtained by converting general formula [N-1] into an acid halide with a halogenating agent and then reacting it with general formula [N-2] or general formula [N-3]. The reaction proceeds using a base in a suitable solvent, usually from -20°C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 0.5 hours to 24 hours. Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phenylphosphonyldichloride, etc. Examples of the base include triethylamine, pyridine, etc. Examples of the solvent include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, toluene, etc. Method 3 General formula [N-4] or [N-5] can be obtained by using general formula [N-1] as a mixed acid anhydride and then reacting it with general formula [N-2] or general formula [N-3]. The reaction proceeds using a base in a suitable solvent, usually from -20°C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 0.5 hours to 24 hours. Examples of the reagent for forming the mixed acid anhydride include acid anhydrides such as methyl chloroformate, ethyl chloroformate, isobutyloxycarbonyl chloride, pivaloyl chloride, etc. Examples of the base include triethylamine, DIEPA, pyridine, N-methylmorpholine, etc. Examples of the solvent include methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, tetrahydrofuran, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, toluene, etc. Examples of the base include triethylamine, DIEPA, pyridine, N-methylmorpholine, etc.

[0218] Synthesis method O The manufacturing method described here is for compounds represented by general formula (I) in which W is an imidazolyl group and R 6a1 is -(CR Y11 R Y11’ ) n10 -W 10a -Y 10b -W 10b is substituted, and further R 6a2 , R6a3 is suitable for producing an intermediate substituted with, i.e., the following compound [O-3].

[0219]

Chemical formula

[0220] (In the formula, each symbol has the same meaning as described above.)

[0221] The general formula [O-3] is obtained by the alkylation reaction of the general formula [O-1] and the general formula [O-2]. The alkylation reaction proceeds in a suitable solvent usually from 0 °C to the reflux temperature of the solvent using a base and an alkylating agent such as alkyl halide. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 30 minutes to 24 hours. Examples of the base include inorganic bases such as sodium hydride, potassium hydroxide, cesium carbonate, and potassium carbonate, and alkoxides such as potassium tert-butoxide and sodium methoxide. As a reaction accelerator, for example, NaI or TBAI may be used. Examples of the solvent include N,N-dimethylformamide, tetrahydrofuran, acetonitrile, toluene, NMP, dimethyl sulfoxide, and the like.

[0222] Synthesis method P In the production method described herein, among the compounds represented by the general formula (I), W is an imidazolyl group, and R 6a1 is -(CR Y11 R Y11’ ) n10 -W 10a -W 10b substituted with, (W 10a is an optionally substituted divalent aryl group having 6 to 10 carbon atoms, or an optionally substituted divalent heteroaryl group containing 1 to 6 atoms selected from nitrogen, oxygen, or sulfur atoms and having 5 to 10 ring-constituting atoms, W 10b is an optionally substituted aryl group having 6 to 10 carbon atoms, or an optionally substituted heteroaryl group containing 1 to 6 identical or different atoms selected from nitrogen, oxygen, and sulfur atoms and having 5 to 10 ring-constituting atoms), and further R6a2 and R 6a3 is suitable for producing an intermediate substituted with, that is, the following compound [P-3].

[0223]

Chemical formula

[0224] (In the formula, each symbol has the same meaning as described above.)

[0225] General formula [P-3] is obtained by the coupling reaction of general formula [P-1] and general formula [P-2]. The reaction preferably proceeds at 0 °C to heating, especially from room temperature to the boiling point of the solvent, in a suitable solvent in the presence of a palladium catalyst, a phosphine ligand, and a base. The reaction time and the palladium catalyst, phosphine ligand, base, and solvent used are the same as in the second step of synthesis method M.

[0226] Synthesis method Q The production method described here is suitable for producing an intermediate in which, among the compounds represented by general formula (I), E is a bond, X is an optionally substituted aryl group, or an optionally substituted heteroaryl group, that is, the following compound [Q-3].

[0227]

Chemical formula

[0228] (In the formula, each symbol has the same meaning as described above.)

[0229] The method for obtaining general formula [Q-3] uses any one of the following two methods, for example. Method 1 The general formula [Q-3] can be obtained by the SnAr reaction of the general formula [Q-1] and the general formula [Q-2]. The reaction proceeds in a suitable solvent in the presence of a base, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 30 minutes to 48 hours. Examples of the base include inorganic bases such as sodium hydride, potassium hydroxide, cesium carbonate, and potassium carbonate; alkoxides such as potassium t-butoxide and sodium methoxide; and organic bases such as triethylamine, DBU, and DIPEA. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethyl sulfoxide, NMP, toluene, xylene, and acetonitrile. Method 2 The general formula [Q-3] can be obtained by the coupling reaction of the general formula [Q-1] and the general formula [Q-2]. The reaction preferably proceeds in a suitable solvent at 0 °C to heating, especially from room temperature to the boiling point of the solvent, in the presence of a palladium catalyst, a phosphine ligand and a base. The reaction time varies depending on the raw materials, solvent and reaction temperature used, but is usually from 1 hour to 72 hours. Examples of the palladium catalyst include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0) or its chloroform adduct. Examples of the phosphine ligand include triphenylphosphine, 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-(dicyclohexylphosphino)-2,6-diisopropoxy-1,1′-biphenyl, 2-di-tert-butylphosphino-2′-4′-6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′-6′-dimethoxybiphenyl, 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl, tri-o-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-(di-tert-butylphosphino)-1,1-binaphthyl, tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, and the like.A reagent in which a palladium catalyst and a phosphine ligand form a complex may be used. For example, tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), bis(tri-tert-butylphosphine)palladium(0), chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)(2’-amino-1,1’-biphenyl-2-yl)palladium(II), [(2-dicyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)palladium(II) methanesulfonate, etc. may be mentioned. Examples of the base include sodium tert-butoxide, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, etc. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, alcohol solvents such as methanol, ethanol, propanol, butanol, N,N-dimethylformamide, NMP, or a mixed solvent of these organic solvents and water, etc.

[0230] Synthesis method R1 The production method described herein is for a compound represented by the general formula (I) in which E is -CO- and X is -CHR m -X 1 -X 2 Among them, X 1is suitable for producing an intermediate substituted with a triazolyl group, i.e., the following compound [R1-4].

[0231] [Chemical formula]

[0232] (In the formula, PG 3 represents a protecting group for a carboxylic acid, and examples of the protecting group represented by PG 3 include, for example, alkyl. Each symbol has the same meaning as described above.)

[0233] General formula [R1-3] is obtained by the click reaction of general formula [R1-1] and general formula [R1-2]. The reaction proceeds in a suitable solvent at 0 °C to the reflux temperature of the solvent in the presence of a suitable metal catalyst. Examples of the metal catalyst include Cu, CuSO4, Zn(OAc)2, etc. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 5 minutes to 24 hours. As a reaction accelerator, SODIUM ASCORBATE or the like may be used. As the solvent, water, methanol, ethanol, t-BuOH, dimethyl sulfoxide, or a mixed solvent thereof, etc. are used. General formula [R1-4] is obtained by subjecting general formula [R1-3] to basic conditions or acidic conditions. The reaction proceeds in a suitable solvent usually from room temperature to the reflux temperature of the solvent using a base or an acid. The reaction time and the base and solvent used are the same as in the fourth step of Synthesis Method C.

[0234] Synthesis Method R2 The production method described here is suitable for producing an intermediate in which X among the compounds represented by general formula (I) is substituted with a pyrazolyl group, i.e., the following compound [R-4]. m -X 1 -X 2 Among them, X 1 is substituted with a pyrazolyl group, i.e., the following compound [R-4].

[0235] [Chemical formula]

[0236] (In the formula, each symbol has the same meaning as described above.)

[0237] General formula [R2-3] is obtained by the alkylation reaction of general formula [R2-1] and general formula [R2-2]. The reaction proceeds in a suitable solvent in the presence of a suitable base at 0 °C to the reflux temperature of the solvent. The reaction time and the base, solvent, and reaction accelerator used are the same as in Synthesis Method O. General formula [R2-4] is obtained by subjecting general formula [R2-3] to basic conditions or acidic conditions. The reaction proceeds in a suitable solvent using a base or an acid, usually from room temperature to the reflux temperature of the solvent. The reaction time and the base and solvent used are the same as in the fourth step of Synthesis Method C.

[0238] Synthesis Method R3 The production method described herein is suitable for producing an intermediate in which E is -CO-, X is -CHR m -X 1 -X 2 among the compounds represented by general formula (I), and R m is an optionally substituted alkyl group having 1 to 10 carbon atoms, and X 1 is an intermediate substituted with an oxadiazolyl group, that is, the following compound [R3-6].

[0239]

Chemical formula

[0240] (In the formula, each symbol has the same meaning as described above.)

[0241] General formula [R3-3] can be derived from general formula [R3-1] and general formula [R3-2] according to a known method (for example, WO2016044386). General formula [R3-5] is obtained by the alkylation reaction of general formula [R3-3] and general formula [R3-4]. The reaction proceeds in a suitable solvent in the presence of a suitable base at 0 °C to the reflux temperature of the solvent. The reaction time and the base, solvent, and reaction accelerator used are the same as in Synthesis Method O. General formula [R3-6] is obtained by subjecting general formula [R3-5] to basic conditions or acidic conditions. The reaction proceeds in a suitable solvent using a base or an acid, usually from room temperature to the reflux temperature of the solvent. The reaction time, as well as the base and solvent used, are the same as in the fourth step of Synthesis Method C.

[0242] Synthesis Method R4 The production method described herein is suitable for producing an intermediate in which, among the compounds represented by general formula (I), E is -CO-, X is -CHR m -X 1 -X 2 Among them, R m is an optionally substituted alkyl group having 1 to 10 carbon atoms, X 1 is substituted with an isoxazolyl group, that is, the following compound [R4-4].

[0243]

Chemical formula

[0244] (In the formula, each symbol has the same meaning as described above.)

[0245] General formula [R4-3] is obtained by an alkylation reaction of general formula [R4-1] and general formula [R4-2]. The reaction proceeds in a suitable solvent in the presence of a suitable base at 0 °C to the reflux temperature of the solvent. The reaction time, as well as the base, solvent, and reaction accelerator used, are the same as in Synthesis Method O. General formula [R4-4] is obtained by subjecting general formula [R4-3] to basic conditions or acidic conditions. The reaction proceeds in a suitable solvent using a base or an acid, usually from room temperature to the reflux temperature of the solvent. The reaction time, as well as the base and solvent used, are the same as in the fourth step of Synthesis Method C.

[0246] Synthesis Method S The production method described herein is for a compound represented by general formula (I) in which E is -CO- and X is -CHR m -X 1 -X 2 Among them, X 1 is -NR 1X -, X 2is suitable for producing a compound in which -CO- is further substituted with L-A, that is, the following compound [S-7].

[0247] [Chemical formula]

[0248] (In the formula, each symbol has the same meaning as described above.)

[0249] General formula [S-2] is obtained by deprotection with an acid from general formula [S-1]. The reaction proceeds using an appropriate acid in an appropriate solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 30 minutes to 24 hours. Examples of the acid include hydrochloric acid, trifluoroacetic acid, PTSA, PPTs, etc. Examples of the solvent include 1,4-dioxane, dichloromethane, ethyl acetate, methanol, toluene, etc. General formula [S-4] is obtained by a condensation reaction between general formula [S-2] and general formula [S-3]. The reaction proceeds using a condensing agent in the presence of an appropriate base in an appropriate solvent at 0°C to the reflux temperature of the solvent. The reaction time, as well as the condensing agent, solvent, reaction accelerator, and base used, are the same as in Synthetic Method N. General formula [S-5] is obtained by deprotection with an acid of general formula [S-4]. The reaction proceeds using an appropriate acid in an appropriate solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time, as well as the condensing agent, solvent, reaction accelerator, and base used, are the same as in the first step of Synthetic Method S. General formula [S-7] is obtained by a condensation reaction between general formula [S-5] and general formula [S-6]. The reaction proceeds using a condensing agent in the presence of an appropriate base in an appropriate solvent at 0°C to the reflux temperature of the solvent. The reaction time, as well as the condensing agent, solvent, reaction accelerator, and base used, are the same as in Synthetic Method N.

[0250] Synthetic Method T The production method described here is suitable for producing a compound in which E in the compound represented by general formula (I) is substituted with -CO-, that is, the following compound [T-3].

[0251] [Chemical formula]

[0252] (In the formula, each symbol has the same meaning as described above.)

[0253] General formula [T-3] is obtained by the condensation reaction of general formula [T-1] and general formula [T-2]. The reaction proceeds in a suitable solvent in the presence of a suitable base and using a condensing agent at 0 °C to the reflux temperature of the solvent. The reaction time and the condensing agent, solvent, reaction accelerator, and base used are the same as in synthesis method N.

[0254] Synthesis method U The manufacturing method described here is suitable for manufacturing a compound in which the connecting part with the chemical linker in the compound represented by general formula (I) is -CONR L1 -, that is, the following compound [U-3].

[0255] [Chemical formula]

[0256] (In the formula, each symbol has the same meaning as described above.)

[0257] General formula [U-3] is obtained by the condensation reaction of general formula [U-1] and general formula [U-2]. The reaction proceeds in a suitable solvent in the presence of a suitable base and using a condensing agent at 0 °C to the reflux temperature of the solvent. The reaction time and the condensing agent, solvent, reaction accelerator, and base used are the same as in synthesis method N.

[0258] Synthesis method V The manufacturing method described here is suitable for manufacturing a compound in which the connecting part with the chemical linker in the compound represented by general formula (I) is -O-, that is, the following compound [V-3].

[0259] [Chemical formula]

[0260] (In the formula, each symbol has the same meaning as described above.)

[0261] General formula [V-3] is obtained by the alkylation reaction of general formula [V-1] and general formula [V-2]. The reaction proceeds in a suitable solvent in the presence of a suitable base at 0 °C to the reflux temperature of the solvent. The reaction time and the base, solvent, and reaction accelerator used are the same as in Synthesis Method O.

[0262] Synthesis Method W The production method described here is suitable for producing a compound in which the connecting part with the chemical linker in the compound represented by general formula (I) is -S-, that is, the following compound [W-3].

[0263]

Chemical formula

[0264] (In the formula, each symbol has the same meaning as described above.)

[0265] General formula [W-2] is obtained by the alkylation reaction of general formula [W-1] and general formula [V-2]. The reaction proceeds in a suitable solvent in the presence of a suitable base at 0 °C to the reflux temperature of the solvent. The reaction time and the base, solvent, and reaction accelerator used are the same as in Synthesis Method O.

[0266] Synthesis Method X The production method described here is suitable for producing a compound in which the connecting part with the chemical linker in the compound represented by general formula (I) is -NR L1 - or -NR L1 CO-, that is, the following compound [X-3] or compound [X-4].

[0267]

Chemical formula

[0268] (In the formula, each symbol has the same meaning as described above.)

[0269] General formula [X-3] is obtained by the alkylation reaction of general formula [X-1] and general formula [V-2]. The reaction proceeds in a suitable solvent at 0 °C to the reflux temperature of the solvent in the presence of a suitable base. The reaction time and the base, solvent, and reaction accelerator used are the same as those in Synthesis Method O. General formula [X-4] is obtained by the condensation reaction of general formula [X-1] and general formula [X-2]. The reaction proceeds in a suitable solvent at 0 °C to the reflux temperature of the solvent in the presence of a suitable base using a condensing agent. The reaction time and the condensing agent, solvent, reaction accelerator, and base used are the same as those in Synthesis Method N.

[0270] The starting compounds in the above method can be produced in the same manner as the known methods and / or the methods described in the following examples. In addition, the introduction of a protecting group to a functional group and the removal of a functional group protecting group can be carried out with reference to known methods (such as PROTECTIVE GROUPS in ORGANIC SYNTHESIS (written by Theodora W. Greene, Peter G.M. Wuts), etc.). Further, the compounds of the present invention and intermediate compounds produced by the above method can be structurally converted into another target compound or intermediate by the methods described in the following examples and / or known methods or combinations thereof.

[0271] The compound represented by general formula (I) produced by the above-described method can be purified to any purity by subjecting it to conventional purification means, such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. Further, if necessary, it can be made into a pharmacologically acceptable salt by treating it with an acid or a base, etc. in a suitable solvent (water, alcohol, ether, etc.). Furthermore, the obtained compound of the present invention or its pharmacologically acceptable salt can be made into a hydrate or a solvate by treating it with water, a water-containing solvent, or other solvents.

[0272] The compounds of the present invention or their pharmacologically acceptable salts include racemic compounds, stereoisomers, and mixtures of these compounds, including isotope-labeled and radiolabeled compounds. Such isomers can be isolated by standard separation techniques including fractional crystallization and chiral column chromatography. Also, the compounds of the present invention have asymmetric carbon atoms. Thus, enantiomers or diastereomers are included. A mixture of diastereomers can be separated into their individual diastereomers by methods well known in the prior art based on their physical / chemical differences, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by chiral column chromatography or by reacting the enantiomeric compound with a suitable optically active compound to convert it into a mixture of diastereomers, separating each diastereomer, and then converting the individual diastereomers back to the corresponding enantiomers. The compounds of the present invention may be any of the diastereomers, enantiomers, and mixtures thereof, including any isomers.

[0273] [Use of the Target Proteolytic Inducing Compounds of the Present Invention]

[0274] The compounds of the present invention have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and can be used as a medicament for preventing or treating diseases caused by dysregulation of protein activity in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.).

[0275] Diseases caused by such dysregulation of protein activity include, but are not limited to, for example, asthma, multiple sclerosis, cancer, cilia-related diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive disorders, infertility, Angelman syndrome, Canavan disease, pediatric steatorrhea, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome; Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis; Celluloplasmin deficiency, type II achondrogenesis, achondroplasty, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric ochronosis, alpha1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, enamel hypoplasia, ALA dehydratase deficiency, Anderson Fabry disease, androgen insensitivity, anemia, diffuse body angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple joint laxity (Ehlers-Danlos syndrome #joint laxity type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, type II neurofibromatosis, Becker-Stevenson cutis verticis gyrata syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia bilateral acoustic neuroma (type II neurofibromatosis), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), Birt-Hogg-Dubé syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal muscular atrophy (Kennedy disease), Burger-Grütz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, camptomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat eye syndrome, CAVD (congenital absence of the vas deferens), Kallmann heart face syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia syndrome (achondroplasty), oto-spinal macroepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal osteogenesis imperfecta, Coffin-Lowry syndrome, Cockayne syndrome, familial adenomatous polyposis, congenital erythropoietic porphyria, congenital heart disease,Methemoglobinemia / congenital methemoglobinemia, achondrogenesis, X-linked sideroblastic anemia, connective tissue disease, conotruncal anomaly face syndrome, Cooley anemia (beta-thalassemia), copper storage disease (Wilson disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint anomalies (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cowden syndrome, Kufs disease (myotonic dystrophy), Byler-Stevenson cutis verticis gyrata syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Asherman syndrome, degenerative neuropathy including De Grouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity, diffuse globoid cell sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity, Down syndrome, short stature, erythropoietic protoporphyria, erythrocyte 5-aminolevulinate synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich ataxia, familial episodic polyserositis, late-onset cutaneous porphyria, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic cystic fibrosis, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grönblad-Strandberg syndrome (elastic pseudoxanthoma), Günther disease (congenital erythropoietic porphyria), hemochromatosis, Hallervorden-Spatz syndrome, sickle cell anemia, hemophilia, hepatic erythropoietic porphyria (HEP), von Hippel-Lindau disease, Huntington disease, Hutchinson-Gilford progeria syndrome (progeria), androgen excess, chondrodysplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insl-Astry syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, tabes dorsalis, Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome, lysyl hydroxylase deficiencyMachado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Moebius-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Horan syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Prader-Willi syndrome, hemochromatosis, primary gout (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, progressive chorea, chronic hereditary (Huntington's) (Huntington disease), progressive muscular atrophy, spinal muscular atrophy, propionic academia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), von Recklinghausen disease (type I neurofibromatosis), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, type 3 RFALS, Ricker syndrome, Riley-Day syndrome, Lucy Levy syndrome, severe achondrogenesis with growth retardation and melanosis (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis complex), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Strudwick type SED (spondyloepiphyseal dysplasia, Strudwick type), SEDc (congenital spondyloepiphyseal dysplasia) SEMD, Strudwick type (spondyloepiphyseal dysplasia, Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary neuropathy with a tendency to compressive paralysis), Treacher Collins syndrome, triple X syndrome (trisomy X), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual disorders and blindness (Alström syndrome),Floric disease, Waardenburg syndrome, Micro syndrome (Warburg Sjo Fledelius syndrome), Weissenger-Tubimuller syndrome, Wolf-Hirschhorn syndrome, Wolf periodic disease, Weissenger-Tubimuller syndrome, and xeroderma pigmentosum; Examples include viral infections such as HIV and HCV.

[0276] As used herein, "prevention" includes prevention of the onset of a disease (the entire disease state or one or more disease states) and delay in the onset of the disease. "Preventive effective amount" refers to the dose of compound (I) sufficient to achieve such an objective.

[0277] As used herein, "treatment" includes cure of a disease (the entire disease state or one or more disease states), improvement of the disease, and suppression of the progression of the severity of the disease. "Therapeutic effective amount" refers to the dose of compound (I) sufficient to achieve such an objective.

[0278] In practicing the present invention, the compound of the present invention (compound (I) or a pharmaceutically acceptable salt thereof) can be used in any form, either alone or in the form of a pharmaceutical composition containing the compound of the present invention as an active ingredient together with a pharmaceutically acceptable carrier.

[0279] Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), syrups, solutions, emulsions, suspensions, controlled release preparations (e.g., immediate release preparations, sustained release preparations, sustained release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal adhesive films), injections (e.g., subcutaneous injections, intravenous injections (e.g., bolus), intramuscular injections, intraperitoneal injections), drip infusions, transdermal absorption type preparations, ointments, lotions, patches, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.

[0280] In this specification, as the "pharmaceutically acceptable carrier", various carriers commonly used in the field of pharmaceutical technology can be used.

[0281] Specific examples of the "pharmaceutically acceptable carrier" include, for example, in solid preparations, excipients (such as lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (such as magnesium stearate, talc, colloidal silica, etc.), binders (such as crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose, etc.), and disintegrants (such as starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.), and the like can be used.

[0282] In liquid preparations, solvents (such as water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizers (such as polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (such as surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, glycerol monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, etc.), isotonic agents (such as glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol, etc.), buffers (such as buffer solutions of phosphates, citrates, etc.), and soothing agents (such as benzyl alcohol, etc.), and the like can be used.

[0283] If necessary, formulation additives such as preservatives (e.g., paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, α-tocopherol, etc.), coloring agents, sweeteners, etc. may be further added.

[0284] Although the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., it can be produced by adding the compound of the present invention in a proportion of usually 0.01 to 99% (w / w), preferably 0.1 to 85% (w / w) based on the total amount of the formulation. The pharmaceutical composition can be produced by a method conventional in the field of pharmaceutical technology according to its form. The pharmaceutical composition of the present invention may be formed into a sustained-release preparation containing an active ingredient. (Regarding the administration subject) The compound of the present invention can be expected to have low toxicity and few side effects, and also has excellent properties as a pharmaceutical. Therefore, the compound of the present invention can be safely administered to mammals (especially humans). (Regarding the administration route) In practicing the present invention, the compound of the present invention can be administered orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, ophthalmic, intracerebral, rectal, vaginal, intraperitoneal administration, and administration to the lesion) alone or as a pharmaceutical composition. (Regarding the dosage) The dosage of the compound of the present invention varies depending on the administration subject, administration route, age and symptoms of the administration subject, but is not particularly limited. For example, when administered orally, the dosage is 1 to 100 mg per administration as the compound of the present invention, and when administered parenterally, the dosage is 0.1 to 1000 mg. (Regarding the use as a prodrug) Compound (I) can also be used in the form of its prodrug. The prodrug of Compound (I) refers to a compound that is converted into Compound (I) by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis, etc. to change into Compound (I), or a compound that undergoes hydrolysis, etc. by gastric acid, etc. to change into Compound (I). Examples of the prodrug of Compound (I) include compounds in which the amino group of Compound (I) is acylated, alkylated, or phosphorylated [e.g., compounds in which the amino group of Compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, etc.]; compounds in which the hydroxyl group of Compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of Compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); compounds in which the carboxyl group of Compound (I) is esterified or amidated [e.g., compounds in which the carboxyl group of Compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methyl amidated, etc.]. These compounds can be produced from Compound (I) by methods known per se. Also, the prodrug of Compound (I) may be one that changes into Compound (I) under physiological conditions, as described on pages 163 to 198 of Volume 7, Molecular Design, "Development of Pharmaceuticals" published by Hirokawa Shoten in 1990. (Regarding combination use with other agents) The compounds of the present invention have extremely low toxicity as described above and can be used in combination with other drugs for the prevention or treatment of target diseases, and excellent preventive and / or therapeutic effects can be expected by combination use with other drugs. Further, it can also be expected to reduce the dosage of other drugs by such combination therapy and reduce the side effects they have. Drugs that can be used in combination with such compounds of the present invention (hereinafter abbreviated as combined drugs) can be appropriately selected in view of the type of the patient's disease, the severity of its symptoms, and the like.

[0285] The administration form of the combined drug is not particularly limited, and at the time of administration, the compound of the present invention and the combined drug can be combined. For example, (1) administration of a preparation containing a combination of the compound of the present invention and the combined drug, (2) simultaneous or separate administration of two preparations obtained by separately formulating the compound of the present invention and the combined drug by the same administration route, (3) simultaneous or separate administration of two preparations obtained by separately formulating the compound of the present invention and the combined drug by different administration routes, and the like can be used. A preferable form can be appropriately selected according to the actual situation in the medical field.

[0286] A preparation containing a combination of the above compound of the present invention and the combined drug can be appropriately produced by those skilled in the art according to the pharmaceutical composition containing the compound of the present invention described above.

[0287] The dosage of the combined drug can be appropriately selected based on the dosages used clinically. Further, the mixing ratio of the compound of the present invention and the combined drug can be appropriately selected according to the disease and symptoms of the administration subject, the administration route, the type of the combined drug used, and the like. Usually, it can be appropriately determined according to the actual situation in the medical field based on the general clinical dosage of the combined drug used.

Example

[0288] Hereinafter, the present invention will be described more specifically with reference examples and examples regarding the synthesis of compound (I) and test examples regarding the pharmacological activity of compound (I). However, these are merely examples, and the present invention is not limited thereto.

[0289] In the tables (Table 1) listing the "structural formulas of reference example compounds" and (Table 2) listing the "structural formulas of example compounds" described below, the meanings of the following notations attached to the structural formulas will be explained. The notation "or 1" indicates that the carbon atom to which it is attached has a single configuration, but the absolute configuration has not been confirmed. The notation "wavy line" indicates that in a compound having two or more asymmetric carbon atoms, the stereochemistry of the carbon atom to which it is attached is a mixture of R-form and S-form. The notation "solid line" (attached to an asymmetric carbon atom) indicates a racemic form.

[0290] Here, the representative abbreviations used in the descriptions of the following reference examples and examples will be explained. (Abbreviation Table) BH3·THF: Tetrahydrofuran-borane Boc: t-Butoxycarbonyl Boc2O: Di-tert-butyl dicarbonate Cu: Copper CuSO4: Copper sulfate DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene DCM: Dichloromethane DIBAL-H: Diisobutylaluminum hydride DIPEA: N,N-Diisopropylethylamine DMAP: 4-Dimethylaminopyridine DME: 1,2-Dimethoxyethane DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide DMT-MM: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate Et3N: Triethylamine ESI: Electrospray Ionization g: gram HATU: O-(7-azabenzotriazol-1-yl)-N,N,N’,N’,-tetramethyluronium hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOBt: 1-hydroxybenzotriazole HPLC: High Performance Liquid Chromatography IPE: Diisopropyl Ether M: Molar Concentration MeOH: Methyl Alcohol mmol: Millimole MS: Mass Spectrometry n-: Normal (unbranched) Na2SO4: Sodium Sulfate Anhydrous NaI: Sodium Iodide NBS: N-Bromosuccinimide NCS: N-Chlorosuccinimide NIS: N-Iodosuccinimide NMP: N-Methyl-2-pyrrolidone NMR: Nuclear Magnetic Resonance p-: para Pd(dppf)Cl2·CH2Cl2: [1,1’-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct PdCl2(AmPhos)2: Dichlorobis[di-tert-butyl(4‐dimethylaminophenyl)phosphine]palladium(II) PdCl2(PPh3)2: Dichlorobis(triphenylphosphine)palladium(II) pH: -log[H+] PPTs: Pyridinium p-toluenesulfonate PTSA: p-Toluenesulfonic Acid RuPhos: 2-Dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl SNAr: Aromatic Nucleophilic Substitution Reaction TBAI: Tetrabutylammonium Iodide TBS: tert-Butyldimethylsilyl t-BuOH: tert-Butyl alcohol tert-: tertiary THF: Tetrahydrofuran WSC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) Zn(OAc)2: Zinc acetate

[0291] [Reference Example] Reference Example 1: Synthesis of tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0292] 3,3-Dibromo-1,1,1-trifluoro-propan-2-one (5 g) was dissolved in water (61.8 mL), sodium acetate (4.4 g) was added at room temperature, and the mixture was stirred at 100 °C for 30 minutes. After completion of the reaction, the reaction solution was added to a mixed solution of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-formylpyrrolidine-1-carboxylate (3 g), methanol (152 mL), and 7M ammonia-methanol (26 mL) at 0 °C and stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 85:15) to obtain the title compound (3.4 g) as a colorless powder. MS(ESI) m / z: 436.4 [M+H]+

[0293] Reference Example 2: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[4-(Trimethoxymethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0294] tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[4-(Trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (2.2 g) described in Reference Example 1 was dissolved in methanol (12 mL), 5M sodium methoxide-methanol (3.6 mL) was added, and the mixture was stirred at 100 °C for 10 minutes under microwave irradiation. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.3 g) as a brown powder. MS(ESI) m / z: 470.4 [M-H]-

[0295] Reference Example 3: Synthesis of Methyl 2-[(2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-1-[(2-Methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-yl]-1H-imidazole-5-carboxylate

[0296] To a solution of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (1312 mg) in methanol (6.0 mL) was added 5M sodium methoxide-methanol solution (2100 μL), and the mixture was stirred at 100 °C for 10 minutes under microwave irradiation. After allowing to cool to room temperature, water and saturated brine were added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, it was filtered and concentrated under reduced pressure. To the obtained residue were added DCM (30 mL) and trifluoroacetic acid (7.5 mL), and the mixture was stirred at room temperature for 3 hours. After cooling to -15 °C, 1M aqueous sodium hydroxide solution (88 mL) was added dropwise over 8 minutes. After completion of the dropwise addition, the temperature was raised to room temperature, and sodium hydrogen carbonate (1680 mg) was added to adjust the pH to around 8. Ethyl acetate (30 mL) and Boc2O (1047 mg) were added, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 76:24 to 55:45) to obtain the title compound (1033 mg) as a pale red powder. MS(ESI) m / z: 426.3 [M+H]+

[0297] Reference Example 4: Synthesis of 2-[(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid

[0298] Methyl 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-5-carboxylate (528 mg) described in Reference Example 3 was dissolved in methanol (5 mL), 1 M aqueous sodium hydroxide solution (6.2 mL) was added, and the mixture was stirred at 50 °C for 3 days. After completion of the reaction, 1 M hydrochloric acid (5 mL) was added, and the reaction solution was concentrated under reduced pressure. The reaction solution was adsorbed onto PoraPak Rxn RP 60 cc and washed with water (60 mL). Then, it was eluted with methanol (60 mL), and the eluate was concentrated under reduced pressure. After that, the title compound (299 mg) was obtained as a white powder by azeotroping successively with ethanol and toluene. MS(ESI) m / z: 298.1 [M+H]+

[0299] Reference Example 5: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-[4-[methyl-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0300] 2-[(2S,4R)-4-Hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid (140 mg) described in Reference Example 4 was dissolved in N-methylpyrrolidone (940 μL), HATU (179 mg) was added at room temperature, and the mixture was stirred for 20 minutes. At room temperature, a mixed solution of N-methyl-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine (154 mg), diisopropylamine (240 μL), and N-methylpyrrolidone (470 μL) was added, and the mixture was stirred for about 17 hours. HATU (56 mg) was added at room temperature and stirred for about 3 hours. After completion of the reaction, water and dimethyl sulfoxide were added, and the title compound (133 mg) was obtained as a pale yellow viscous substance by purification by preparative HPLC (10 mM aqueous ammonium carbonate solution - acetonitrile). MS(ESI) m / z: 496.5 [M-H]-

[0301] Reference Example 6: Synthesis of 2-[(2S,4R)-4-Hydroxypyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide Hydrochloride

[0302] tert-Butyl (2S,4R)-4-hydroxy-2-[4-[methyl-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (133 mg) described in Reference Example 5 was dissolved in methanol (1.1 mL), and 4M hydrochloric acid-dioxane (284 μL) was added at room temperature, followed by stirring overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the title compound (122 mg) as a light brown viscous solid. MS(ESI) m / z: 398.2 [M+H]+

[0303] Reference Example 7: Synthesis of Methyl 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylate

[0304] Methyl 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-5-carboxylate (150 mg) described in Reference Example 3 was dissolved in 1,4-dioxane (4 mL), and 4M hydrochloric acid-dioxane (6.2 mL) was added at room temperature, followed by stirring for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Further, it was azeotroped three times with toluene. To the obtained residue, DMF (4 mL), 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (77 mg), diisopropylethylamine (183 μL), and HATU (174 mg) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5). The obtained residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (98 mg) as a pale yellow powder. MS(ESI) m / z: 393.4 [M+H]+

[0305] Reference Example 8: Synthesis of 2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid

[0306] Methyl 2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylate (266 mg) described in Reference Example 7 was dissolved in methanol (6.8 mL), 1M aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred at 60 °C for 19 hours. After completion of the reaction, 1M hydrochloric acid (6 mL) was added, and the reaction solution was concentrated under reduced pressure. The reaction solution was adsorbed onto PoraPak Rxn RP 60 cc and washed with water. Then, it was eluted with methanol, and the eluate was concentrated under reduced pressure to obtain the title compound (253 mg) as a colorless powder. MS(ESI) m / z: 379.4 [M+H]+

[0307] Reference Example 9: Synthesis of 4-(4-methylthiazol-5-yl)benzaldehyde

[0308] 4-Bromobenzaldehyde (10 g), palladium acetate (243 mg), potassium carbonate (10.6 g) were added with dimethylacetamide (180 mL) and 4-methylthiazole (10720 mg), and after nitrogen substitution, the mixture was stirred at 150 °C for 1.5 hours. After completion of the reaction, ethyl acetate was added, filtered through celite, and the filtrate was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 85:15 to 70:30) to obtain the title compound (9.2 g) as a yellow powder. MS(ESI) m / z: 204.0 [M+H]+

[0309] Reference Example 10: Synthesis of N-(cyclobutylmethyl)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine

[0310] 4-(4-Methylthiazol-5-yl)benzaldehyde (100 mg) described in Reference Example 9 was dissolved in dichloromethane (5 mL), cyclobutylmethanamine (63 mg) was added at room temperature, and the mixture was stirred for 30 minutes. Then, sodium triacetoxyborohydride (150 mg) was added, and the mixture was stirred for about one and a half hours. After completion of the reaction, 1M aqueous sodium hydroxide solution and chloroform were added, the organic layer was separated with a Phase-separator (registered trademark), and concentrated under reduced pressure. The obtained residue was purified by NH silica gel chromatography (hexane:ethyl acetate = 95:5 to 70:30) to obtain the title compound (103 mg) as a pale yellow oil. MS (ESI) m / z: 273.1 [M+H]+

[0311] Reference Example 11: Synthesis of 2-Methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]propan-1-amine

[0312] 4-(4-Methylthiazol-5-yl)benzaldehyde (100 mg) described in Reference Example 9 was dissolved in DCM (5 mL), 2-methylpropan-1-amine (74 μL) was added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (150 mg) was added, and the mixture was stirred for 3 hours as it was. After completion of the reaction, chloroform and 1M aqueous sodium hydroxide solution were added to the reaction mixture, the organic layer was separated with a Phase-separator (registered trademark), and concentrated under reduced pressure. Purification by NH silica gel column chromatography (hexane:ethyl acetate = 95:5 to 70:30) gave the title compound (108 mg) as a pale yellow oil. MS (ESI) m / z: 261.1 [M+H]+

[0313] Reference Example 12: Synthesis of Methyl 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylate

[0314] tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[4-(trimethoxymethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (2.3 g) described in Reference Example 2 was dissolved in dichloromethane (12 mL), and TFA (48 mL) was added thereto at 0 °C, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Water, 1 M aqueous sodium hydroxide solution, and a mixed solvent of ethyl acetate and methanol (10% methanol) were added to the obtained residue for extraction. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel chromatography (ethyl acetate:methanol = 95:5 to 50:50). The obtained residue was dissolved in DMF (10 mL), and HATU (1.12 g), (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3,3-dimethyl-butanoic acid (1085 mg), and diisopropylethylamine (1.5 mL) were added thereto at room temperature, followed by stirring for 30 minutes. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate = 95:5 to 50:50) to obtain the title compound (1.5 g) as a pale red viscous substance. MS(ESI) m / z: 661.4 [M+H]+

[0315] Reference Example 13: Synthesis of Methyl 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-[tert-butyl(dimethyl)silyl]oxypyrrolidin-2-yl]-1H-imidazole-4-carboxylate

[0316] Methyl 2-[(2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylate (1.5 g) described in Reference Example 12 was dissolved in methanol (7.6 mL), diethylamine (2.4 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate:methanol = 98:2 to 20:80). The obtained residue was dissolved in dichloromethane (23 mL), triethylamine (1.3 mL) and acetic anhydride (240 μL) were added at 0 °C, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water and chloroform were added for extraction. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5) to obtain the title compound (774 mg) as a pale yellow viscous substance. MS(ESI) m / z: 481.3 [M+H]+

[0317] Reference Example 14: Synthesis of 2-[(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid

[0318] Methyl 2-[(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-[tert-butyl(dimethyl)silyl]oxypyrrolidin-2-yl]-1H-imidazole-4-carboxylate (709 mg) described in Reference Example 13 was dissolved in methanol (10 mL), 1 M aqueous sodium hydroxide solution (5.9 mL) was added under stirring at 0 °C, the temperature was raised to 50 °C, and the mixture was stirred overnight. After completion of the reaction, the reaction mixture was cooled to 0 °C, 1 M hydrochloric acid (5.9 mL) was added, and the mixture was concentrated under reduced pressure. The reaction solution was dissolved in water, PoraPak TMIt was adsorbed onto Rxn RP and washed with water (45 mL). Then it was eluted with MeOH (90 mL) and concentrated under reduced pressure to obtain the title compound (489 mg) as a colorless powder. MS (ESI) m / z: 353.2 [M+H]+

[0319] Reference Example 15: Synthesis of 1-[3-(4-methylthiazol-5-yl)phenyl]ethanone

[0320] Using 1-(3-bromophenyl)ethanone, the same reaction and treatment as in Reference Example 9 were carried out to obtain the title compound. MS (ESI) m / z: 218.1 [M+H]+

[0321] Reference Example 16: Synthesis of 1-O-tert-butyl 2-O-[2-[3-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-oxoethyl] (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate

[0322] 1-[3-(4-Methylthiazol-5-yl)phenyl]ethanone (615 mg) described in Reference Example 15 was dissolved in acetic acid (5.6 mL), trimethylphenylammonium tribromide (1596 mg) was added, and the mixture was heated with stirring at 90 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to 0 °C and added dropwise to saturated aqueous sodium bicarbonate (70 mL). The pH was adjusted to 10, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (785 mg) and Et3N (1.9 mL) were added, and the mixture was stirred at room temperature for 20 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) gave the title compound (489 mg) as an orange viscous substance. MS (ESI) m / z: 447.4 [M+H]+

[0323] Reference Example 17: Synthesis of tert-Butyl (2S,4R)-4-Hydroxy-2-[5-[3-(4-Methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0324] 1-O-tert-Butyl 2-O-[2-[3-(4-Methyl-1,3-thiazol-5-yl)phenyl]-2-oxoethyl] (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (485 mg) described in Reference Example 16 was dissolved in xylene (5.4 mL), ammonium acetate (418 mg) was added, and the mixture was heated with stirring at 140 °C for 1.5 hours. The reaction solution was returned to room temperature, saturated aqueous bilayer solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (chloroform:methanol = 100:0 to 90:10) gave the title compound (384 mg) as a light brown powder. MS(ESI) m / z: 427.4 [M+H]+

[0325] Reference Example 18: Synthesis of (3R,5S)-5-[5-[3-(4-Methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidin-3-ol Hydrochloride

[0326] tert-Butyl (2S,4R)-4-Hydroxy-2-[5-[3-(4-Methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (380 mg) described in Reference Example 17 was dissolved in methanol (4.4 mL), 4M hydrochloric acid-methanol (2.2 mL) was added, and the mixture was heated with stirring at 60 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (415 mg) as a yellow powder. MS(ESI) m / z: 327.3 [M+H]+

[0327] Reference Example 19: Synthesis of Methyl 2-[(2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-1-[(2S)-3,3-Dimethyl-2-[(2-Methylpropan-2-yl)oxycarbonylamino]butanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylate

[0328] tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[4-(Trimethoxymethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (1.2 g) described in Reference Example 2 was dissolved in DCM (25 mL), trifluoroacetic acid (6.3 mL) was added, and the mixture was heated and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was azeotroped with toluene, quenched with saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted 3 times with ethyl acetate / 10% methanol, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in DMF (21 mL), DIPEA (1.4 mL), (2S)-2-(tert-Butoxycarbonylamino)-3,3-dimethyl-butanoic acid (686 mg), and HATU (1209 mg) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, saturated brine was added, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title compound (1058 mg) was obtained as a pale red powder by purification by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 60:40). MS(ESI) m / z: 539.5 [M+H]+

[0329] Reference Example 20: Synthesis of N-Methyl-1-[3-(4-Methylthiazol-5-yl)phenyl]methanamine

[0330] The title compound was obtained by performing the same reaction and treatment as in Example 56 using 1-(3-Bromophenyl)-N-methyl-methanamine, 4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole, and potassium carbonate instead of sodium carbonate. MS(ESI) m / z: 219.2 [M+H]+

[0331] Reference Example 21: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate

[0332] tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-formylpyrrolidine-1-carboxylate (4551 mg) was dissolved in 7M ammonia-methanol (19 mL), 39% aqueous glyoxal solution (6.3 mL) was added, and the mixture was heated with stirring at room temperature for 8 hours. After quenching with saturated brine, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (hexane:ethyl acetate = 50:50) gave the title compound (2.6 g) as a colorless viscous substance. MS(ESI) m / z: 368.3 [M+H]+

[0333] Reference Example 22: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(3-Phenylphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0334] tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (170 mg) described in Reference Example 21 was dissolved in DMF (1 mL), cesium carbonate (450 mg) and 3-phenylbenzyl bromide (174 mg) were added, and the mixture was heated with stirring at 70 °C for 3 hours. Chloroform and water were added to the reaction mixture, the organic layer was separated with a Phase-separator (registered trademark), and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane:ethyl acetate = 90:10~50:50) gave the title compound (191 mg) as a pale yellow oily substance. MS(ESI) m / z: 534.7 [M+H]+

[0335] Reference Example 23: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(3-Chlorophenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0336] tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (307 mg) described in Reference Example 21 was dissolved in DMF (1 mL), cesium carbonate (826 mg) and 3-chlorobenzyl bromide (160 μL) were added, and the mixture was heated with stirring at 70 °C for 3.5 hours. Chloroform and water were added to the reaction mixture, and the organic layer was separated with a Phase-separator (registered trademark) and concentrated under reduced pressure. The title compound (319 mg) was obtained as a pale yellow oil by purification by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50). MS(ESI) m / z: 492.6, 494.6 [M+H]+

[0337] Reference Example 24: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[[3-(4-Methyl-1,3-thiazol-5-yl)phenyl]methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0338] tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[(3-chlorophenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate (104 mg) described in Reference Example 23, 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (72 mg), XPhos Pd G2 (18 mg), XPhos (30 mg), sodium carbonate (90 mg), 1,4-dioxane (1 mL), and water (200 μL) were added, the mixture was purged with nitrogen, and heated with stirring at 100 °C for 3.5 hours. Chloroform and water were added to the reaction mixture, the organic layer was separated using a Phase-separator (registered trademark), and concentrated under reduced pressure. The title compound (38 mg) was obtained as a pale yellow oil by purification by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 20:80). MS(ESI) m / z: 555.4 [M+H]+

[0339] Reference Example 25: Synthesis of tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[2-(3-chlorophenyl)ethyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0340] tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (216 mg) described in Reference Example 21 was dissolved in DMF (1 mL), cesium carbonate (611 mg) and 1-(2-bromoethyl)-3-chlorobenzene (260 μL) were added, and the mixture was heated with stirring at 70 °C overnight. 1-(2-Bromoethyl)-3-chlorobenzene (260 μL) was added and the mixture was further heated with stirring at 70 °C for 6 hours. Chloroform and water were added to the reaction mixture, the organic layer was separated using a Phase-separator (registered trademark), and concentrated under reduced pressure. The title compound (70 mg) was obtained as a pale yellow oil by purification by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50). MS(ESI) m / z: 506.4 / 508.4 [M+H]+

[0341] Reference Example 26: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(Dimethyl)silyl]oxy-2-[1-[2-[3-(4-Methyl-1,3-Thiazol-5-Yl)Phenyl]Ethyl]Imidazol-2-Yl]Pyrrolidine-1-Carboxylate

[0342] tert-Butyl (2S,4R)-4-[tert-Butyl(Dimethyl)silyl]oxy-2-[1-[2-(3-Chlorophenyl)Ethyl]Imidazol-2-Yl]Pyrrolidine-1-Carboxylate (65 mg) described in Reference Example 25, 4-Methyl-5-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)Thiazole (56 mg), XPhos Pd G2 (10 mg), XPhos (18 mg), Sodium Carbonate (56 mg), 1,4-Dioxane (1 mL), and Water (200 μL) were added, purged with nitrogen, and heated with stirring at 100 °C for 1.5 hours. The title compound (74 mg) was obtained as a brown oil by purification by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 20:80, chloroform:methanol = 95:5). MS(ESI) m / z: 569.7 [M+H]+

[0343] Reference Example 27: Synthesis of N-(Cyclopropylmethyl)-4-Phenyl-Butan-1-Amine

[0344] 4-Phenylbutan-1-amine (257 mg) was dissolved in THF (5 mL), and cyclopropanecarboxaldehyde (160 μL), sodium triacetoxyborohydride (1050 mg), and acetic acid (100 μL) were added at 0 °C and stirred at room temperature for 22 hours. After completion of the reaction, chloroform and water were added to the reaction mixture, the organic layer was separated with a Phase-separator (registered trademark), and concentrated under reduced pressure. The title compound (90 mg) was obtained as a colorless oil by purification by preparative HPLC (10 mM aqueous ammonium carbonate-acetonitrile). MS(ESI) m / z: 204.1 [M+H]+

[0345] Synthesis of N-(Cyclopropylmethyl)-4-(4-pyridyl)butan-1-amine

[0346] To 4-(4-pyridyl)butan-1-amine (204 mg) was added THF (5.0 mL), and cyclopropanecarboxaldehyde (120 μL), acetic acid (80 μL), and sodium triacetoxyborohydride (845 mg) were added at 0 °C, followed by stirring at room temperature for 22 hours. After completion of the reaction, chloroform and water were added to the reaction mixture, and the organic layer was separated with a Phase-separator (registered trademark) and concentrated under reduced pressure. The title compound (13 mg) was obtained as a yellow oil by purification with preparative HPLC (10 mM aqueous ammonium carbonate - acetonitrile). MS (ESI) m / z: 205.1 [M+H]+

[0347] Synthesis of N-[[4-(4-Methylthiazol-5-yl)phenyl]methyl]propan-2-amine

[0348] To 4-(4-methylthiazol-5-yl)benzaldehyde (60 mg) described in Reference Example 9 was added DCM (3.0 mL), isopropylamine (38 μL) was added, and the mixture was stirred at room temperature for about 30 minutes. Further, sodium triacetoxyborohydride (90 mg) was added, and the mixture was stirred at room temperature for about 2 hours. After completion of the reaction, chloroform and 1M aqueous sodium hydroxide solution were added to the reaction mixture, and the organic layer was separated with a Phase-separator (registered trademark) and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 95:5 to 70:30) to obtain the title compound (47 mg) as a pale yellow oil. MS (ESI) m / z: 247.1 [M+H]+

[0349] Synthesis of 2,2,2-Trifluoro-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]ethanamine

[0350] Using 4-(4-methylthiazol-5-yl)benzaldehyde and 2,2,2-trifluoroethanamine described in Reference Example 9, the same reactions and treatments as in Reference Example 10 were carried out to obtain the title compound. MS(ESI) m / z: 287.1 [M+H]+

[0351] Reference Example 31: Synthesis of Ethyl 2-(4-bromopyrazol-1-yl)-3-methylbutanoate

[0352] Using 4-bromo-1H-pyrazole, ethyl 2-bromo-3-methyl-butanoate, and DMSO instead of DMF, the same reactions and treatments as in Reference Example 22 were carried out to obtain the title compound. MS(ESI) m / z: 275.1, 277.1 [M+H]+

[0353] Reference Example 32: Synthesis of Ethyl 2-[4-(2-methoxypyridin-4-yl)pyrazol-1-yl]-3-methylbutanoate

[0354] Using ethyl 2-(4-bromopyrazol-1-yl)-3-methylbutanoate described in Reference Example 31 and (2-methoxy-4-pyridyl)boronic acid, the same reactions and treatments as in Example 56 were carried out to obtain the title compound. MS(ESI) m / z: 304.1 [M+H]+

[0355] Reference Example 33: Synthesis of 2-[4-(2-methoxypyridin-4-yl)pyrazol-1-yl]-3-methylbutanoic acid

[0356] Using ethyl 2-[4-(2-methoxypyridin-4-yl)pyrazol-1-yl]-3-methylbutanoate described in Reference Example 32 and ethanol instead of methanol, the same reactions and treatments as in Reference Example 8 were carried out to obtain the title compound. MS(ESI) m / z: 276.2 [M+H]+

[0357] Reference Example 34: Synthesis of 2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide

[0358] 2-[(2S,4R)-4-Hydroxypyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide hydrochloride (40 mg) described in Reference Example 6, 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (25 mg), and WSC·HCl (24 mg) were dissolved in DCM (420 μL), Et3N (35 μL) and HOBt (17 mg) were added, and the mixture was stirred at room temperature for 2.5 hours. After adding MeOH, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution - acetonitrile) to obtain the title compound (19 mg) as a white powder. MS (ESI) m / z: 577.3 [M-H]-

[0359] Reference Example 35: Synthesis of tert-butyl (2S,4R)-2-[4-[cyclopropylmethyl-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate

[0360] To 2-[(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid (20 mg) described in Reference Example 4, NMP (0.35 mL) was added, followed by the addition of HATU (26 mg), and the mixture was stirred at room temperature for 30 minutes. Separately, a solution was prepared by adding NMP (0.35 mL) and DIPEA (0.035 mL) to N-(cyclopropylmethyl)-1-[4-(4-methylthiazol-5-yl)phenyl]methanamine (18 mg) described in Reference Example 106, and the solution was added to the reaction solution and stirred at room temperature for about 1 hour. After completion of the reaction, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine / water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol = 100:0 to 90:10) to obtain the title compound (26 mg) as a colorless oil. MS(ESI) m / z: 538.5 [M+H]+

[0361] Reference Example 36: Synthesis of N-(cyclopropylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide

[0362] tert-Butyl (2S,4R)-2-[4-[cyclopropylmethyl-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate (26 mg) described in Reference Example 35 was dissolved in 1,4-dioxane (0.4 mL), and 4M hydrochloric acid-dioxane (0.4 mL) was added at room temperature, followed by stirring overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Further, it was azeotroped with toluene three times. The obtained residue was dissolved in N,N-dimethylformamide (0.5 mL), 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (13 mg), HATU (22 mg), and diisopropylethylamine (34 μL) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform:methanol = 100:0 to 90:10) to obtain the title compound (19 mg) as a white powder. MS(ESI) m / z: 617.4 [M-H]-

[0363] Reference Example 37: Synthesis of tert-Butyl N-[[4-(4-Methyl-1,3-thiazol-5-yl)phenyl]methyl]-N-[2-(oxan-2-yloxy)ethyl]carbamate

[0364] Sodium hydride (20 mg) was added to DMF (1.6 mL) and tert-butyl N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]carbamate (50 mg), and the mixture was stirred at room temperature for about 20 minutes. 2-(2-Bromoethoxy)tetrahydropyran (18 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. After completion of the reaction, chloroform and saturated ammonium chloride aqueous solution were added to the reaction mixture, the organic layer was separated with Phase-separator (registered trademark), and concentrated under reduced pressure. The title compound (18 mg) was obtained as a colorless oil by purification by preparative HPLC (10 mM ammonium carbonate aqueous solution-acetonitrile). MS(ESI) m / z: 443.4 [M+H]+

[0365] Reference Example 38: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

[0366] To tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2 g) described in Reference Example 21, DCM (20 mL) was added, followed by addition of NBS (2130 mg), and the mixture was stirred at room temperature for about 2 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 60:40) to obtain the title compound (2.4 g) as a colorless powder. MS(ESI) m / z: 524.2 / 526.2 / 528.2 [M+H]+

[0367] Reference Example 39: Synthesis of tert-Butyl (2S,4R)-2-(5-Bromo-1H-imidazol-2-yl)-4-[tert-Butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate

[0368] To tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (791 mg) described in Reference Example 38, ethanol (14 mL) and water (7 mL) were added, followed by addition of sodium sulfite (9488 mg), and the mixture was stirred at 100 °C for about 2 days. After returning to room temperature, saturated brine was added, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 80:20) to obtain the title compound (463 mg) as a white powder. MS(ESI) m / z: 446.1 / 448.1 [M+H]+

[0369] Reference Example 40: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[5-(3-Methoxyphenyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0370] To tert-Butyl (2S,4R)-2-(5-Bromo-1H-imidazol-2-yl)-4-[tert-Butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate (33 mg) described in Reference Example 39 were added DME (1 mL) and water (0.30 mL), followed by addition of potassium carbonate (31 mg), (3-Methoxyphenyl)boronic acid (20 mg), and PdCl2(AmPhos)2 (5 mg), and the mixture was stirred at 115 °C overnight. Further, DME (1 mL) and water (0.30 mL) were added, PdCl2(AmPhos)2 (5 mg) and (3-Methoxyphenyl)boronic acid (17 mg) were added, and the mixture was stirred at 115 °C for 3 hours. After returning to room temperature, filtration through Celite was performed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 67:33) to obtain the title compound (30 mg) as a colorless oil. MS(ESI) m / z: 474.2 [M+H]+

[0371] Reference Example 41: Synthesis of tert-Butyl (2S,4R)-4-Hydroxy-2-[5-[(4-Methoxyphenyl)methyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0372] (2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (200 mg) was dissolved in DMF (8.6 mL), and 1-amino-3-(4-methoxyphenyl)propan-2-one hydrochloride (205 mg), DIPEA (0.45 mL), and HATU (395 mg) were added at room temperature, followed by stirring for about 9 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (ethyl acetate:methanol = 100:0 to 95:5). The obtained residue was dissolved in xylene (2.9 mL), ammonium acetate (113 mg) was added, and the mixture was stirred at 150 °C for about 4 hours. After completion of the reaction, an aqueous sodium hydroxide solution and ethyl acetate were added for extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated. The title compound (8.2 mg) was obtained as a yellow powder by purification by preparative HPLC (10 mM aqueous ammonium carbonate - acetonitrile). MS (ESI) m / z: 374.4 [M + H]+

[0373] Reference Example 42: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-[(3-methoxyphenyl)methyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0374] Using tert-butyl (2S,4R)-2-(5-bromo-1H-imidazol-2-yl)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate described in Reference Example 39 and 2-[(3-methoxyphenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, the same reaction and treatment as in Reference Example 40 were carried out to obtain the title compound. MS (ESI) m / z: 488.3 [M + H]+

[0375] Reference Example 43: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-[2-(methylcarbamoyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0376] Using tert-butyl (2S,4R)-2-(5-bromo-1H-imidazol-2-yl)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate described in Reference Example 39 and [2-(methylcarbamoyl)phenyl]boronic acid, the same reaction and treatment as in Reference Example 40 were carried out to obtain the title compound. MS(ESI) m / z: 501.4 [M+H]+

[0377] Reference Example 44: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[(3-phenoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0378] Using tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate described in Reference Example 21 and 1-(chloromethyl)-3-phenoxy-benzene, the same reaction and treatment as in Reference Example 23 were carried out to obtain the title compound. MS(ESI) m / z: 550.6 [M+H]+

[0379] Reference Example 45: Synthesis of (3R,5S)-5-[1-[(3-phenoxyphenyl)methyl]imidazol-2-yl]pyrrolidin-3-ol hydrochloride

[0380] Using tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[(3-phenoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate described in Reference Example 44, the same reaction and treatment as in Reference Example 6 were carried out to obtain the title compound. MS(ESI) m / z: 336.3 [M+H]+

[0381] Reference Example 46: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(2-Phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0382] Using 1-(Bromomethyl)-2-phenylmethoxybenzene and tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate described in Reference Example 21, the same reaction and treatment as in Reference Example 23 were carried out to obtain the title compound. MS(ESI) m / z: 562.4 [M-H]-

[0383] Reference Example 47: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(3-Phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0384] Using tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate described in Reference Example 21 and 1-Benzyloxy-3-(bromomethyl)benzene, the same reaction and treatment as in Reference Example 23 were carried out to obtain the title compound. MS(ESI) m / z: 564.4 [M+H]+

[0385] Reference Example 48: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(2-Phenoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0386] Using tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate and 1-(bromomethyl)-2-phenoxy-benzene, the same reactions and treatments as in Reference Example 23 were carried out to obtain the title compound. MS(ESI) m / z: 550.4 [M+H]+

[0387] Reference Example 49: Synthesis of tert-butyl (2S,4R)-2-[4-[ethyl-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate

[0388] Using 2-[(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid and N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]ethanamine described in Reference Example 4, the same reactions and treatments as in Reference Example 35 were carried out to obtain the title compound. MS(ESI) m / z: 512.3 [M+H]+

[0389] Reference Example 50: Synthesis of tert-butyl N-methyl-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate

[0390] Using potassium acetate instead of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]-N-methylcarbamate, 4-methylthiazole, and potassium carbonate, the same reactions and treatments as in Reference Example 9 were carried out to obtain the title compound. MS(ESI) m / z: 333.2 [M+H]+

[0391] Reference Example 51: Synthesis of (1S)-N-methyl-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine hydrochloride

[0392] Using tert-butyl N-methyl-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate described in Reference Example 50 and performing the same reactions and treatments as in Reference Example 6 using 1,4-dioxane instead of methanol, the title compound was obtained. MS(ESI) m / z: 233.2 [M+H]+

[0393] Reference Example 52: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-[4-[methyl-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0394] Using 2-[(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxylic acid described in Reference Example 4 and (1S)-N-methyl-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine hydrochloride described in Reference Example 51 and performing the same reactions and treatments as in Reference Example 35, the title compound was obtained. MS(ESI) m / z: 512.5 [M+H]+

[0395] Reference Example 53: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[(2-hydroxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0396] To a solution of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[(2-phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate (20 mg) in ethyl acetate (0.33 mL) was added 10% Pd / C (4 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, the atmosphere was replaced with nitrogen, the insoluble matter was filtered off through Celite and washed with chloroform, and then the filtrate was concentrated under reduced pressure to obtain the title compound (15 mg) as a yellow oil. MS(ESI) m / z: 474.4 [M+H]+

[0397] Reference Example 54: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[[2-[(4-Methyl-1,3-thiazol-5-yl)methoxy]phenyl]methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0398] To a solution of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(2-Hydroxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate (15 mg) described in Reference Example 53 in DMF (0.32 mL) were added cesium carbonate (32 mg) and 5-(Bromomethyl)-4-methyl-thiazole hydrobromide (13 mg), and the mixture was stirred at 60 °C overnight. After cooling to room temperature, chloroform and water were added to the reaction mixture, and the organic layer was separated with Phase-separator (registered trademark) and concentrated under reduced pressure. The residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution - acetonitrile) to obtain the title compound (6.4 mg) as a brown oil. MS(ESI) m / z: 585.5 [M+H]+

[0399] Reference Example 55: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(3-Hydroxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0400] Using tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[1-[(3-Phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate described in Reference Example 47, the same reaction and treatment as in Reference Example 53 were carried out to obtain the title compound. MS(ESI) m / z: 474.3 [M+H]+

[0401] Reference Example 56: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[[3-[(4-methyl-1,3-thiazol-5-yl)methoxy]phenyl]methyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0402] Using tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[(3-hydroxyphenyl)methyl]imidazol-2-yl]pyrrolidine-1-carboxylate described in Reference Example 55 and 5-(bromomethyl)-4-methyl-thiazole hydrobromide, the same reaction and treatment as in Reference Example 54 were carried out to obtain the title compound. MS(ESI) m / z: 585.5 [M+H]+

[0403] Reference Example 57: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-iodo-4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0404] tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (241 mg) described in Reference Example 1 was dissolved in DCM (5.5 mL), then NIS (250 mg) was added, and the mixture was stirred overnight at room temperature under light shielding. Subsequently, pyridinium p-toluenesulfonate (140 mg) was added, and the mixture was stirred for 6 hours at room temperature under light shielding. After adding a saturated aqueous solution of sodium sulfite, the aqueous layer was extracted with dichloromethane, the organic layer was separated with a Phase-separator (registered trademark), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate = 98:2 to 96:4) to obtain the title compound (201 mg) as a white powder. MS(ESI) m / z: 560.1 [M-H]-

[0405] Reference Example 58: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(Dimethyl)silyl]oxy-2-[5-(4-Methoxyphenyl)-4-(Trifluoromethyl)-1H-Imidazol-2-Yl]Pyrrolidine-1-Carboxylate

[0406] Using tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-iodo-4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate described in Reference Example 57 and (4-methoxyphenyl)boronic acid, the same reaction and treatment as in Example 56 were carried out to obtain the title compound. MS(ESI) m / z: 542.3 [M+H]+

[0407] Reference Example 59: Synthesis of 2-[(2S,4R)-4-Hydroxy-1-[(2-Methylpropan-2-Yl)Oxycarbonyl]Pyrrolidine-2-Yl]-5-(4-Methoxyphenyl)-1H-Imidazole-4-Carboxylic Acid

[0408] tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (52 mg) described in Reference Example 58 was dissolved in 1,4-dioxane (1.3 mL), 1M aqueous sodium hydroxide solution (0.67 mL) was added, and the mixture was stirred at room temperature for 7 hours. Then, it was stirred at 40 °C overnight and further stirred at 50 °C for 5 hours. 1M aqueous sodium hydroxide solution (0.10 mL) was added, and the mixture was further stirred at 50 °C for 2 hours. After adding 1M hydrochloric acid (770 μL), the reaction solution was concentrated under reduced pressure. After azeotroping with toluene, the residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution - acetonitrile) to obtain the title compound (6.5 mg) as a colorless oil. MS(ESI) m / z: 404.1 [M+H]+

[0409] Reference Example 60: Synthesis of tert-Butyl (2S,4R)-4-Hydroxy-2-[5-(4-Methoxyphenyl)-4-(Methylcarbamoyl)-1H-Imidazol-2-Yl]Pyrrolidine-1-Carboxylate

[0410] The title compound was obtained by performing the same reaction and treatment as in Example 54 using 2-[(2S,4R)-4-Hydroxy-1-[(2-Methylpropan-2-Yl)Oxycarbonyl]Pyrrolidin-2-Yl]-5-(4-Methoxyphenyl)-1H-Imidazole-4-Carboxylic Acid, Methylamine Hydrochloride, and DMF instead of DCM as described in Reference Example 59. MS(ESI) m / z: 417.1 [M+H]+

[0411] Reference Example 61: Synthesis of tert-Butyl (2S,4R)-2-[4,5-Bis(3-Methoxyphenyl)-1H-Imidazol-2-Yl]-4-[tert-Butyl(Dimethyl)Silyl]Oxy-Pyrrolidine-1-Carboxylate

[0412] The title compound was obtained by performing the same reaction and treatment as in Reference Example 40 using tert-Butyl (2S,4R)-4-[tert-Butyl(Dimethyl)Silyl]Oxy-2-(4,5-Dibromo-1H-Imidazol-2-Yl)Pyrrolidine-1-Carboxylate and (3-Methoxyphenyl)Boronic Acid as described in Reference Example 38. MS(ESI) m / z: 580.3 [M+H]+

[0413] Reference Example 62: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(Dimethyl)Silyl]Oxy-2-[1-(Naphthalen-1-Ylmethyl)Imidazol-2-Yl]Pyrrolidine-1-Carboxylate

[0414] To a solution of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-formylpyrrolidine-1-carboxylate (150 mg) in DCM (1518 μL) were added 1-naphthylmethanamine (100 μL) and magnesium sulfate (83 mg), and the mixture was stirred at room temperature overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the concentrated residue were added a solution of ammonium acetate (47 mg) in methanol (1517 μL) and 39% aqueous glyoxal solution (78 μL), and the mixture was stirred at room temperature for 7 hours. A solution of ammonium acetate (29 mg) in methanol (758 μL) and 39% aqueous glyoxal solution (39 μL) were added, and the mixture was subsequently stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 67:33 to 47:53 to 0:100) to obtain the title compound (77 mg) as a pale yellow oil. MS(ESI) m / z: 508.4 [M+H]+

[0415] Reference Example 63: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0416] Using tert-butyl (2S,4R)-2-(5-bromo-1H-imidazol-2-yl)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate and (4-methoxyphenyl)boronic acid described in Reference Example 39, the same reaction and treatment as in Reference Example 40 were carried out to obtain the title compound. MS(ESI) m / z: 474.2 [M+H]+

[0417] Reference Example 64: Synthesis of tert-butyl-[(3R,5S)-5-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyrrolidin-3-yl]oxy-dimethylsilane

[0418] tert-Butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (27 mg) described in Reference Example 63 was dissolved in DCM (1.5 mL), trifluoroacetic acid (0.50 mL) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and then azeotroped with toluene to obtain the title compound (34 mg) as a yellow powder. MS(ESI) m / z: 374.1 [M+H]+

[0419] Reference Example 65: Synthesis of 1-Amino-3-[4-(trifluoromethyl)phenyl]propan-2-one Hydrochloride

[0420] To a solution of 1-bromo-3-[4-(trifluoromethyl)phenyl]propan-2-one (3765 mg) in DMF (13 mL), sodium diformylamide (1337 mg) was added under ice-cooling, and the mixture was stirred for 1 hour and then stirred at room temperature overnight. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Isopropanol (26 mL) and concentrated hydrochloric acid (26 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was washed by suspension with IPE, collected by filtration, and dried under reduced pressure to obtain the title compound (3.0 g) as a white powder. MS(ESI) m / z: 218.2 [M+H]+

[0421] Reference Example 66: Synthesis of tert-Butyl (2S,4R)-4-Hydroxy-2-[[2-Oxo-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl]pyrrolidine-1-carboxylate

[0422] (2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid, 1-amino-3-[4-(trifluoromethyl)phenyl]propan-2-one hydrochloride described in Reference Example 65, and the same reaction and treatment as in Example 54 were carried out using DMF instead of DCM to obtain the title compound. MS(ESI) m / z: 429.3 [M-H]-

[0423] Reference Example 67: Synthesis of tert-Butyl (2S,4R)-4-Hydroxy-2-[5-[[4-(Trifluoromethyl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0424] Using tert-Butyl (2S,4R)-4-Hydroxy-2-[[2-Oxo-3-[4-(Trifluoromethyl)phenyl]propyl]carbamoyl]pyrrolidine-1-carboxylate described in Reference Example 66, the same reaction and treatment as in Reference Example 82 were carried out to obtain the title compound. MS(ESI) m / z: 412.2 [M+H]+

[0425] Reference Example 68: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[5-[3-(Methylcarbamoyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0426] Using tert-Butyl (2S,4R)-2-(5-Bromo-1H-imidazol-2-yl)-4-[tert-Butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate described in Reference Example 39 and 3-(Methylaminocarbonyl)phenylboronic acid instead of (3-Methoxyphenyl)boronic acid, the same reaction and treatment as in Reference Example 40 were carried out to obtain the title compound. MS(ESI) m / z: 501.3 [M+H]+

[0427] Reference Example 69: Synthesis of tert-Butyl (2S,4R)-2-[5-[(4-Bromophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate

[0428] (2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (200 mg) was dissolved in DMF (5 mL), and 1-amino-3-(4-bromophenyl)propan-2-one hydrochloride (252 mg), DIPEA (0.45 mL), and HATU (395 mg) were added, followed by stirring at room temperature for about 1 hour. After completion of the reaction, water was added to the reaction solution, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol = 100:0 to 95:5). To the obtained crude purified product, xylene (10 mL) and ammonium acetate (338 mg) were added, and the mixture was stirred at 150 °C for about 3 hours. After completion of the reaction, the mixture was returned to room temperature, 1M aqueous sodium hydroxide solution was added, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 to 90:10) to obtain the title compound (66 mg) as a yellow oil. MS(ESI) m / z: 422.3 / 424.3 [M+H]+

[0429] Reference Example 70: Synthesis of tert-Butyl N-[(2S)-1-[(2S,4R)-2-[5-[(4-Bromophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[0430] tert-Butyl (2S,4R)-2-[5-[(4-bromophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate (66 mg) described in Reference Example 69 was dissolved in 1,4-dioxane (3 mL), 4M hydrochloric acid-dioxane (1.2 mL) was added, and the mixture was stirred at room temperature for about 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and further azeotroped with toluene. To the residue were added DMF (5.0 mL), N-Boc-L-tert-leucine (47 mg), DIPEA (0.081 mL), and HATU (83 mg), and the mixture was stirred at room temperature for about 1 hour. After completion of the reaction, 1M aqueous sodium hydroxide solution was added, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 to 90:10) to obtain the title compound (34 mg) as a pale yellow oil. MS(ESI) m / z: 535.4 / 537.5 [M+H]+

[0431] Reference Example 71: Synthesis of tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-carbamothioylpyrrolidine-1-carboxylate

[0432] tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-carbamoylpyrrolidine-1-carboxylate (976 mg) was dissolved in THF (10 mL), Lawesson's reagent (916 mg) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, it was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 80:20 to 0:100) to obtain the title compound (978 mg) as a colorless powder. MS(ESI) m / z: 359.5 [M-H]-

[0433] Reference Example 72: Synthesis of Benzyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate

[0434] Using benzyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-formylpyrrolidine-1-carboxylate, the same reactions and treatments as in Reference Example 21 were carried out to obtain the title compound. MS(ESI) m / z: 402.4 [M+H]+

[0435] Reference Example 73: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[1-[2-(4-chlorophenyl)ethyl]imidazol-2-yl]pyrrolidine-1-carboxylate

[0436] Using tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate described in Reference Example 21 and 1-(2-bromoethyl)-4-chloro-benzene, the same reactions and treatments as in Reference Example 22 were carried out to obtain the title compound. MS(ESI) m / z: 506.2 / 508.2 [M+H]+

[0437] Reference Example 74: Synthesis of tert-butyl (2S,4R)-2-[[3-(2-chlorophenyl)-2-oxopropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate

[0438] (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid and 1-amino-3-(2-chlorophenyl)propan-2-one hydrochloride were used to carry out the same reactions and treatments as in Example 44 to obtain the title compound. MS(ESI) m / z: 395.2 / 397.0 [M-H]-

[0439] Reference Example 75: Synthesis of tert-butyl (2S,4R)-2-[5-[(2-chlorophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate

[0440] Using tert-butyl (2S,4R)-2-[[3-(2-chlorophenyl)-2-oxopropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate described in Reference Example 74, the same reactions and treatments as in Reference Example 91 were carried out to obtain the title compound. MS(ESI) m / z: 378.1 / 380.1 [M+H]+

[0441] Reference Example 76: Synthesis of tert-butyl N-[(2S)-1-[(2S,4R)-2-[5-[(2-chlorophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[0442] Using tert-butyl (2S,4R)-2-[5-[(2-chlorophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidine-1-carboxylate described in Reference Example 75 and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid, the same reactions and treatments as in Example 59 were carried out to obtain the title compound. MS(ESI) m / z: 491.2 / 493.2 [M+H]+

[0443] Reference Example 77: Synthesis of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[5-[2-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

[0444] Using tert-butyl (2S,4R)-2-(5-bromo-1H-imidazol-2-yl)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate described in Reference Example 39 and [2-(trifluoromethyl)phenyl]boronic acid, the same reactions and treatments as in Reference Example 40 were carried out to obtain the title compound. MS(ESI) m / z: 512.5 [M+H]+

[0445] Reference Example 78: Synthesis of tert-Butyl N-[(2S)-1-[(2S,4R)-4-Hydroxy-2-[5-[2-(Trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl] Carbamate

[0446] Using tert-Butyl (2S,4R)-4-[tert-Butyl(dimethyl)silyl]oxy-2-[5-[2-(Trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate and (2S)-2-(tert-Butoxycarbonylamino)-3,3-dimethyl-butanoic acid described in Reference Example 77, the same reaction and treatment as in Example 59 were carried out to obtain the title compound. MS(ESI) m / z: 511.4 [M+H]+

[0447] Reference Example 79: Synthesis of N-Formyl-N-[2-Oxo-3-[2-(Trifluoromethyl)phenyl]propyl] Formamide

[0448] Under a nitrogen atmosphere, 1-Bromo-3-[2-(Trifluoromethyl)phenyl]propan-2-one (1.0 g) was dissolved in DMF (4 mL), and sodium diformylamide (379 mg) was gradually added under ice-cooling and stirred for 1 hour. The temperature was raised to room temperature and stirred overnight. After completion of the reaction, water was added for quenching, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane:ethyl acetate = 90:10~67:33) gave the title compound (664 mg) as a gray powder. MS(ESI) m / z: 272.0 [M-H]-

[0449] Reference Example 80: Synthesis of 1-Amino-3-[2-(Trifluoromethyl)phenyl]propan-2-one Hydrochloride

[0450] N-Formyl-N-[2-oxo-3-[2-(trifluoromethyl)phenyl]propyl]formamide (663 mg) described in Reference Example 79 was dissolved in a mixed solution of concentrated hydrochloric acid (3.7 mL) / isopropanol (3.7 mL) and stirred at room temperature for 2 days. After completion of the reaction, the mixture was concentrated under reduced pressure, azeotroped with toluene, the obtained residue was washed by suspension with IPE, filtered, and dried under reduced pressure to obtain the title compound (510 mg) as a gray powder. MS(ESI) m / z: 218.2 [M+H]+

[0451] Reference Example 81: Synthesis ...

Claims

1. 1-[(2S,4R)-4-Hydroxy-2-[4-(4-phenoxypiperidine-1-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[4-(4-phenylpiperidine-1-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, N-(Cyclobutylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-(2-methylpropyl)-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[(4-phenylphenyl)methyl]-1H-imidazole-4-carboxamide, N-[(2S)-1-[(2S,4R)-4-Hydroxy-2-[5-[3-(4-methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, 2-[(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-(2-pyridin-2-ylethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(4-phenylbutyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-(2-phenylethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[2-(2-methoxyphenyl)ethyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[2-(3-methoxyphenyl)ethyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[2-(4-methoxyphenyl)ethyl]-1H-imidazole-4-carboxamide, N-[(2S)-1-[(2S,4R)-2-[4-(3,4-Dihydro-1H-2,7-naphthyridine-2-carbonyl)-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(2-chlorophenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(3-chlorophenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(4-chlorophenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(2-fluorophenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(3-fluorophenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(4-fluorophenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[[2-(trifluoromethyl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[[3-(trifluoromethyl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[[4-(trifluoromethyl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(2-methoxyphenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(3-methoxyphenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[(1-methylpyrazol-3-yl)methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(3-phenylpropyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[[3-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(naphthalen-2-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(naphthalen-1-ylmethyl)-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-[1-[(3-phenylphenyl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[[3-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[2-[3-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-(Cyclopropylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-(4-phenylbutyl)-1H-imidazole-4-carboxamide, N-(Cyclopropylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-(4-pyridin-4-ylbutyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-N-propan-2-yl-1H-imidazole-4-carboxamide, N-[(2S)-1-[(2S,4R)-2-[4-(6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carbonyl)-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, 2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-N-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-(1-pyridin-4-ylpiperidin-4-yl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[(4-phenyl-1,3-thiazol-2-yl)methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[(1-pyridin-4-ylpiperidin-4-yl)methyl]-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-[5-[3-(4-methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[5-[3-(4-methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-[4-(2-methoxypyridin-4-yl)pyrazol-1-yl]-3-methylbutan-1-one, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-(pyridin-2-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-(pyridin-3-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(pyridin-2-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(pyridin-4-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-benzyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-benzyl-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(2-phenylethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]-N-methyl-N-(pyridin-3-ylmethyl)-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-(Cyclopropylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-(Cyclopropylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-(Cyclopropylmethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-(2-Hydroxyethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-hydroxy-2-[5-(3-methoxyphenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-hydroxy-2-[5-[(4-methoxyphenyl)methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-hydroxy-2-[5-[(3-methoxyphenyl)methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 2-[2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]-N-methylbenzamide, 1-[(2S,4R)-4-hydroxy-2-[1-[(3-phenoxyphenyl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[(2-phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[(3-phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[(3-phenylmethoxyphenyl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[(2-phenoxyphenyl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, N-Ethyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-[1-[[2-[(4-methyl-1,3-thiazol-5-yl)methoxy]phenyl]methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[[3-[(4-methyl-1,3-thiazol-5-yl)methoxy]phenyl]methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[5-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-5-(4-methoxyphenyl)-N-methyl-1H-imidazole-4-carboxamide, 1-[(2S,4R)-2-[4,5-Bis(3-methoxyphenyl)-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-(naphthalen-1-ylmethyl)imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[5-[[4-(trifluoromethyl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutan-1-one, 3-[2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]-N-methylbenzamide, N-[(2S)-1-[(2S,4R)-2-[5-[(4-bromophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-2-[1-[2-(4-chlorophenyl)ethyl]imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-2-[5-[(2-chlorophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-hydroxy-2-[5-[2-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-hydroxy-2-[5-[[2-(trifluoromethyl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-hydroxy-2-[5-[[3-(trifluoromethyl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-hydroxy-2-[1-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-2-[5-(4-bromophenyl)-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-hydroxy-2-[5-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-2-[5-[(3-bromophenyl)methyl]-1H-imidazol-2-yl]-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-Hydroxy-2-[5-[[3-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-Hydroxy-2-[5-[[4-(trifluoromethyl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(1S)-1-[(2S,4R)-4-Hydroxy-2-[5-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, N-[(2S)-1-[(2S,4R)-4-Hydroxy-2-[1-[2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-N-methyl-1-[[3-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-N-(pyridin-4-ylmethyl)imidazole-4-carboxamide, 2-[2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]imidazol-1-yl]-N-phenylacetamide, 4-[2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]-N-methylbenzamide, N-[(2S)-1-[(2S,4R)-4-Hydroxy-2-[4-(phenylmethoxymethyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]acetamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-isopropyl-N-(3-phenoxypropyl)-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-[1-[(1R)-1-(1-naphthyl)ethyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N,5-dimethyl-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-[1-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, N-Cyclopropyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-N-tetrahydrofuran-3-yl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-N-tetrahydropyran-4-yl-1H-imidazole-4-carboxamide, N-Cyclobutyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-hydroxy-2-[4-(3-phenoxypyrrolidine-1-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-hydroxy-2-[4-(3-phenylazetidine-1-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, N-Cyclohexyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-Cyclopentyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-hydroxy-2-[4-(3-phenylpyrrolidine-1-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-hydroxy-2-(1H-imidazol-2-yl)pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-[1-[[5-(4-fluorophenyl)-3-pyridyl]methyl]imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 2-[(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidin-2-yl]-N-(cyclopropylmethyl)-N-(4-phenylbutyl)-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-[1-[2-[4-(4-Methylthiazol-5-yl)phenyl]ethyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-(1H-Benzimidazol-2-yl)-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[1-[(3-Phenyl-1,2,4-oxadiazol-5-yl)methyl]imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-[1-[(3,5-Dimethyl-1-phenyl-pyrazol-4-yl)methyl]imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N,N-dimethyl-1H-imidazole-4-carboxamide, N-[(1S)-1-[(2S,4R)-4-Hydroxy-2-[1-[[3-(4-Methylthiazol-5-yl)phenyl]methyl]imidazol-2-yl]pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]acetamide, N-[(1S)-1-[(2S,4R)-4-Hydroxy-2-[1-[2-[3-(4-Methylthiazol-5-yl)phenyl]ethyl]imidazol-2-yl]pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]acetamide, N-(2-Acetamidoethyl)-2-[(2S,4R)-1-[(2S)-2-[(1-Fluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidin-2-yl]-N-(4-phenylbutyl)-1H-imidazole-4-carboxamide, N-[(1S)-1-[(2S,4R)-2-[4-[[Cyclopropylmethyl(4-phenylbutyl)amino]methyl]-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide, N-[2-[Acetyl(methyl)amino]ethyl]-2-[(2S,4R)-1-[(2S)-2-[(1-Fluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidin-2-yl]-N-(4-phenylbutyl)-1H-imidazole-4-carboxamide, N-[(1S)-1-[(2S,4R)-2-[5-[2-(3-Chlorophenyl)ethyl]-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]acetamide, N-[(1S)-1-[(2S,4R)-2-[5-[2-(4-Chlorophenyl)ethyl]-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]acetamide, 1-[(2S,4R)-4-Hydroxy-2-[1-(2-Naphthylmethyl)imidazol-2-yl]pyrrolidin-1-yl]-2-(3-Methoxyisoxazol-5-yl)-3-methyl-butan-1-one, (2S)-1-[(2S,4R)-4-Hydroxy-2-(1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-2-[4-(3-Methylisoxazol-5-yl)-1H-1,2,3-triazol-1-yl]butan-1-one, N-[(1S)-1-[(2S,4R)-2-[4-[[Cyclopropanecarbonyl(4-phenylbutyl)amino]methyl]-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide, N-[(1S)-1-[(2S,4R)-2-[4-[[Cyclopropylmethyl(4-phenylbutanoyl)amino]methyl]-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide, N-Cyclopropyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-(5-phenylpentyl)-1H-imidazole-4-carboxamide, N-(2-Benzyloxyethyl)-N-cyclopropyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxamide, N-Cyclopropyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-(4-phenylbutyl)-1H-imidazole-4-carboxamide, 1-Fluoro-N-[(1S)-1-[(2S,4R)-4-hydroxy-2-[1-methyl-4-(4-phenylpiperidine-1-carbonyl)imidazol-2-yl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide, (2S,3S)-2-(4-Ethoxytriazol-1-yl)-1-[(2S,4R)-4-hydroxy-2-(1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-pentan-1-one, N-[(1S,2S)-1-[(2S,4R)-4-hydroxy-2-(1H-imidazol-2-yl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-(3-methylisoxazol-5-yl)acetamide, 1-[(2S,4R)-2-[4-(7-Bromo-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-[4-(6-bromo-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-hydroxy-2-[4-[4-(4-pyridyl)piperidine-1-carbonyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-hydroxy-2-[4-(4-phenylpiperazine-1-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-[4-(4-benzyloxypiperidine-1-carbonyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-[4-(3-benzyloxypiperidine-1-carbonyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-hydroxy-2-[4-[4-(6-methyl-3-pyridyl)piperidine-1-carbonyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-hydroxy-2-[4-[4-(5-methyl-2-pyridyl)piperidine-1-carbonyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-2-[4-[4-[(2-fluorophenyl)methyl]piperazine-1-carbonyl]-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-Hydroxy-2-[4-(2-phenylmorpholine-4-carbonyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[(2S,4R)-4-Hydroxy-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, 1-[2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carbonyl]-N-phenyl-piperidine-3-carboxamide, N-[1-[2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carbonyl]pyrrolidin-3-yl]-N-methyl-benzamide, 1-[(2S,4R)-2-[4-(4-anilinopiperidine-1-carbonyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidin-1-yl]-2-(3-methoxyisoxazol-5-yl)-3-methyl-butan-1-one, N-Ethyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-[[4-(methylcarbamoyl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-[[4-(Dimethylcarbamoyl)phenyl]methyl]-N-ethyl-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-methyl-N-[[4-(2-methyl-4-pyridyl)phenyl]methyl]-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-methyl-N-[[4-(6-methyl-3-pyridyl)phenyl]methyl]-1H-imidazole-4-carboxamide, N-[[1-[(2-fluorophenyl)methyl]-4-piperidyl]methyl]-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-methyl-1H-imidazole-4-carboxamide, 2-[(2S,4R)-4-Hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-methyl-N-[(1-phenyl-4-piperidyl)methyl]-1H-imidazole-4-carboxamide, 1-benzyl-4-[2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-imidazole-4-carbonyl]piperazin-2-one, N-(2-anilinoethyl)-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-methyl-1H-imidazole-4-carboxamide, N-[(1R)-2-(benzylamino)-1-methyl-2-oxo-ethyl]-2-[(2S,4R)-4-hydroxy-1-[2-(3-methoxyisoxazol-5-yl)-3-methyl-butanoyl]pyrrolidin-2-yl]-N-methyl-1H-imidazole-4-carboxamide, 1-[(2S,4R)-4-Hydroxy-2-(1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-2-[4-(3-methylisoxazol-5-yl)pyrazol-1-yl]butan-1-one, 1-[(2S,4R)-4-Hydroxy-2-(1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-2-(5-propyl-1,2,4-oxadiazol-3-yl)butan-1-one, and 1-[(2S,4R)-4-Hydroxy-2-(1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-2-(5-propyl-1,3,4-oxadiazol-2-yl)butan-1-one, a compound selected therefrom or a salt thereof.

2. Use of the compound according to claim 1 or a salt thereof for producing a target proteolysis-inducing compound which is a bifunctional compound having a VHL-binding ligand and a target-directed ligand.

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