WO2012115159A1 - Polypeptide compound - Google Patents

Abstract

[Problem] To provide an antibacterial agent, particularly a novel polypeptide compound having an antifungal activity or a salt thereof. [Solution] The present inventors considered a novel antibacterial agent and found that excellent antifungal activity can be achieved by introducing a benzoyl group having a cyclic substituent at the carbonyl ortho position, as a partial structure for a natural polypeptide compound, thereby completing the present invention. This polypeptide compound has excellent antifungal activity and can be used as a prophylactic and/or a therapeutic agent for various fungal infections.

Description

Polypeptide compounds

The present invention relates to a pharmaceutical, particularly a novel polypeptide compound having antifungal activity or a pharmaceutically acceptable salt thereof.

Infectious diseases caused by fungi are roughly classified into superficial dermatomycosis caused by infection from the skin (such as ringworm) and deep mycosis caused by respiratory or oral infection (such as Candida and Aspergillus). Deep mycosis develops in patients with various risk factors such as immunodeficiency and anticancer drug administration, and once it develops, it often becomes intractable and has a poor prognosis. In particular, when invasive pulmonary aspergillosis develops, the mortality rate is 58% throughout the disease, especially 87% in bone marrow transplant patients. However, there are few effective treatment means and drugs, and even the standard drugs voriconazole and ambisome have a low effective rate of 60% or less. Therefore, a new antifungal agent having a strong activity is demanded.
As an antifungal compound, for example, Patent Document 1 discloses a compound represented by the following formula.

(Wherein R ¹ is H, R ² is an acyl group, R ³ is OH, R ⁴ is OH, R ⁵ is H, R ⁶ is H, etc.).
In Patent Documents 2, 3, 5 and 6, as in Patent Document 1, a group corresponding to R ² is defined as acyl, and compounds in which R ² is various benzoyl groups are disclosed. However, a compound in which a ring group is substituted at the ortho position of the carbonyl is not disclosed as a substituent of the benzoyl group.
Patent Document 4 discloses a compound in which the group corresponding to R ² defined above is a benzoyl group, and discloses a compound in which a methyl group is present at the ortho position of the carbonyl. Compounds with substituted groups are not disclosed.

US patent US5569646 International Publication WO02 / 068456 Pamphlet International Publication WO03 / 068807 Pamphlet International Publication WO99 / 40108 Pamphlet International Publication WO98 / 236377 Pamphlet International Publication WO99 / 11210 Pamphlet

Provided is a compound useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and / or treating mycosis.

As a result of intensive studies on an excellent preventive and / or therapeutic agent for mycosis, the present inventors have found that the compound of the formula (I) has an excellent antifungal activity and completed the present invention. The compound has the following formula at a specific carbon atom on the B ring in the compound of formula (I)

A compound represented by the formula:
That is, the present invention relates to a compound containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a compound containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and an excipient. Relates to the composition.

Wherein R ¹ is -NH ₂ , -OH, -NH-lower alkylene-NH ₂ , -lower alkylene-NH-lower alkyl, -lower alkylene-N (lower alkyl) ₂ , -NH-lower alkylene- C (= O) OH or -NHCH (OH) C (= O) OH,
R ² is -S (= O) ₂ OH, -CH ₂ CH (OH) CH ₂ OH, -lower alkylene-C (= O) OH, lower alkyl, or H,
A ring is a nitrogen-containing heterocycle, aryl, or cycloalkyl,
R ^A is H, lower alkyl, -lower alkylene-NH ₂ , -lower alkylene-NH-lower alkyl, -lower alkylene-N (lower alkyl) ₂ , -lower alkylene-OH, -lower alkylene-O-lower alkyl , -Lower alkylene-C (= O) OH, -lower alkylene-S (= O) ₂ OH, -lower alkylene-S (= O) ₂ O-lower alkyl, -C (= O) O-lower alkyl, -C (= O) - lower alkylene -NH _2, -C (= O) - lower alkylene - NH- lower alkyl, -C (= O) - lower alkylene -N (lower alkyl) _2, -C (= O ) -NH ₂ optionally substituted with lower alkylene-OH, —C (═NH) —NH ₂ , —CH (lower alkylene-OH) ₂ , or cycloalkyl,
X is a single bond, lower alkylene, -NH-, or -N (lower alkyl)-
R ^B and R ^C are the same or different, and H or halogen,
The ring B is represented by the following formula (II), formula (III-a), or formula (III-b)

A group represented by
* Indicates the position at which the group bonds to X in formula (I), ** indicates the position at which the group bonds to R ^B in the formula (I),
Ring D is a nitrogen-containing heteroaryl or aryl,
R ^D represents the following formulas (IV) to (VI)

Or a group represented by -LOR ¹⁰¹ ,
L is lower alkylene, higher alkylene, -O-, -O-lower alkylene, or a single bond,
E ring is a heterocyclic group,
F ring and F1 ring are the same or different and each represents cycloalkyl,
Fg ring is cycloalkyl or aryl,
Efg ring is a heterocyclic group, cycloalkyl or aryl,
R ^E is H, lower alkyl, -O-lower alkyl, or halogen,
R ¹⁰¹ represents lower alkyl, -lower alkylene-cycloalkyl, or -higher alkylene-cycloalkyl,
R ^Z1 or R ^Z2 is the same or different and is ^optionally substituted with H, halogen, halogen or lower alkyl, aryl, lower alkyl, higher alkyl, —O-lower alkyl, —O-higher alkyl, —O -Cycloalkyl, -O-aryl, -O-lower alkylene-aryl, -higher alkylene-O-lower alkyl, cycloalkyl, or -C (= O) O-lower alkylene-aryl. )

The present invention also relates to a pharmaceutical composition for preventing and / or treating mycosis comprising a compound of formula (I) or a salt thereof, ie, prevention of mycosis comprising a compound of formula (I) or a salt thereof. The present invention relates to an agent and / or a therapeutic agent.
The present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of mycosis, formula (I) for the prevention or treatment of fungal infections. And a method for preventing and / or treating mycosis comprising administering to a patient an effective amount of a compound of formula (I) or a salt thereof.
The invention also relates to a compound of formula (I) for use in the treatment of mycosis.

The compound of formula (I) or a salt thereof has antifungal activity and can be used as a preventive or therapeutic agent for mycosis.

Hereinafter, the present specification will be described in detail.
In the present specification, “lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like. In another embodiment, it is C _1-4 alkyl. Yet another embodiment is C _1-3 alkyl. Yet another embodiment is methyl or ethyl.
“Lower alkylene” means a divalent group (C _1-6 alkylene) formed by removing any one hydrogen atom of the above “lower alkyl”, and one embodiment is C _1-4 alkylene. Another embodiment is methylene or ethylene.

“Higher alkyl” means linear or branched alkyl having 7 to 12 carbon atoms (hereinafter abbreviated as C _7-12 ), for example, heptyl, 1-propylbutyl, octyl, nonyl, decyl, dodecyl. is there. In another embodiment, it is C _7-8 alkyl. Yet another embodiment is heptyl or octyl.

“Higher alkylene” means a divalent group (C _7-12 alkylene) formed by removing any one hydrogen atom of the above “higher alkyl”, and as an embodiment, C _7-10 alkylene. Another embodiment is heptanediyl or octanediyl.

“Halogen” means F, Cl, Br, I.
“Cycloalkyl” is a C _3-10 saturated hydrocarbon ring group, which may have a bridge. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like. In another embodiment, it is C _3-8 cycloalkyl. Yet another embodiment is cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, adamantyl.
“Aryl” is a C _6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, for example, phenyl or naphthyl, and in another embodiment, phenyl.

“Heterocycle” group refers to i) a 3-8 membered, alternatively 5-7 membered monocyclic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, And ii) the monocyclic heterocycle is condensed with one or two rings selected from the group consisting of a monocyclic heterocycle, a benzene ring, a C _5-10 cycloalkane and a C _5-10 cycloalkene. A ring group selected from bicyclic to tricyclic heterocycles containing 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen formed in a ring. Ring atoms such as sulfur or nitrogen may be oxidized to form oxides or dioxides.

The “heterocyclic” group includes the following embodiments.
(1) Monocyclic saturated heterocyclic group
(a) those containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl and the like;
(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like;
(c) those containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl;
(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as oxathiolanyl;
(e) those containing 1 to 2 oxygen atoms, such as oxiranyl, oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl and the like;

(2) Monocyclic unsaturated heterocyclic group
(a) those containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl 1,2,3,6-tetrahydropyridyl and the like;
(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like;
(c) those containing 1 to 2 sulfur atoms, such as thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl and the like;
(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically, dihydrooxathiopyranyl and the like;
(e) those containing 1 to 2 oxygen atoms, such as furyl, pyranyl, oxepinyl, dioxolyl and the like;

(3) Fused polycyclic saturated hetero ring group
(a) those containing 1 to 5 nitrogen atoms, such as quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl;
(b) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl and the like;
(c) those containing 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as 2,6-dioxabicyclo [3.2.2] oct-7-yl;

(4) Fused polycyclic unsaturated heterocyclic group
(a) those containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahydrobenzoimidazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, Benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl;
(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, for example benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothia Zolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzooxadiazolyl, benzisothiazolyl, benzisoxazolyl, imidazo [2,1-b] [ 1,3,4] thiadiazolyl, etc .;
(c) those containing 1 to 3 sulfur atoms, such as benzothienyl, benzodithiopyranyl, dibenzo [b, d] thienyl, etc .;
(d) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, such as benzooxathiopyranyl, phenoxazinyl and the like;
(e) those containing 1 to 3 oxygen atoms, such as benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, dibenzo [b, d] furanyl, methylenedioxyphenyl, Ethylenedioxyphenyl and the like;
Such.

The “nitrogen-containing heterocycle” group is one of the above “heterocycle” groups (1) (a), (1) (b), (2) (a), (2) (b), (3) A substance containing at least one nitrogen atom, such as (a), (3) (b), (4) (a) and (4) (b).
“Heteroaryl” is a monocyclic or condensed polycyclic heterocyclic group having aromaticity among (2) and (4) of the above “heterocyclic” group.
For example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl etc. monocyclic heteroaryl, indolyl, isoindolyl, benzoimidyl , Indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, imidazopyridyl, pyrazolopyridyl, phthalazinyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, imidazothiazolyl, benzoisoxazolyl, benzofuranyl, Bicyclic [2,1-b] [1,3,4] thiadiazolyl, benzothienyl, imidazothiadiazolyl, etc. Triaryl heteroaryl such as roaryl, carbazolyl, dibenzo [b, d] furanyl, dibenzo [b, d] thienyl, and other embodiments include pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, imidazo Pyridyl, pyrazolopyridyl, benzothiadiazolyl, benzoxazolyl, imidazothiazolyl, imidazothiadiazolyl, and in yet another embodiment, pyrimidinyl, oxazolyl, imidazo [2,1-b] [1,1-b 3,4] thiadiazolyl or imidazochiadiazolyl.

“Nitrogen-containing heteroaryl” refers to a monocyclic or condensed polycyclic ring containing at least one nitrogen atom among the above “heteroaryl”. For example, as an embodiment, imidazothiadiazolyl, pyrimidinyl, or oxadiazolyl can be mentioned. As another embodiment, imidazo [2,1-b] [1,3,4] thiadiazolyl, pyrimidinyl, 1,2,4-oxadiazolyl may be mentioned.
“5- to 6-membered monocyclic nitrogen-containing heteroaryl” is the above monocyclic “nitrogen-containing heteroaryl” having 5 or 6 atoms constituting the ring, and pyridyl, pyrimidinyl, thiazolyl, thiadiazolyl, Examples include oxazole or oxadiazolyl.
"5-membered or 5-membered condensed polycyclic nitrogen-containing heteroaryl or 5-membered or 6-membered condensed polycyclic nitrogen-containing heteroaryl" is a group of benzimidazole, imidazothiadiazolyl, indole among the above "nitrogen-containing heteroaryl". Benzoxazole, imidazo [2,1-b] [1,3,4] thiadiazolyl, and the like.

“Heterocycloalkyl” refers to (1) (a), (1) (b), (3) (a), (3) (b) of the above “heterocyclic” group or “heterocyclic” Of the group (2) (a), (2) (b), (4) (a), (4) (b) is a heterocyclic group having no aromaticity. For example, azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, 1,2,3,6-tetrahydropyridyl, pyrazolidinyl, piperazinyl, azocanyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, morpholinyl, Monocyclic heterocycloalkyl such as dihydrotriazinyl and tetrahydropyridyl, and bicyclic heterocycloalkyl such as quinuclidyl and 7-azabicyclo [2.2.1] heptyl.

“Nitrogen-containing heterocycloalkyl” refers to the above “heterocycloalkyl” containing at least one nitrogen atom. Some embodiments include piperidyl, piperazinyl, tetrahydropyridyl and the like. In another embodiment, it is 1,2,3,6-tetrahydropyridyl.
The “6-membered nitrogen-containing heterocycloalkyl” refers to the above-mentioned “nitrogen-containing heteroalkyl” having 6 atoms constituting the ring. Some embodiments include piperidyl, piperazinyl, tetrahydropyridyl and the like. In another embodiment, it is 1,2,3,6-tetrahydropyridyl.
The “6-membered monocyclic heterocycle” group refers to a group having 6 atoms constituting the ring among the above (1) and (2). Some embodiments include piperidyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, pyridyl, pyrimidinyl, pyrazinyl and the like.

“Ring group” means a cyclic group such as nitrogen-containing heteroaryl, nitrogen-containing heterocycloalkyl, aryl, or cycloalkyl in the above definition, and when there are two bonds, it is divalent. Indicates a group.

In the present specification, “optionally substituted” means unsubstituted or having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.

Certain embodiments of the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof are shown below.
(1) A compound in which the A ring is a monocyclic saturated heterocyclic group.
(2) A compound in which the A ring is a 6-membered monocyclic heterocyclic group.
(3) A compound in which the A ring is a monocyclic unsaturated heterocyclic group or a condensed polycyclic unsaturated heterocyclic group.
(4) A compound in which the A ring is a nitrogen-containing heterocycloalkyl.
(5) A compound in which the A ring is a 6-membered nitrogen-containing heterocycloalkyl.
(6) A compound in which the A ring is a group represented by 1,2,3,6-tetrahydropyridyl or piperidyl.
(7) A compound in which the B ring is a group represented by the formula (II).
(8) A compound wherein the ring B is a group represented by the formula (III-a) or the formula (III-b).

(9) The compound in which the D ring is a nitrogen-containing heteroaryl.
(10) A compound wherein the D ring is selected from monocyclic nitrogen-containing heteroaryl or condensed polycyclic nitrogen-containing heteroaryl.
(11) The compound wherein the D ring is a 5- to 6-membered monocyclic nitrogen-containing heteroaryl.
(12) A compound in which the D ring is a 5-membered to 5-membered condensed polycyclic nitrogen-containing heteroaryl or a 5-membered to 6-membered condensed polycyclic nitrogen-containing heteroaryl.
(13) A compound in which the ring D is imidazothiadiazolyl, pyridyl, pyrimidinyl, or oxadiazolyl.
(14) A compound wherein the D ring is imidazo [2,1-b] [1,3,4] thiadiazolyl.
(15) The compound wherein R ^D is a group represented by formula (V) or formula (VI).
(16) The compound wherein the E ring in R ^D is a monocyclic saturated heterocyclic group or a monocyclic unsaturated heterocyclic group.
(17) The compound wherein the E ring in R ^D is nitrogen-containing heterocycloalkyl.
(18) The compound wherein the E ring in R ^D is a 6-membered nitrogen-containing heterocycloalkyl.
(19) The compound wherein the E ring in R ^D is 1,2,3,6-tetrahydropyridyl, piperazinyl or piperidyl.

(20) The compound wherein the Efg ring in R ^D is nitrogen-containing heterocycloalkyl.
(21) The compound wherein the Efg ring in R ^D is a 6-membered nitrogen-containing heterocycloalkyl.
(22) The compound wherein the Fg ring in R ^D is cycloalkyl or aryl.
(23) The compound wherein R ¹ is —NH ₂ , —OH, —NHCH ₂ CH ₂ NH ₂ , —NHCH ₂ C (═O) OH, or —NHCH (OH) C (═O) OH.
(24) The compound wherein R ² is —S (═O) ₂ OH, —CH ₂ CH (OH) CH ₂ OH, —CH ₂ C (═O) OH, lower alkyl, or H.
(25) R ^A is H, lower alkyl, -lower alkylene-NH ₂ , -lower alkylene-OH, -lower alkylene-O-lower alkyl, -lower alkylene-C (= O) OH, -lower alkylene-S (= O) OH, -C ( = O) OH, -C (= O) O- lower alkyl, -C (= O) - lower alkylene _{-NH 2, -C (= O)} CH (NH 2) CH ₂ OH, —CH (CN) —NH ₂ , —CH (-lower alkylene-OH) ₂ , or a compound that is cycloalkyl.
(26) The compound wherein X is a single bond.
(27) The compound wherein L is a single bond, lower alkylene, -O- or -O-lower alkylene-.

(28) The compound wherein L is a single bond, —CH ₂ CH ₂ —, —O—, or —O—CH ₂ —.
(29) The compound wherein R ^A is -lower alkylene-OH, -C (= O) -lower alkylene-NH ₂ , cycloalkyl, lower alkyl, or H.
(30) The compound wherein R ^A is —CH ₂ CH ₂ —OH.
(31) The compound wherein R ^A is methyl.
(32) The compound wherein R ¹ is —NH ₂ .
(33) The compound wherein R ² is —S (═O) ₂ OH or methyl.
(34) The compound wherein R ² is —S (═O) ₂ OH.
(35) The compound wherein R ^B is H.
(36) A compound which is a combination of two or more of the groups shown in the compounds (1) to (35) above.
Examples of specific compounds encompassed by the present invention include the following compounds (37) to (84) or pharmaceutically acceptable salts thereof.

(37) A compound which is a group shown in the compound of (3) and a group shown in the compound of (10).
(38) A compound which is a group shown in the compound of (4) and a group shown in the compound of (10).
(39) A compound which is a group shown in the compound of (5) and a group shown in the compound of (10).
(40) A compound which is a group shown in the compound of (3) and a group shown in the compound of (11).
(41) A compound which is a group shown in the compound of (4) and a group shown in the compound of (11).
(42) A compound which is a group shown in the compound of (5) and a group shown in the compound of (11).
(43) A compound which is a group shown in the compound of (3) and a group shown in the compound of (12).
(44) A compound which is a group shown in the compound of (4) and a group shown in the compound of (12).
(45) A compound which is a group shown in the compound of (5) and a group shown in the compound of (12).
(46) A compound which is the group shown in the compound of (3), the group shown in the compound of (7), and the group shown in the compound of (10).
(47) A compound which is the group shown in the compound of (4), the group shown in the compound of (7), and the group shown in the compound of (10).
(48) A compound which is the group shown in the compound of (5), the group shown in the compound of (7), and the group shown in the compound of (10).
(49) A compound which is the group shown in the compound of (3), the group shown in the compound of (7), and the group shown in the compound of (11).
(50) A compound which is the group shown in the compound of (4), the group shown in the compound of (7), and the group shown in the compound of (11).

(51) A compound which is the group shown in the compound of (5), the group shown in the compound of (7), and the group shown in the compound of (11).
(52) A compound which is the group shown in the compound of (3), the group shown in the compound of (7), and the group shown in the compound of (12).
(53) A compound which is the group shown in the compound of (4), the group shown in the compound of (7), and the group shown in the compound of (12).
(54) A compound which is the group shown in the compound of (5), the group shown in the compound of (7), and the group shown in the compound of (12).
(55) A compound which is a group shown in the compound of (6) and a group shown in the compound of (10).
(56) A compound which is a group shown in the compound of (6) and a group shown in the compound of (11).
(57) A compound which is a group shown in the compound of (6) and a group shown in the compound of (12).
(58) A compound which is the group shown in the compound of (6), the group shown in the compound of (7), and the group shown in the compound of (10).
(59) A compound which is the group shown in the compound of (6), the group shown in the compound of (7), and the group shown in the compound of (11).
(60) A compound which is the group shown in the compound of (6), the group shown in the compound of (7), and the group shown in the compound of (12).
(61) A compound which is the group shown in the compound of (7) and the group shown in the compound of (10).
(62) A compound which is a group shown in the compound of (7) and a group shown in the compound of (11).

(63) A compound which is a group shown in the compound of (7) and a group shown in the compound of (12).
(64) A compound which is a group shown in the compound of (3) and a group shown in the compound of (15).
(65) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (11), and a group shown in the compound of (15) .
(66) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (11), and a group shown in the compound of (18) .
(67) A compound shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (11), and a group shown in the compound of (21) .
(68) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (12), and a group shown in the compound of (15) .
(69) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (12), and a group shown in the compound of (18) .

(70) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (12), and a group shown in the compound of (21) .
(71) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (13), and a group shown in the compound of (18) .
(72) A compound shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (13), and a group shown in the compound of (21) .
(73) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (14), and a group shown in the compound of (18) .
(74) A compound which is a group shown in the compound of (4), a group shown in the compound of (7), a group shown in the compound of (14), and a group shown in the compound of (21) .
(75) A compound which is a group shown in the compound of (6) and a group shown in the compound of (9). .

(76) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and X is a single bond , and the a group B ring represented by the formula (II), an R ^B is H, an R ^c is H, D ring imidazo [2,1-b] [1,3,4] thiadiazolyl , Pyridyl, pyrimidinyl, or 1,2,4-oxadiazolyl, R ^D is a group represented by the formula (V), the E ring is piperazinyl or piperidyl, and L is —CH ₂ CH ₂ — Wherein the Fg ring is phenyl.
(77) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and R ^A is — CH ₂ CH ₂ —OH, X is a single bond, B ring is a group represented by formula (II), R ^B is H, R ^c is H, and D ring is imidazo [2 , 1-b] [1,3,4] thiadiazolyl, pyridyl, pyrimidinyl, or 1,2,4-oxadiazolyl, R ^D is a group represented by formula (V), and ring E is piperazinyl or A compound that is piperidyl, L is —CH ₂ CH ₂ —, and the Fg ring is phenyl.
(78) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and X is a single bond and a is a group B ring represented by the formula (II), an R ^B is H, an R ^c is H, a group R ^D is represented by formula (V), E ring is in a piperazyl A compound in which the Fg ring is phenyl.

(79) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and R ^A is — CH ₂ CH ₂ --OH, X is a single bond, the B ring is a group represented by the formula (II), R ^B is H, R ^c is H, R ^D is a formula (V ), E ring is piperidyl, L is a single bond, and Fg ring is cycloalkyl.
(80) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and R ^A is — CH ₂ CH ₂ —OH, X is a single bond, B ring is a group represented by formula (II), R ^B is H, R ^c is H, and D ring is oxadiazolyl , R ^D is a group represented by formula (V), E ring is piperidyl, L is —CH ₂ CH ₂ —, and Fg ring is cycloalkyl.
(81) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and X is a single bond and a is a group B ring represented by the formula (II), R ^B is H, R ^c is H, D ring is oxadiazolyl, a group R ^D is represented by formula (V) A compound in which the E ring is piperidyl, L is a single bond, and the Efg ring is piperazine or piperidine.

(82) R ¹ is —NH ₂ , R ² is —S (═O) ₂ OH, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, and R ^A is methyl X is a single bond, B ring is a group represented by formula (II), R ^B is H, R ^c is H, D ring is pyrimidinyl, and R ^D is formula ( A compound represented by VI), wherein L is —O—CH ₂ — and the Efg ring is phenyl.
(83) R ¹ is —NH ₂ , R ² is Me, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, X is a single bond, and the B ring is a formula A group represented by (II), R ^B is H, R ^c is H, R ^D is a group represented by the formula (V), the E ring is piperidinyl, and L is a single bond. A compound in which the Fg ring is cycloalkyl.
(84) R ¹ is —NH ₂ , R ² is Me, the A ring is 1,2,3,6-tetrahydropyridyl-4-yl, R ^A is H, and X is a single bond and a is a group B ring represented by the formula (II), an R ^B is H, R ^c is H, D ring is a pyrimidine, a group R ^D is represented by formula (V) A compound in which the E ring is piperazinyl, L is —CH ₂ CH ₂ —, and the Fg ring is phenyl.
Specific examples of the compound included in the present invention include a compound selected from the following groups (85) to (88) or a pharmaceutically acceptable salt thereof.

(85) Hydrogen sulfate 5-{(2R) -2-[(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-amino-1- Hydroxy-3-oxopropyl] -2,11,15-trihydroxy-6-[(1R) -1-hydroxyethyl] -9- (3- [1- (2-hydroxyethyl) -1,2,3 , 6-Tetrahydropyridin-4-yl] -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazole-6 -Yl} [1,1′-biphenyl] -4-carboxamide) -16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrolo [2,1-c: 2 ', 1'-l] [1,4,7,10,13,16] hexaazacyclohenicosin-23-yl] -2-hydroxyethyl} -2-hydroxyphenyl ester.
(86) Hydrogen sulfate 5-{(2R) -2-[(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-Amino-1- Hydroxy-3-oxopropyl] -2,11,15-trihydroxy-6-[(1R) -1-hydroxyethyl] -9- (3- [1- (2-hydroxyethyl) -1,2,3 , 6-Tetrahydropyridin-4-yl] -4 '-{5- [4- (2-phenylethyl) piperazin-1-yl] pyrimidin-2-yl} [1,1'-biphenyl] -4-carboxamide ) -16-Methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrolo [2,1-c: 2 ', 1'-l] [1,4,7,10 , 13, 16] Hexaazacyclohenicosin-23-yl] -2-hydroxyethyl} -2-hydroxyphenyl ester.
(87) Hydrogen sulfate 5-[(2R) -2-{(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-amino-1- Hydroxy-3-oxopropyl] -9- {4 '-(5- {4-[(4,4-dimethylcyclohexyl) oxy] piperidin-1-yl} -1,2,4-oxadiazole-3- Yl) -3- [1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl] [1,1'-biphenyl] -4-carboxamide} -2,11,15- Trihydroxy-6-[(1R) -1-hydroxyethyl] -16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrolo [2,1-c: 2 ' , 1'-l] [1,4,7,10,13,16] hexaazacyclohenicosin-23-yl} -2-hydroxyethyl] -2-hydroxyphenyl ester.
(88) N-{(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-Amino-1-hydroxy-3-oxopropyl] -2 , 11,15-Trihydroxy-6-[(1R) -1-hydroxyethyl] -23-[(1R) -1-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl] -16-methyl -5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipirolo [2,1-c: 2 ', 1'-l] [1,4,7,10,13,16] Hexaazacyclohenicosin-9-yl} -4 '-(5- {4- [2- (4-ethoxyphenyl) ethyl] piperazin-1-yl} pyrimidin-2-yl) -3- (1, 2,3,6-Tetrahydropyridin-4-yl) [1,1′-biphenyl] -4-carboxamide.

In the compound of the formula (I), geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

Furthermore, the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

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

Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

(Production method)
The compound of the formula (I) and salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
Further, the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the above protecting group, or further reacts with the obtained compound of the formula (I). Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below. (General manufacturing method 1)

The compound (I) of the present invention can be produced by reacting the compound (Q) with the compound (P-1). This reaction is a condensation reaction between the amino group of compound (Q) and the corresponding carboxylic acid of (P-1). In this reaction, the compound (Q) and the compound (P-1) are used in an equal amount or in an excess amount, and a mixture of these in the presence of a condensing agent, in a solvent inert to the reaction, under cooling to heating, The mixture is preferably stirred at -20 ° C to 60 ° C for 0.1 hour to 5 days. Examples of the solvent include, but are not limited to, aromatic hydrocarbons (such as toluene or xylene), halogenated hydrocarbons (such as DCM, DCE, or chloroform), ethers (such as diethyl ether, THF, or dioxane). Etc.), an aprotic solvent (for example, DMF, DMSO, EtOAc, MeCN), water, and a mixed solvent thereof. Examples of condensing agents include, but are not limited to, BOP, HBTU, EDCI, DPPA, phosphorus oxychloride. It may be preferable for the reaction to use an additive (eg HOBt). It may be advantageous to carry out the reaction in the presence of an organic base (such as TEA, DIPEA or NMM) or an inorganic base (such as K ₂ CO ₃ or KOH) in order to facilitate the reaction.

Compound (I) can also be obtained by isolating compound (P-1) as a reactive derivative and then reacting with compound (Q). Examples of reactive derivatives of the carboxylic acid form (P-1) are obtained by reacting with an acid halide obtained by reacting with a halogenating agent (for example, phosphorus oxychloride, thionyl chloride, etc.), isobutyl chloroformate, etc. Examples thereof include mixed acid anhydrides or active esters obtained by condensation with HOBt or the like. The reaction between the compound (P-1) and the reactive derivative is performed under cooling to heating, preferably in a solvent inert to the reaction such as DMF, halogenated hydrocarbons, aromatic hydrocarbons, ethers, It can be performed at -20 ° C to 60 ° C. In the reaction, it may be advantageous to cause the reaction to proceed smoothly in the presence of a base (for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.). Pyridine can also serve as a solvent.
[Literature] SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, 1st volume, Academic Press Inc. (2005) (Maruzen)
(General production method 2-1)

(Wherein R ^A1 represents —CH (—R ′) — R ″. R ′ or R ″ are the same or different and represent H or lower alkyl, provided that R ^A1 represents —CH (The total number of carbon atoms in the (-R ')-R''group is 1 to 6.)
The compound (I-1) of the present invention can be obtained by reacting the compound (P-2) and the compound (P-3-1).
In this reaction, an equivalent amount of compound (P-2) and compound (P-3-1) or an excess amount of one of them is used, and a mixture of these in a solvent inert to the reaction in the presence of a reducing agent, The mixture is stirred at 45 ° C. with heating under reflux, preferably at 0 ° C. to room temperature, usually for 0.1 hour to 5 days. Examples of the solvent used here include, but are not limited to, alcohols such as MeOH and EtOH, ethers such as diethyl ether, DMF, halogenated hydrocarbons, and mixtures thereof. Examples of the reducing agent include NaBH (OAc) ₃ , NaBH ₃ CN, NaBH _{4 and the} like. As an example of the compound (P-3-1), 1,4-dioxane-2,5-diol and the like are used in addition to the aldehyde or ketone represented by the general formula O = C (—R ′) — R ″. be able to. It may be preferable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves or an acid such as AcOH, hydrochloric acid, titanium (IV) isopropoxide complex. Depending on the reaction, imine may be generated by condensation between compound (P-2) and compound (P-3-1), and may be isolated as a stable intermediate. In such a case, compound (I) can be obtained by the reduction reaction of this imine intermediate. Further, instead of the treatment with the reducing agent, a reduction catalyst (for example, palladium carbon, Raney nickel, etc.) is used in a solvent such as MeOH, EtOH, EtOAc or the like in the presence or absence of an acid such as AcOH or hydrochloric acid. The reaction can also be carried out. In this case, it is preferable to carry out the reaction under a hydrogen atmosphere at normal pressure to 50 atm and under cooling to heating.
[Reference]
A. R. Katritzky and R. J. K. Taylor, `` Comprehensive Organic Functional Group Transformations II '', Volume 2, Elsevier Pergamon, 2005 The Chemical Society of Japan `` Experimental Chemistry Course (5th Edition) '' Volume 14 (2005) (Maruzen)
(General production method 2-2)

(In the formula, Lvg represents a leaving group.)
The compound (I-2) of the present invention can also be obtained by alkylating the compound (P-2) with the compound (P-3-2). Here, examples of the leaving group Lvg include halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like.
In this reaction, an equivalent amount of compound (P-2) and compound (P-3-2) or an excess amount of one of them is used, and a mixture thereof is cooled in a solvent inert to the reaction or without solvent. From 0 to 80 ° C., usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but are aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane and THF, or halogenated hydrocarbons such as DCM and chloroform, DMF, DMSO. , EtOAc, MeCN and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as Et ₃ N or DIPEA, or an inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ or KOH in order to facilitate the reaction.
[Reference]
SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, 1st volume, Academic Press Inc., 1991, Chemical Society of Japan, "Experimental Chemistry Course (5th edition)" 14th volume (2005) (Maruzen)
(General manufacturing method 3)

(In the formula, X ¹ represents a single bond or —CH ₂ —. Lvg has the same definition as described above.)
Compound (I-3) is a compound in which X of compound (I) is X ¹ . Compound (I-1) can be produced from compound (P-4) and compound (P-5). This reaction is a method for producing compound (I-1) by so-called Suzuki coupling in which an aryl compound (P-4) and a boric acid compound (P-5) are reacted. The reaction can be carried out without heating in a solvent inert to the reaction such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, aprotic solvents, etc., from room temperature under heating and reflux. The reaction is carried out in the presence of palladium, a phosphine ligand and a metal base. As palladium, divalent palladium such as Pd (OAc) _{2 and} zerovalent palladium such as Pd ₂ (dba) ₃ can be used. As the phosphine ligand, bidentate ligands such as BINAP and DPPF, monodentate ligands such as P (Bu ^t ) ₃ , and the like can be used. As the metal _{base, K 2 CO 3, Cs 2} CO 3, potassium phosphate, it can be used NaOBu ^t like. Here, the leaving group Lvg includes halogen, trifluoromethanesulfonyloxy and the like.
(General manufacturing method 4)

(In the formula, X ² represents NH or N (Me).)
Compound (I-4) are compounds X is X ² of the compound (I). Compound (I-2) can be obtained by reacting compound (P-4) with compound (P-6). In this reaction, compound (P-4) and compound (P-6) are used in an equal amount or in excess of one, and the mixture is heated in a solvent inert to the reaction or in the absence of solvent and from under cooling. The mixture is stirred under reflux, preferably at 0 ° C. to 80 ° C., usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether, THF, dioxane and DME, DCM, 1,2-dichloroethane, chloroform and the like , Halogenated hydrocarbons, DMF, DMSO, EtOAc, MeCN and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as Et ₃ N, DIPEA or NMM, or an inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ or KOH, in order to facilitate the reaction. is there.
[Reference]
SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, 1st volume, Academic Press Inc., 1991, Chemical Society of Japan, "Experimental Chemistry Course (5th edition)" 14th volume (2005) (Maruzen)

Among the compounds of formula (I), a compound in which the nitrogen atom of the A ring forms a quaternary ammonium salt can be produced by N-alkylation reaction of the nitrogen-containing heterocycloalkyl group of the compound of the present invention.
The N-alkylation reaction can be carried out by a conventional N-alkylation reaction. Specifically, the compound of the present invention is alkylated in a sufficient amount to alkylate the amino group of the A ring. The reaction can be carried out by stirring in an inert solvent such as DMF, CHCl ₃ , MEK, MeCN, or THF, under ice-cooling to room temperature, or optionally with heating. Examples of the alkylating agent include alkyl halides and lower alkyl methanesulfonates.
(Intermediate production method 1)

(In the formula, R means a protecting group for a carboxyl group.)
Compound (P-1) can be produced by deprotecting the carboxyl group from compound (P-7). For example, it can be deprotected by a hydrolysis reaction.
(Intermediate production method 2)

Compound (P-7-1) is a compound in which X of compound (P-7) is X ¹ , and Compound (P-7-2) is a compound in which X of compound (P-7) is X ² . This reaction is performed by reacting compound (P-5) or compound (P-6) with compound (P-8) as a starting material, respectively, to give compound (P-7-1) and compound (P-6), respectively. -7-2) can be manufactured. With respect to the reaction conditions, the desired compound can be produced under the same conditions as in General Production Method 3 or General Production Method 4.

Compound (P-7) can be produced by reacting compounds (P-9) and (P-10). One of Y and Z is Lvg, and the other is boronic acid or boronic ester. With respect to the reaction conditions, the desired compound can be produced under the same conditions as in General Production Method 3.

In addition, for all the above reactions, the methods described in the production examples or examples of the present specification or methods according thereto can be adopted, and the compounds are known methods, methods obvious to those skilled in the art, Or it can manufacture by the method as described in the manufacture example or Example of this specification, or the method according to it.

(Raw material production method)
The raw material compound represented by the general formula (Q) used in the production of the compound of the present example is an international publication WO97 / 32975, an international publication WO99 / 40108, an international publication WO2000 / 064927, an international publication WO2002 / 072621. In addition, it can be produced in the same manner as the method shown in International Publication WO2003 / 068807 or International Publication WO2009 / 057568 or the method described.

The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates, or crystalline polymorphs. The salt of the compound of formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

The pharmacological activity of the compound of formula (I) was confirmed by the following test.
Test Example 1: Sensitivity measurement for C. glabrata; Echinocandin resistant strain, Candida glabrata FP2135 Serum MIC (minimum inhibitory concentration) was determined. A suspension of 10 ⁶ cells / mL was prepared with a hemocytometer and an inoculum size of approximately 5 × 10 ³ to 2 × 10 ⁴ cells / mL was obtained. The microplate was incubated for 24 hours at 37 ° C. in a 5% CO ₂ atmosphere. The MIC for this strain was defined as the lowest concentration of test compound at which growth was completely inhibited. The MIC for all Echinocandins (Caspofungin, Anidulafungin and Micafungin) on the market was> 64 μg / mL.
Test Example 2: Sensitivity measurement for Aspergillus fumigatus strain Aspergillus fumigatus strain was measured in the same manner as in Test Example 1.

Table 1 below shows the test results of Test Example 1 for some representative compounds of the present invention. In the table, Ex indicates an example number. Values are the MIC against C. glabrata (C. glabrata; Echinocandin resistant strain), and the geometric mean of MEC against Aspergillus fumigatus (A. As shown.

Test Example 3: Antifungal susceptibility measurement in human serum MIC (minimum inhibitory concentration) in human serum was determined by a micro liquid dilution method using human serum buffered with 20 mM HEPES buffer (pH 7.4) as a test medium. It was. A suspension with 10 ⁷ cells / mL was prepared with a hemocytometer and an inoculum size of approximately 2.5 × 10 ³ to 2 × 10 ⁵ cells / mL was obtained. The microplate was incubated for 24 hours at 37 ° C. in a 5% CO 2 atmosphere. MIC for Candida was defined as the lowest concentration of the test compound at which growth was completely inhibited, and MEC for Aspergillus was defined as the lowest concentration of the test compound at which growth was sufficiently inhibited compared to the growth control.
Values are MIC, Aspergillus fumigatus (A. fumigatus) is shown as the geometric mean value of MEC for 3 clinical isolates (A. fumigatus 20030, 20024, and 200293 strains).

The compounds in the table are as follows.
Compound A is the compound of Example 19 of US Pat. No. 5,556,646.
Compound B is the compound of Example 8 of WO98 / 23637.
Compound C is the compound of Example 100 of WO96 / 11210.
Compound D is the compound of Example 94 of WO99 / 40108.
As a result of each of the above tests, it was found that the representative compounds of formula (I) shown in the table have antifungal activity. The compound also had antifungal activity against not only C. albicans and A. fumigatus but also C. parapsilosis and C. glabrata; Echinocandin resistant strains.
From these results, it was confirmed that the antifungal activity was superior as compared with conventional compounds. From this, the compound of the formula (I) can be useful as a prophylactic or therapeutic agent for various fungal infections, particularly infection diseases caused by the following fungi.
Acremonium;
Aspergillus (for example, Aspergillus clubatas, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus tereus, Aspergillus vesilcolor);
Blast Mrs. (eg Blast Mrs. dermatitis);
Candida (e.g. Candida albicans, Candida glabrata, Candida guilliermondi, Candida kefir, Candida crusei, Candida paracylosis, Candida stellatoidea, Candida tropicalis, Candida utilis, etc.);
Cladosporium (eg Cladosporium trichoides);
Coccidioides (eg coccidioides imimitis);
Cunning Amera (eg Cunning Amera Elegance);
Dermatophytes;
Exofiara (eg, Exofiara del machitisis, Exofiara spinifera, etc.);
Epidermophyton (eg Epidermophyton floccum);
Foncea (eg foncea pedrosoi);
Geotricum (eg Geotricum candidum);
Histoplasma (for example, histoplasma capsulatum mutant capsulatsum etc.);
Malassezia (eg, Malassezia furfur, etc.);
Microsporum (eg, microsporum canis, microsporum dipseum, etc.);
Paracoccidioides (eg, paracoccidioides brasiliensis);
Penicillium (eg, Penicillium manefei);
Fialophora;
Pneumocystis (eg, Pneumocystis jiroveci);
Pseudoaleseria (eg pseudoaleseria boise);
Saccharomyces (eg Saccharomyces cerevisiae);
Skoplariopsis;
Sporotrix (eg Sporotrix Schenky, etc.);
Trichophyton (for example, Trichophyton Mentagrophytes, Trichophyton rubrum, etc.).
In another embodiment, the compound of formula (I) may be useful as a prophylactic or therapeutic agent for the following fungal infections and infectious diseases caused by fungi.
Aspergillus (for example, Aspergillus clubatas, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus tereus, Aspergillus vesilcolor);
Candida (e.g. Candida albicans, Candida glabrata, Candida guilliermondi, Candida kefir, Candida crusei, Candida paracylosis, Candida stellatoidea, Candida tropicalis, Candida utilis, etc.);
Pneumocystis (eg, Pneumocystis jiroveci);
Pseudoaleseria (eg pseudoaleseria boise);
Saccharomyces (eg Saccharomyces cerevisiae).

The above fungi are skin, eyes, hair, nails, oral mucosa, gastrointestinal tract, bronchial, lung, endocardium, brain, meninges, urinary organs, buttocks, oral cavity, eyeball, whole body, kidney, heart, ear canal, It is well known to cause various infectious diseases in bone, nasal cavity, sinus cavity, spleen, liver, subcutaneous tissue, lymphatic vessel, gastrointestinal tract, joint, muscle, tendon, stromal plasma cell in lung, blood vessel and the like.

Accordingly, the compounds of formula (I) can be used in various infectious diseases such as dermatophytosis (e.g. ringworm, etc.), gallbladder, candidiasis, geotrichumosis, sandy hair, aspergillosis, penicillosis, sporotricosis, Prevention and / or prevention of chromomises, coccidioidomycosis, histoplasmosis, blastosomiasis, paracoccidioidomycosis, pseudoaleseriosis, foot mycosis, fungal keratitis, otomycosis, pneumocystis, fungiemia, etc. Useful for treatment.

A pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is an excipient normally used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. Can be prepared by a commonly used method.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

A transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid, or semi-solid state, and can be produced according to a conventionally known method. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

In particular, in the case of prevention and / or treatment of fungal infections, the aforementioned injections for parenteral administration or transmucosal agents such as inhalants and nasal agents are preferred.

In general, in the case of oral administration, the appropriate daily dosage is about 0.001 to 100 mg / kg, preferably 10 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

The compound of formula (I) can be used in combination with various prophylactic or therapeutic agents for diseases for which the compound of formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

Hereinafter, based on an Example, the manufacturing method of the compound of Formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown in a manufacture example, respectively. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below. It can also be produced by methods that are obvious.

Moreover, the following abbreviations may be used in this specification, an Example, a manufacture example, and a postscript table | surface.
Ag ₂ O = silver oxide, AgOTf = silver trifluoromethanesulfonate, BINAP = 1,1′-binaphthalene-2,2′-diylbis (diphenylphosphine), BOC or boc = tert-butyloxycarbonyl, BOP = hexafluoric acid Benzotriazol-1-yloxytris (dimethylamino) phosphonium, Boc ₂ O = ditert-butyl dicarbonate, Bn = benzyl, DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene, CH ₂ Cl ₂ or DCM = dichloromethane, CO = carbon monoxide, DCE = dichloroethane, DIPEA = N, N-diisopropylethylamine, DMAc = N, N-dimethylacetamide, DMF = N, N-dimethylformamide, DMI = 1,3-dimethyl -2-imidazolidinone, DMSO = dimethyl sulfoxide, DPPA = diphenyl phosphate azide, DPPP = 1,3-bis (diphenylphosphino) propane, EDCI, WSC = 3-ethyl-1- (3-dimethylaminopropyl) Carbodiimi Et ₃ N = triethylamine, EtOAc = ethyl acetate, EtOH = ethanol, FMOC = fluorenylmethyloxycarbonyl, HBTU = o-benzotriazole-N, N, N ′, N′-tetramethyl-uronium-hexafluoro Phosphate, HOBt = 1-hydroxybenzotriazole, Hex = hexane, K ₃ PO ₄ = Tripotassium phosphate, KOAc = potassium acetate, LHMDS = lithium bistrimethylsilylamide, MeI = methyl iodide, MS3A = molecular sieve 3 angstrom, MeCN = Acetonitrile, MgSO ₄ = anhydrous magnesium sulfate, NIS = N-iodosuccinimide, NMM = N-methylmorpholine, NMP = N-methylpyrrolidone, NaBH ₃ CN = sodium cyanoborohydride, NaBH (OAc) ₃ = triacetoxyborohydride sodium, NaBH ₄ = sodium borohydride, Na ₂ S ₂ O ₃ = thiosulfate isocyanatomethyl Um, Na ₂ SO ₄ = sodium sulfate anhydride, NaBH (OAc) ₃ = sodium triacetoxyborohydride, NaHCO ₃ = sodium hydrogen carbonate, NaOtBu = sodium tert-butoxide, Pd / C = palladium on carbon, Pd ₂ (dba) ₃ = Tris (dibenzylideneacetone) dipalladium (0), PdCl ₂ (dppf) CH ₂ CL ₂ = 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex, TBAI = tetrabutylammonium iodide , TEA or Et ₃ N = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TfOH = trifluoromethylsulfonic acid, AcOH = acetic acid, brine = saturated saline, n-BuOH = normal butanol, n- = normal, sat . = Saturated, tert- = tertiary.

In particular, the following abbreviations may be used in structural formulas.
BOC = tertiary butoxycarbonyl, Bn = benzyl, Et = ethyl, FMOC = fluorenylmethyloxycarbonyl, Me = methyl, OMe = methoxy, OBn = benzyloxy, OEt = ethoxy, OMe = methoxy, OiPr = isopropoxy, OnBu = normal butyloxy, OnPn = normal pentyloxy, OnPr = normal propoxy, OtBu = tertiary butyloxy, Tf = trifluoromethanesulfonate, Cbz = benzyloxycarbonyl, iPr = isopropyl, nBu = normal butyl, nHep = normal heptyl , NHex = normal hexyl, nOct = normal octyl, nPn = normal pentyl, nPr = normal propyl, tBu- = tertiary butyl.
In the table below, (HCl) indicates isolation as a hydrochloride salt.

Production Example 1
To a solution of 6-chloro-2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] -1,3-benzothiazole (0.501 g) in toluene (5 mL) was added 4-cyclohexyl-4-methoxypiperidine. (343 mg), Pd ₂ (dba) ₃ (66.3 mg), 2 ′-(dichlorohexylphosphono) -N, N-dimethylbiphenyl-2-amine (42.7 mg) and NaOtBu (0.195 g) were added. Irradiated at 160 ° C for 1 hour in the wave. 0.1M HCl was added to the reaction mixture and stirred for several minutes. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent; Hexane: CHCl ₃ = 50: 50 to 30:70), 6- (4-cyclohexyl-4-methoxypiperidin-1-yl) -2- [4- (tetrahydro -2H-pyran-2-yloxy) phenyl] -1,3-benzothiazole (734 mg) was obtained.

In the same manner as in Production Example 1, the compounds of Production Example 1-1 to Production Example 1-7 shown in the table below were produced.

Production Example 2
Methyl 4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazol-6-yl} -3- (1,2 , 3,6-Tetrahydropyridin-4-yl) biphenyl-4-carboxylate (201 mg) dissolved in a mixed solvent of CH ₂ Cl ₂ (4.26 mL) and MeOH (2.13 mL), 4-Dioxane-2,5-diol (79.8 mg) and NaBH (OAc) ₃ (140 mg) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added sat.NaHCO ₃ aqueous solution at 0 ° C., and the mixture was extracted with CHCl ₃ . The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The resulting residue was washed with MeCN and methyl 3- [1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl] -4 '-{2- [4- (2 -Phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazol-6-yl} biphenyl-4-carboxylate (164 mg) was obtained as a white solid.

In the same manner as in Production Example 2, the compounds of Production Example 2-1 to Production Example 2-48 shown in the table below were produced.

Production Example 3
2-Bromo-6- (4-bromophenyl) imidazo [2,1-b] [1,3,4] thiadiazole (54 g) in DMAc (840 mL) solution with 1- (2-phenylethyl) piperazine ( 34.3 g) and Et ₃ N (36.5 g) were added, and the mixture was stirred at a bath temperature of 90 ° C. for 3 hours. The reaction mixture was allowed to cool and then stirred for 3 hours. The resulting precipitate was suspended in water and collected by filtration, and the precipitate was washed with water and a small amount of MeCN to give 6- (4-bromophenyl) -2- [4- (2-Phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazole (64.7 g) was obtained.

In the same manner as in Production Example 3, the compounds of Production Example 3-1 to Production Example 3-4 shown in the table below were produced.

Production Example 4
Piperazine (2.66 g) was added to a solution of 3-bromo-5- (4-bromophenyl) -4,5-dihydro-1,2-oxazole (4.70 g) in NMP (70.5 mL) and stirred at 130 ° C for 3 hours. did. The reaction solution was partitioned by adding water and EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to obtain a crude product. The residue was dissolved in CH ₂ Cl ₂ , Et ₃ N (2.58 mL) and Boc ₂ O (4.37 g) were added, and the mixture was stirred at room temperature. The reaction mixture was extracted with water and EtOAc, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl ₃ : EtOAc = 98: 2) and tert-butyl 4- [5- (4-bromophenyl) -4,5-dihydro-1,2-oxazole -3-yl] piperazine-1-carboxylate (3.3 g) was obtained.

Production Example 5A
6- (4-Bromophenyl) -2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazole (20 g), {3- [1- (tert-Butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -4- (methoxycarbonyl) phenyl} boronic acid (23.1 g) in dioxane (600 mL) and water (60 mL) Mix the mixed solution of K ₃ PO ₄ (22.6 g), 1,2,3,4,5-pentaphenyl-1 '-(di-tert-butylphosphino) ferrocene (1.58 g) with nitrogen did. Pd ₂ (dba) ₃ (488.7 mg) was added, and the system was again depressurized and replaced with nitrogen. The mixture was stirred at 100 ° C. for 24 hours under a nitrogen atmosphere. The reaction solution was allowed to cool and the precipitate was filtered. The resulting precipitate was suspended in water (500 mL) and filtered. The obtained white powder was suspended in MeCN (300 mL), stirred under heating to reflux for 30 minutes, and allowed to cool. The precipitate was filtered, washed with a small amount of acetonitrile, and tert-butyl 4- [4- (methoxycarbonyl) -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2 , 1-b] [1,3,4] thiadiazol-6-yl} biphenyl-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (25.3 g) was obtained.

In the same manner as in Production Example 5A, the compounds of Production Example 5A-47 were produced from Production Example 5A-1 shown in the table below.

Production Example 5B
4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (1.2 g), KOAc (750 mg), tert-butyl To 4-{[(trifluoromethyl) sulfonyl] oxy} -3,6-dihydropyridine-1 (2H) -carboxylate (1.6 g) was added dioxane (20 mL) degassed with ultrasound for 20 minutes. The reaction system was replaced with nitrogen three times. Pd ₂ (dba) ₃ (68 mg) and dicyclohexyl (2 ', 6'-dimethoxybiphenyl-2-yl) phosphine (245 mg) were added to the reaction system, and the reaction system was again replaced with nitrogen three times. did. The reaction mixture was stirred at 110 ° C. (internal temperature 95 ° C.) for 3 hours. Return to room temperature, add methyl 2-chloro-4- (tetrahydro-2H-pyran-2-yloxy) benzoate (1 g), K ₃ PO ₄ (750 mg), H ₂ O (2 mL), and add 110 ° C. The mixture was stirred at an internal temperature of 95 ° C. for 2 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Hexane / EtOAc system) and tert-butyl 4- [2- (methoxycarbonyl) -5- (tetrahydro-2H-pyran-2-yloxy) phenyl] -3, 6-Dihydroxypyridine-1 (2H) -carboxylate (1.3 g) was obtained as an orange oil.

In the same manner as in Production Example 5B, the compound of Production Example 5B-15 was produced from Production Example 5B-1 shown in the table below.

Production Example 5C
1- [3- (4-Bromophenyl) -1,2,4-oxadiazol-5-yl] -4-[(4,4-dimethylcyclohexyl) oxy] piperidine (243 mg), {3- [ 1- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -4- (methoxycarbonyl) phenyl} boronic acid (223 mg), K ₃ PO ₄ (356 mg), palladium A mixed solution of acetate (12.6 mg) and tricyclohexylphosphine (15.7 mg) in dioxane (4.86 mL) -water (1.22 mL) was stirred at room temperature for 1 hour. EtOAc and water were added to the reaction solution, followed by filtration through celite. The filtrate was partitioned and the organic layer was washed with brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Hexane / EtOAc system) and tert-butyl 4- [4 '-(5- {4-[(4,4-dimethylcyclohexyl) oxy] piperidin-1-yl } -1,2,4-oxadiazol-3-yl) -4- (methoxycarbonyl) biphenyl-3-yl] -3,6-dihydroxypyridine-1 (2H) -carboxylate (220 mg) in white Obtained as a solid.

In the same manner as in Production Example 5C, the compounds of Production Example 5C-27 were produced from Production Example 5C-1 shown in the table below.

Production Example 5D
tert-Butyl 4- [2- (methoxycarbonyl) -5-{[(trifluoromethyl) sulfonyl] oxy} phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate (441 mg), 4,4 , 4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (277 mg), triphenylphosphine (33.3 mg), KOAc (279 mg ) And dioxane (5 mL), and the inside of the reaction vessel containing the mixture was depressurized and purged with nitrogen. PdCl ₂ (PPh ₃ ) ₂ was added and the atmosphere was replaced with nitrogen again, followed by stirring at a bath temperature of 100 ° C. for 20 hours. The reaction mixture was allowed to warm to room temperature, water was added and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography and tert-butyl 4- [2- (methoxycarbonyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate (480 mg) was obtained.

In the same manner as in Production Example 5D, the compounds of Production Example 5D-6 were produced from Production Example 5D-1 shown in the table below.

Production Example 5E
4- {5- [4- (2-Phenylethyl) piperazin-1-yl] pyrimidin-2-yl} phenyl trifluoromethanesulfonate (2.1 g), [3-chloro-4- (methoxycarbonyl) phenyl] boronic acid (1.1 g), 2.0 M Na ₂ CO ₃ aqueous solution (5.4 mL), tetrakistriphenylphosphine palladium (0), and DME (21 mL) were mixed, and nitrogen was blown, followed by stirring for 2 hours with heating under reflux. The reaction mixture was poured into water, and the resulting solid was collected by filtration, washed with water and MeCN, dried under reduced pressure at 40 ° C., and methyl 3-chloro-4 ′-{5- [4- (2-phenyl). Ethyl) piperazin-1-yl] pyrimidin-2-yl} biphenyl-4-carboxylate (1.95 g) was obtained.

In the same manner as in Production Example 5E, the compounds of Production Example 5E-29 were produced from Production Example 5E-1 shown in the table below.

Production Example 5F
4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (0.125 g), DIPEA (0.16 mL) and tert-butyl 4- [3- (methoxycarbonyl) -7-{[(trifluoromethyl) sulfonyloxy] oxy} -2-naphthyl] -3,6-dihydropyridine-1 (2H) -carboxylate (0.228 g) Dioxane (2 mL) degassed by sonication for 20 minutes was added. The reaction system was replaced with nitrogen three times. Biphenyl-2-yl (dicyclohexyl) phosphine (0.032 g) and Pd (OAc) ₂ (5 mg) were added to the reaction system, and the reaction system was again substituted with nitrogen three times. The reaction mixture was stirred at 80 ° C. for 1 hour. Return to room temperature, water (0.8 mL), K ₃ PO ₄ (0.28 g), tricyclohexylphosphine (0.025 g), Pd (OAc) ₂ (5 mg) and 1- [3- (4-bromophenyl) -1 , 2,4-oxadiazol-5-yl] -4- [2- (4-fluorophenyl) ethyl] piperazine (0.19 g) was added and stirred at 80 ° C. overnight. The reaction mixture was diluted with CHCl ₃ (30 mL), and washed with water (20 mL). The organic layer was separated, dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl ₃ / MeOH system), and tert-butyl 4- {7- [4- (5- {4- [2- (4-fluorophenyl) ethyl] piperazine- 1-yl} -1,2,4-oxadiazol-3-yl) phenyl] -3- (methoxycarbonyl) -2-naphthyl} -3,6-dihydropyridine-1 (2H) -carboxylate (0.074 mg ) Was obtained as a yellow solid.

Production Example 5G
Under a nitrogen atmosphere, add 0.5M 9-borabicyclo [3.3.1] nonane THF solution (5.00 mL) to a THF solution (1.20 mL) of tert-butyl 4-methylenepiperidine-1-carboxylate (240 mg) and heat for 1 hour. Refluxed. Methyl 4-chloro-2-{[(trifluoromethyl) sulfonyl] oxy} benzoate (323 mg), K ₃ PO ₄ (538 mg), PdCL ₂ (dppf) CH ₂ CL ₂ (62.0 mg), Water (0.845 mL) was added and stirred at 80 ° C. for 12 hours. Water was added to the reaction solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex: EtOAc system), and tert-butyl 4- [5-chloro-2- (methoxycarbonyl) benzyl]. Piperidine-1-carboxylate (184 mg) was obtained as a pale yellow oil.

Production Example 6
tert-butyl 4- [5-hydroxy-2- (methoxycarbonyl) phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate (5.33 g), 1,1,1-trifluoro-N-phenyl- A DMF solution (50 mL) of N-[(trifluoromethyl) sulfonyl] methanesulfonamide (6.30 g) and DIPEA (d = 0.742, 8 mL) was stirred at room temperature for 5 hours. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hex / EtOAc system), and tert-butyl 4- [2- ( Methoxycarbonyl) -5-{[(trifluoromethyl) sulfonyl] oxy} phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate (6.7 g) was obtained as a yellow oil.

In the same manner as in Production Example 6, the compounds of Production Example 6-1 to Production Example 6-26 shown in the table below were produced.

Production Example 7
5- [4- (2-phenylethyl) piperazin-1-yl] -1,3-thiazol-2-amine (475 mg) and 2-bromo-1- (4-bromophenyl) ethanone (460 mg) The mixture was stirred at 90 ° C. in n-BuOH (6 mL) for 1 hour. The reaction mixture was allowed to cool to room temperature, EtOH (5 mL) was added, the precipitate was collected by filtration, the resulting solid was washed with EtOH, dried at 40 ° C. under reduced pressure, and 6- (4-bromophenyl ) -2- [4- (2-Phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3] thiazole (731 mg) was obtained as a purple solid.

Production Example 8
To a solution of 5-fluoro-2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyrimidine (7.20 g) in DMSO (72 mL) was added 1- (2-phenylethyl) piperazine (9.93 mL) and K ₂ CO ₃ (7.26 g) was added and the mixture was stirred at 140 ° C. for 20 hours. After cooling to room temperature, water (100 mL) was added to the reaction mixture, and the resulting precipitate was collected by filtration. The obtained powder was washed with IPE and dried overnight at 40 ° C. under reduced pressure to give 5- [4- (2-phenylethyl) piperazin-1-yl] -2- [4- (tetrahydro-2H-pyran -2-yloxy) phenyl] pyrimidine (10.06 g) was obtained.

In the same manner as in Production Example 8, the compounds of Production Example 8-1 to Production Example 8-26 shown in the table below were produced.

Production Example 9
To a solution of 5-fluoro-2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyrimidine (500 mg) in NMP (2.5 mL) was added (2R) -2-methylpiperazine (547 mg) and K ₂ CO ₃ (1.26 g) was added and the mixture was stirred at 140 ° C. for 6 hours. Furthermore, (2R) -2-methylpiperazine (547 mg) and K ₂ CO ₃ (1.26 g) were added, and the mixture was stirred overnight. To the reaction solution were added brine (10 mL) and water (10 mL), and the mixture was extracted 3 times with EtOAc. The organic layer was washed 4 times with brine, dried over MgSO ₄ and concentrated under reduced pressure. Phenylacetaldehyde (245 μL) and NaBH (OAc) ₃ (502 mg) were added to a CH ₂ Cl ₂ solution (3.5 mL) of the obtained residue, and the mixture was stirred at room temperature for 1 hour. A sat. NaHCO ₃ aqueous solution was slowly added to the reaction mixture, and the mixture was extracted twice with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ and the resulting residue was purified (Hexane: CHCl ₃ : EtOAc = 1: 1: 1 to 0:70:30) and purified by 5-[(3R) -3-methyl-4 -(2-Phenylethyl) piperazin-1-yl] -2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyrimidine (600 mg) was obtained.

In the same manner as in Production Example 9, the compound of Production Example 9-1 shown in the table below was produced.

Production Example 10
3- [1- (tert-Butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo A mixture of [2,1-b] [1,3,4] thiadiazol-6-yl} biphenyl-4-carboxylic acid (1 g), BOP (768 mg), DMF, DIPEA (d = 0.742, 662 μL) Was stirred at room temperature for 1 hour. The compound of Example No. 169 (1.50 g) of International Publication No. WO99 / 40108 was added and stirred at room temperature overnight. EtOAc (100 mL) was added to the reaction solution, and the resulting precipitate was collected by filtration and dried under reduced pressure for 3 hours. After dissolving this powder in a solvent (MeCN: H ₂ O = 1: 1), 1M NaOH aqueous solution was added and diluted with water with stirring. This solution was purified using ODS medium pressure column chromatography and then lyophilized to obtain the compound of Production Example 10 (1.76 g).

In the same manner as in Production Example 10, the compounds of Production Examples 10-1 to 10-24 and Production Examples 10-26 to 10-33 shown in the table below were produced. Production Example 10-25 was obtained by subjecting the condensation reaction to a method according to Production Example 10 and then cyclizing according to the method of Production Example 18.
Isolation and purification include extraction, fractional crystallization, various fractional chromatography (e.g., ODS column chromatography and silica gel column chromatography), etc., ordinary chemical operations and methods described in the production examples or examples of the present specification, Alternatively, a method suitable for the compound among methods equivalent thereto was applied.

Production Example 11
A mixture of the compound of Production Example 33-24 (451 mg), BOP (328 mg), DMF (6.77 mL), and DIPEA (d = 0.742, 282.0 μL) was stirred at room temperature for 1 hour. To the reaction mixture, the compound of Example No. 169 (642 mg) of International Publication WO99 / 40108 was added and stirred at room temperature overnight. EtOAc (300 mL) was added to the reaction solution, and the resulting precipitate was collected by filtration. A MeOH solution of Pd / C (225.5 mg) was added to a MeOH-H ₂ O solution of the filtered product, and the mixture was stirred for 9 hours in an H ₂ atmosphere. Further, Pd / C (90.0 mg) was added to the reaction mixture, and the mixture was stirred for 7 hours. The reaction solution was washed by Celite filtration (H ₂ O: MeCN = 1: 1). After the filtrate was distilled off lightly under reduced pressure, H ₂ O: MeCN = 80: 20 and 1M NaOH aqueous solution were added to the resulting solution, and ODS column chromatography (H ₂ O: MeCN = 80: 20 to 20:80 The compound of Production Example 11 (356 mg) was obtained.

Production Example 12
To a suspension of 2- (4-bromopyridin-2-yl) -1- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] ethanone oxime (1.6 g) in CH ₂ Cl ₂ (16.0 mL) DIPEA (d = 0.726, 1.71 mL) was added, and TFAA (d = 1.49, 865 μL) was added dropwise under ice cooling. The reaction mixture was stirred at 7 ° C. to 10 ° C. for 1 hour and under water cooling for 2 hours. The reaction mixture was washed with 50 mL of water, and the organic layer was dried over MgSO ₄ and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent; Hexane: EtOAc = 80: 20) gave 4-bromo-2- {3- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] -2H-azilene- 2-yl} pyridine (1.38 g) was obtained as an oil.

Production Example 13
Under nitrogen atmosphere, 5-bromo-2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyridine (1.20 g), 4-cyclohexyl-4-methoxypiperidine hydrochloride (1.26 g), Cs ₂ Pd (dba) ₂ , (413 mg) and BINAP (671 mg) were added to a toluene solution (12 mL) of CO ₃ (5.26 g) at room temperature. The reaction solution was refluxed overnight. The mixture was cooled to room temperature, and CHCl ₃ water was added to the reaction solution to partition. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The obtained solid was suspended in IPE and stirred for 30 minutes. The solid was washed and powdered with IPE, and 5- (4-cyclohexyl-4-methoxypiperidin-1-yl) -2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyridine (632 mg) was added. Obtained as an orange solid.

Production Example 14A
tert-butyl 4- {4- (methoxycarbonyl) -4 '-[5- (piperazin-1-yl) pyrimidin-2-yl] biphenyl-3-yl} -3,6-dihydropyridin-1 (2H)- A mixture of carboxylate (400 mg), 1- (2-bromoethyl) -2-methylbenzene (215 mg), K ₂ CO ₃ (199 mg), NaI (162 mg), DMI (13.3 mL) at 140 ° C Stir for 20 hours. After cooling, it was diluted with EtOAc, washed with sat. NaHCO ₃ aqueous solution, and dried over MgSO ₄ . After concentrating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent; CHCl ₃ : EtOAc = 100: 0 to 3: 1) and tert-butyl 4- [4- (methoxycarbonyl) -4 ′. -(5- {4- [2- (2-Methylphenyl) ethyl] piperazin-1-yl} pyrimidin-2-yl) biphenyl-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (160 mg) was obtained.

In the same manner as in Production Example 14A, the compounds of Production Example 14A-15 were produced from Production Examples 14A-1 shown in the table below. Isolation and purification include extraction, fractional crystallization, various fractional chromatography (e.g. ODS column chromatography and silica gel column chromatography), etc., ordinary chemical operations and methods described in the production examples or examples of the present specification, Alternatively, a method suitable for the compound was applied among the methods equivalent thereto.

Production Example 14B
Under cooling with ice, trans-4- [3- (4-bromophenyl) -1,2,4-oxadiazol-5-yl] cyclohexanol (200 mg), CH ₂ Cl ₂ (2 mL), AgOTf ( 1-iodopropane (d = 1.743, 109 μL) was added to a mixture of 310.06 mg) and 2,6-ditert-butylpyridine (d = 0.870, 306.2 μL), and the mixture was stirred for 10 minutes. It returned to room temperature and stirred for 1 hour. The reaction mixture was filtered through celite, and the filtrate was washed with 1M aqueous hydrochloric acid, sat. NaHCO ₃ water, water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; EtOAc / Hexane), and 3- (4-bromophenyl) -5- (trans-4-propoxycyclohexyl) -1,2,4-oxadiazole (168 mg) Was obtained as a white solid.

In the same manner as in Production Example 14B, the compounds of Production Example 14B-4 were produced from Production Examples 14B-1 shown in the table below.

Production Example 14C
Trans-4- [3- (4-bromophenyl) -1,2,4-oxadiazol-5-yl] cyclohexanol (200 mg) and 1.0 M triethyloxonium tetrafluoroborate in dichloromethane (1 mL ) Was stirred at room temperature overnight. Water was added to the reaction solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO ₄ , and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: Hexane / EtOAc system) to obtain the desired product 3- (4-bromo Phenyl) -5- (trans-4-ethoxycyclohexyl) -1,2,4-oxadiazole (173.2 mg) was obtained as a white solid.

Production Example 15
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (300 mg) in THF (3.0 mL) was added Ag ₂ O (690 mg) at 0 ° C., and 6-bromo-3,3-dimethylcyclohexene (640 mg ) In THF. The mixture was stirred at room temperature overnight and filtered, and the filtrate was washed with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. Purified by silica gel chromatography (eluent; Hexane / EtOAc system) and tert-butyl 4-[(4,4-dimethylcyclohexyl-2-en-1-yl) oxy] piperidine-1-carboxylate (121 mg ) Was obtained as a colorless transparent solid.

Production Example 16
tert-Butyl 4- [4- (tert-butoxycarbonyl) -4'-cyanobiphenyl-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (3.2 g), hydroxylamine hydrochloride (1038 mg), NaHCO ₃ (1751 mg) and MeOH (48 mL) were stirred at 80 ° C. for 6 h. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO ₄ , concentrated under reduced pressure, and tert-butyl 4- {4 ′-[amino (hydroxyimino) methyl] -4- (tert-butoxycarbonyl) biphenyl- 3-yl} -3,6-dihydropyridine-1 (2H) -carboxylate (3.2 g) was obtained as a white solid.

In the same manner as in Production 16, the compounds of Production Example 16-1 to Production Example 16-3 shown in the table below were produced.

Production Example 17
A reaction mixture of 1- [4- (benzyloxy) phenyl] -2-bromoethane (2.48 g), 5-bromo-2-pyridinamine (155 g), and 95% EtOH (20 mL) was refluxed for 3 hours, The mixture was further stirred at 60 ° C. for 12 hours. After allowing to cool, the precipitate was collected by filtration to give 2- [4- (benzyloxy) phenyl] -6-bromoimidazo [1,2-a] pyridine (2.76 g) as a solid.

Production Example 18
A mixture of 4-bromo-N ′-({[4- (4-chlorophenyl) cyclohexyl) carbonyl] oxy) benzenecarboxyimidamide (862 mg) and DMAc (8.62 mL) was stirred at 120 ° C. for 6 hours. The reaction solution was returned to room temperature, water was added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to give 3- (4-bromophenyl) -5- [4- (4-chlorophenyl) cyclohexyl] -1,2,4-oxadiazole (732.9 mg) in beige color. Obtained as a powder.

In the same manner as in Production Example 18, the compounds of Production Example 18-1 to Production Example 18-22 shown in the table below were produced.

Production Example 19
4-Bromo-2- {3- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] -2H-azilen-2-yl} pyridine (1.36 g) in MeCN (13.6 mL) under nitrogen atmosphere FeCl ₂ (46.1 g) was added to the mixture, and the mixture was stirred with heating in an oil bath (60 ° C.) for 2 hours. After cooling to room temperature, MeCN was concentrated under reduced pressure. The obtained residue was dissolved in CHCl ₃ (200 mL), and water (100 mL) was added. The insoluble matter was removed by filtration through Celite. The organic layer of the filtrate was separated and the aqueous layer was extracted with CHCl ₃ (50 mL). The extracts were combined, dried over MgSO ₄ and treated with activated carbon. After filtration, the solvent was distilled off from the filtrate. The crude product was purified by silica gel column chromatography (eluent; Hexane: CHCl ₃ = 2: 1) to give 5-bromo-2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyrazolo [1 , 5-a] pyridine (860 mg) was obtained.

Production Example 20
A reaction mixture of 4-bromo-N ′-[(trans-4-methylcyclohexyl) carbonyl] benzohydrazide (300 mg), P ₂ S ₅ (216 mg) and THF (6 mL) was stirred at 50 ° C. for 5 hours. . Water and 1M NaOH aqueous solution (420 μL) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration, dried under reduced pressure, and purified by silica gel column chromatography (eluent; CHCl ₃ : EtOAc = 20: 1) to give 2- (4-bromophenyl) -5- (trans-4 -Methylcyclohexyl) -1,3,4-thiadiazole (223 mg) was obtained as a white solid.

In the same manner as in Production Example 20, the compound of Production Example 20-1 shown in the table below was produced.

Production Example 21
A mixture of 4-bromo-N- [2- (4-cyclohexyl-4-methoxypiperidin-1-yl) -2-oxoethyl] benzamide (1.67 g), pyridine (16.7 mL), P ₂ S ₅ (1.70 g) Was stirred at 100 ° C. for 6 hours. Water was added to the reaction solution, and the mixture was made basic with 1M NaOH aqueous solution and stirred for 15 minutes. The reaction solution was extracted with CHCl ₃ , washed twice with 1M aqueous HCl, water and brine in that order, dried over MgSO ₄ , and concentrated under reduced pressure. MeOH was added to the obtained residue, and the precipitate was collected by filtration. The residue was washed with MeOH and dried under reduced pressure. 1- [2- (4-Bromophenyl) -1,3-thiazol-5-yl] -4-cyclohexyl-4-methoxypiperidine (1.25 g) was beige Obtained as a solid.

Production Example 22
In a glove box, anhydrous CeCl ₃ (7.62 g) was finely pulverized in a three-diameter Kolben filled under a nitrogen stream. The three-diameter Kolben was taken out from the glove box, and the system was replaced with argon. Anhydrous THF was added in Kolben and the reaction mixture was stirred vigorously at room temperature overnight. To the reaction system, a 2.0M diethyl ether solution (15.5 mL) of n-pentylmagnesium bromide was added over 10 minutes, and the internal temperature was kept at 10 ° C. or lower using an ice bath. The reaction mixture was stirred at room temperature for 3 hours. A THF solution of tert-butyl 4-oxopiperidine-1-carboxylate was added to the reaction mixture over 15 minutes, and the internal temperature was kept at 10 ° C. or lower using an ice bath. The reaction mixture was stirred at 4 ° C. for 1.5 hours. To the reaction mixture 10% acetic acid was added slowly and the reaction mixture was extracted twice with EtOAc. The organic layer was washed with water and brine and dried over MgSO ₄ . After filtration, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 120 g; eluent; Hexane: EtOAc = 95: 5 to 75:25) tert-butyl 4-hydroxy-4-pentylpiperidine-1-carboxylate (5.16 g ) Was obtained as a white solid.

In the same manner as in Production Example 22, the compounds of Production Example 22-4 to Production Example 22-4 shown in the table below were produced.

Production Example 23
Bromine (251.8 μL) was added to 2- (4-bromophenyl) -1,3,4-oxadiazole in acetic acid over 10 minutes at room temperature. Stir at room temperature for 1.5 hours. The reaction mixture was heated to 50 ° C. and stirred for 1.5 hours, bromine (114.5 μL) was added, and the mixture was stirred at 50 ° C. for 5 hours. Bromine (114.5 μL) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 5 hours. The reaction solution was returned to room temperature, and 1M NaOH aqueous solution (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and washed with 1M aqueous NaOH (100 mL). The residue obtained after washing with 10% Na ₂ S ₂ O ₃ aqueous solution, water and brine, drying over MgSO ₄ and concentrating under reduced pressure was purified by silica gel column chromatography (Hexane: EtOAc system). -5- (4-Bromophenyl) -1,3,4-oxadiazole (404 mg) was obtained as a white solid.

In the same manner as in Production Example 23, the compounds of Production Example 23-2 to Production Example 23-2 shown in the table below were produced.

Production Example 24
Under an argon atmosphere, LHMDS (4.7 mL) was added to a mixture of 4- (4-bromophenyl) -1,3-oxazole (787 mg) and THF (17.3 mL) at an internal temperature of -65 to -60 ° C over 8 minutes. It was dripped. The reaction mixture was stirred in a MeCN / dry ice bath at an internal temperature of −43 ° C. for 30 minutes. Hexachloroethane (1.66 g) was added, the temperature was raised to room temperature, and the mixture was stirred overnight. EtOAc and water were added to the reaction solution. The organic layer was separated and washed with 0.1M aqueous hydrochloric acid and brine. Dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (Hexane / EtOAc system) to give 4- (4-bromophenyl) -2-chloro-1,3-oxazole (630 mg) as a white solid.

Production Example 25
To a white suspension of 1-benzyl-4- [3- (4-bromophenyl) -1,2,4-oxadiazol-5-yl] pyridinium bromide (1.24 g) at 0 ° C. in NaBH ₄ ( 198 mg) was added in small portions. The yellow reaction suspension was stirred at the same temperature for 1 hour. Solid NH ₄ Cl was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Water was added to the residue, and an extraction operation was performed using a solution of EtOAc: THF = 4: 1. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; Hexane: EtOAc = 80: 20 to 60:40), and 1-benzyl-4- [3- (4-bromophenyl) -1,2,4-oxa Diazol-5-yl] -1,2,3,6-tetrahydropyridine (0.39 g) was obtained as a yellow oil.

Production Example 26
A suspension of n-BuOH (780 mL) of 5-bromo-1,3,4-thiadiazol-2-amine (26 g) and 2-bromo-1- (4-bromophenyl) ethanone (40.1 g) was added. The mixture was stirred at 125 ° C. for 20 hours. The reaction mixture was allowed to cool, poured into EtOH (1600 mL), stirred for 2 hours, and the precipitated solid was collected by filtration. The solid was washed with EtOH to give 2-bromo-6- (4-bromophenyl) imidazo [2,1-b] [1,3,4] thiadiazole as a white powder (38.3 g).

Production Example 27
Under a nitrogen atmosphere, 2-[(6-bromo-1-chloro-2-naphthyl) oxy] tetrahydro-2H-pyran (54.5 g, triisopropyl borate (44 mL), and THF (550 mL) were mixed. 2.76M n-BuLi in hexane (69.4 mL) was added dropwise over 30 minutes at an internal temperature of -65 to -60 ° C., and the mixture was stirred for 1 hour while warming to room temperature. The mixture was added and stirred for 1 hour, and brine (400 mL) was added, and the pH was adjusted with 1 M aqueous hydrochloric acid to pH 4. The mixture was extracted with EtOAc (1000 mL, 500 mL) The organic layer was washed with brine (400 mL), and MgSO _4. After drying with hexane, hexane (600 mL) was added to the residue obtained by concentration under reduced pressure, and the precipitate was collected by filtration and then dried under reduced pressure to give [5-chloro-6- (tetrahydro-2H-pyran-2-yloxy]. ) -2-Naphthyl] boronic acid (46.7 g) was obtained as a white solid.

Production Example 28
Hydroxycarbon imidic dibromide (5.00 g) in DMF (25 mL) was added 1-bromo-4-vinylbenzene (5.41 g) at 5 ° C., followed by dropwise addition of aqueous NaHCO ₃ (6.16 g), Stir overnight. Water was added to the reaction mixture, extraction was performed with EtOAc, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; Hexane: EtOAc = 90: 10) to give 3-bromo-5- (4-bromophenyl) -4,5-dihydroisoxazole (7.14 g) Got.

Production Example 29
To an aqueous solution of sodium periodate (957 mg) and ammonium acetate (345 mg), tert-butyl 4- [2- (methoxycarbonyl) -5- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate (1.32 g) in EtOAc was added and stirred for 3 days. The precipitate was filtered off and washed with EtOAc. The filtrate and the washing solution were combined and separated, and the organic layer was washed with 5% Na ₂ S ₂ O ₃ aqueous solution and brine, dried over MgSO ₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent; CHCl ₃ : MeOH = 100: 0 to 90:10), and {3- [1- (tert-butoxycarbonyl) -1,2,3, 6-Tetrahydropyridin-4-yl] -4- (methoxycarbonyl) phenyl} boronic acid (860 mg) was obtained.

In the same manner as in Production Example 29, the compound of Production Example 29-1 shown in the table below was produced.

Production Example 30
tert-butyl 4- {3- [4- (5-chloro-6-{[(trifluoromethyl) sulfonyl] oxy} -2-naphthyl) phenyl] -1,2,4-oxadiazol-5-yl } Piperazine-1-carboxylate (850 mg), DMI (56.7 mL), Pd (OAc) ₂ (34 mg), Et ₃ N (d = 0.726, 935 μL), Propane-1,3-diylbis (diphenylphosphine) (125 mg) and MeOH (22.6 mL) were charged with carbon monoxide, which was stirred under a carbon monoxide atmosphere for 5 hours at 95 ° C. The reaction mixture was cooled to room temperature and water ( The reaction mixture was filtered and the resulting solid was washed with water, and the solid was dissolved in CHCl _{3. The} organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purified by silica gel chromatography (eluent; Hexane: CHCl ₃ = 50: 50 to EtOAc: CHCl ₃ = 15: 75) and purified by tert-butyl 4- (3- {4- [5-chloro-6- (methoxycarbonyl) ) -2-Naphtyl] phenyl} -1,2,4-oxadiazo 5-yl) piperazine-1-carboxylate (440 mg) as a white solid.

Production Example 31

tert-Butyl 4-hydroxy-4-pentylpiperidine-1-carboxylate (590 mg) was dissolved in THF, and NaH (60% oil suspension, 130 mg) was added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction solution was ice-cooled, iodomethane (0.925 g) was added, and the mixture was stirred for 5 minutes, and further stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was partitioned between EtOAc and water, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure to obtain tert-butyl 4-methoxy-4-pentylpiperidine-1-carboxylate (590 mg) as a colorless transparent oily substance. .

In the same manner as in Production Example 31, the compounds of Production Example 31-1 to Production Example 31-5 shown in the table below were produced.

Production Example 32
NIS (5 g) was added to a solution of 6-acetoxy-2-naphthylic acid (5 g), TBAI (12 g) and Pd (OAc) ₂ (500 mg) in DMF (100 mL). The reaction solution was stirred at 45 ° C. for 8 hours. NIS (5 g) was added to the reaction mixture, and the mixture was stirred at 45 ° C. for 12 hours. NIS (5 g) and Pd (OAc) ₂ (100 mg) were added to the reaction mixture, and after stirring for 20 hours, Pd (OAc) ₂ (100 mg) and NIS (5 g) were added and stirred for 48 hours. The reaction mixture was cooled to 0 ° C. and K ₂ CO ₃ was added. MeI was added to the reaction solution and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc. The organic layer was washed with Na ₂ S ₂ O ₃ aqueous solution, 1M NaOH aqueous solution, H ₂ O, 0.05M HCl twice, H ₂ O, NaHCO ₃ aqueous solution, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (eluent; CHCl ₃ , Hexane / EtOAc) to obtain methyl 6-acetoxy-3-iodo-2-naphthoate (6.37 g) as a yellow solid mixed with impurities. It was.

Production Example 33
Methyl 3- [1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl] -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] 1M NaOH aqueous solution (2.52 mL) was added to a dioxane solution of imidazo [2,1-b] [1,3,4] thiadiazol-6-yl} biphenyl-4-carboxylate (164 mg) and stirred at 100 ° C. for 5 hours. did. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and adjusted to pH 3 with water and 1M aqueous hydrochloric acid. The precipitate was collected by filtration. The obtained solid was washed with IPE and 3- [1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl] -4 ′-{2- [4- (2- Phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazol-6-yl} biphenyl-4-carboxylic acid (151 mg) was obtained.

In the same manner as in Production Example 33, the compounds of Production Examples 33-1 to 33-135 shown in the table below were produced. However, the compound of Production Example 33-25 was obtained by hydrolysis according to the method of Production Example 33, and then adding water to the reaction solution to collect the resulting precipitate.
Isolation and purification include extraction, fractional crystallization, various fractional chromatography (e.g., ODS column chromatography and silica gel column chromatography), etc., ordinary chemical operations and methods described in the production examples or examples of the present specification, Alternatively, a method suitable for the compound among methods equivalent thereto was applied.

Production Example 34
Dess-Martin periodinane (565 mg) was added to a CH ₂ Cl ₂ solution (2 mL) of 2- (3-isopropoxyphenyl) ethanol (200 mg) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added sat. NaHCO ₃ aqueous solution (5 mL) and sat. Na ₂ S ₂ O ₃ aqueous solution (5 mL), and the mixture was extracted twice with CH ₂ Cl ₂ (5 mL). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; Hexane: EtOAc = 90: 10 to 70:30) to give (3-isopropoxyphenyl) acetaldehyde (175 mg) as a colorless oil.

In the same manner as in Production Example 34, the compounds of Production Example 34-1 to Production Example 34-3 shown in the table below were produced.
Production Example 35
A reaction mixture of the compound of Example 161 (110 mg), BOC ₂ O (19.9 mg) and DIPEA (d = 0.742, 31.8 μL) in DMF (2 mL) was stirred at 25 ° C. for 4 hours. The reaction mixture was diluted with EtOAc (20 mL) to form a precipitate that was collected by filtration. The obtained solid was washed with EtOAc to give the compound of Production Example 35 (102 mg).

Production Example 36
A mixture of methyl 2-chloro-4-hydroxybenzoate (8.73 g), 3,4-dihydro-2H-pyran (11.986 g) and PPTS (4 g) in CH ₂ Cl ₂ (65 mL) at room temperature for 18 hours. Stir. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO ₃ aqueous solution. The separated organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Hexane: EtOAc = 9: 1), and methyl 2-chloro-4- ( Tetrahydro-2H-pyran-2-yloxy) benzoate (10.6 g) was obtained as a yellow oil.

In the same manner as in Production Example 36, the compounds of Production Example 36-1 to Production Example 36-3 shown in the table below were produced.
Production Example 37
Under ice-cooling, trans-4- [3- (4-bromophenyl) -1,2,4-oxadiazol-5-yl] cyclohexanol (410 mg), benzyl 2,2,2-trichloroethaneimidate ( TfOH (0.0553 mL) was added to a mixture of 545 mg) and CH ₂ Cl ₂ (6.15 mL). The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was diluted with EtOAc, and sat. NaHCO ₃ aqueous solution was added. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; Hexane: EtOAc system) to give 5- [trans-4- (benzyloxy) Cyclohexyl] -3- (4-bromophenyl) -1,2,4-oxadiazole (293 mg) was obtained as a white solid

Production Example 38
2- [4- (Benzyloxy) phenyl] -6- [4- (2-phenylethyl) piperazin-1-yl] imidazo [1,2-a] pyridine (270 mg), 10% Pd / C (294 mg), MeOH (8.1 mL), and THF (5.4 mL) were stirred overnight at room temperature under 3 atm of hydrogen. The solvent was concentrated under reduced pressure to give 4- {6- [4- (2-phenylethyl) piperazin-1-yl] imidazo [1,2-a] pyridin-2-yl} phenol (194 mg) as a gray solid Obtained.

In the same manner as in Production Example 38, the compound of Production Example 38-1 shown in the table below was produced.

Production Example 39
Under normal pressure hydrogen atmosphere, a mixture of benzyl trans-4- (3-methylbutoxy) cyclohexanecarboxylate (700 mg), EtOAc (19.5 mL), and Pd / C 10% (50% wet 70 mg) was stirred at room temperature for 5 hours. Stir for hours. The reaction solution was filtered through Celite to remove Pd / C, and the filtrate was concentrated under reduced pressure to obtain trans-4- (3-methoxybutoxy) cyclohexanecarboxylic acid (470 mg) as a white solid.

In the same manner as in Production Example 39, the compounds of Production Example 39-1 to Production Example 39-3 shown in the table below were produced.

Production Example 40
tert-Butyl 4- [4- (methoxycarbonyl) -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazole -6-yl} biphenyl-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (287 mg) in dioxane (3.5 mL), 4M HCl / dioxane (3.5 mL) was added, Stir at room temperature for 1 hour. The reaction mixture was diluted with IPE, the precipitate was collected by filtration, washed with IPE, and dried under reduced pressure. CH ₂ Cl ₂ was added to the obtained powder. The organic layer was washed with NaHCO ₃ , brine, the organic layer was concentrated under reduced pressure, and methyl 4 ′-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [ 1,3,4] thiadiazol-6-yl} -3- (1,2,3,6-tetrahydropyridin-4-yl) biphenyl-4-carboxylate (201 mg) was obtained.

In the same manner as in Production Example 40, the compounds of Production Example 40-1 to Production Example 40-23 shown in the table below were produced.
In Production Example 40-2, the reaction was performed according to Production Example 40, and then the reaction mixture was concentrated under reduced pressure to obtain a residual powder.
After the compounds of Production Examples 40-1 to 40-23 were reacted according to Production Example 40, the hydrochloride compound was isolated by the method according to Production Example 40-2, and the other compounds were produced. A compound was isolated and obtained by a method according to Example 40.

Production Example 41
tert-butyl 4- {4- (tert-butoxycarbonyl) -4 '-[5- (trans-4-butoxycarbonyl) -1,2,4-oxadiazol-3-yl] biphenyl-3-yl} A mixture of -3,6-dihydropyridine-1 (2H) -carboxylate (135 mg) and 4M HCl / EtOAc (3 mL) was stirred at room temperature for 2 hours. Stir for another 5 hours. Dioxane, 2M Na ₂ CO ₃ aqueous solution (0.41 mL) and 9H-fluoren-9-ylmethyl chlorocarbonate (55.7 mg) were added to the residue obtained by concentration, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution. The pH was adjusted to 2 with 1M hydrochloric acid and extracted with EtOAc. The reaction solution was washed with water and brine. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and 4 ′-[5- (trans-4-butoxycyclohexyl) -1,2,4-oxadiazol-3-yl] -3- {1-[( [9H-Fluoren-9-ylmethoxy) carbonyl] -1,2,3,6-tetrahydropyridin-4-yl} biphenyl-4-carboxylic acid (150 mg) was obtained as a white foamy solid.

In the same manner as in Production Example 41, the compounds of Production Example 41-1 to Production Example 41-2 shown in the table below were produced.

Production Example 42
Pd / C 10%, 50% wet (1.19 g) was added to a solution of the compound of Production Example 10-2 (2.38 g) in MeOH / H ₂ O (23.8 mL / 23.8 mL), and the resulting mixture was substituted with H ₂ and stirred for 7 hours. did. The reaction solution was filtered through celite. After the filtrate was lightly distilled off under reduced pressure, H ₂ O: MeCN = 80: 20 solution and 1M NaOH aqueous solution were added to the resulting solution, and ODS column chromatography (H ₂ O: MeCN = 80: 20 to 20:80 Purified). The target fraction, MeCN, was distilled off under reduced pressure and then lyophilized to obtain the compound of Production Example 42 (470 mg).

In the same manner as in Production Example 42, the compounds of Production Example 42-1 to Production Example 42-4 shown in the table below were produced. Isolation and purification include extraction, fractional crystallization, various fractional chromatography (ODS column chromatography, silica gel chromatography, etc.) and other normal chemical operations and methods described in the production examples or examples of the present specification, or Of the similar methods, the method suitable for the compound was applied.

Production Example 43
Et ₃ N (15.3 mL) and 2-nitrobenzenesulfonyl chloride (22.3 g) were added to a solution of tert-butylpiperazine-1-carboxylate (17 g) in CH ₂ Cl ₂ (340 mL) under ice-cooling. For 15 minutes and at room temperature for 4.5 hours. Water (150 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine and dried over MgSO ₄ . The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluting with Hexane: EtOAc = 70: 30 to 20:80). The fraction was concentrated under reduced pressure and the residue was triturated with IPE to give tert-butyl 4-[(2-nitrophenyl) sulfonyl] piperazine-1-carboxylate (31.8 g).

Production Example 44
tert-butyl 4- [4- (methoxycarbonyl) -4 '-(5- {4-[(2-nitrophenyl) sulfonyl] piperazin-1-yl} -1,2,4-oxadiazole-3- Yl) biphenyl-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (22.5 g) dissolved in DMF (225 mL), K ₂ CO ₃ (12.8 g), 4-methylbenzenethiol (4.59 g) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and extracted twice with CH ₂ Cl ₂ . The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was dissolved in about 1 L of EtOAc, washed 6 times with water, washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (eluent; Hexane: EtOAc = 1: 1, then CHCl ₃ : MeOH = 95: 5) and tert-butyl 4- [4- (methoxycarbonyl) -4 '-(5-Piperazin-1-yl-1,2,4-oxadiazol-3-yl) biphenyl-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (16.0 g) Obtained as a light brown foam.

Production Example 45
Suspension of 5- [4- (2-phenylethyl) piperazin-1-yl] -2- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] pyrimidine (10.05 g) in dioxane (100 mL) Under ice-cooling, 6M hydrochloric acid (18.8 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH = 8 with 1N NaOH aqueous solution under ice cooling, and the resulting solid was collected by filtration, washed with MeCN, and 4- {5- [4- (2-phenylethyl) piperazin-1-yl] Pyrimidin-2-yl} phenol (8.06 g) was obtained as a cream powder.

In the same manner as in Production Example 45, the compounds of Production Example 45-1 to Production Example 45-19 shown in the table below were produced.

Production Example 46
tert-Butyl 4- [2- (methoxycarbonyl) -5- (tetrahydro-2H-pyran-2-yloxy) phenyl] -3,6-dihydropyridine-1 (2H) -carboxylate (2.65 g), 4-methyl A mixture of benzenesulfonic acid (328 mg) and MeOH (27 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into water (90 mL) and extracted with EtOAc (45 mL). Brine was added to the aqueous layer and extracted again with EtOAc. The organic layers were combined, washed with brine, dried over MgSO ₄ , concentrated under reduced pressure, and tert-butyl 4- [5-hydroxy-2- (methoxycarbonyl) phenyl] -3,6-dihydropyridine-1 (2H ) -Carboxylate (2.04 g) was obtained.

In the same manner as in Production Example 46, the compounds of Production Example 46-1 to Production Example 46-5 shown in the table below were produced.

Production Example 47
6- {4- [5- (benzyloxy) pyrimidin-2-yl] phenyl} -1-chloro-2-naphthyl trifluoromethanesulfonate (200 mg), Pd (OAc) ₂ (8.0 mg) and DPPP (15 mg ) In DMSO / MeOH (16 mL / 4 mL) was added Et ₃ N (d = 0.726, 150 μL) at room temperature. The mixture was stirred at 90 ° C. for 4 hours in a CO atmosphere. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain a crude powder. The crude powder was purified by silica gel column chromatography (eluent; CHCl ₃ : MeOH = 99: 1), and methyl 6- {4- [5- (benzyloxy) pyrimidin-2-yl] phenyl} -1-chloro- 2-Naphthoate (143 mg) was obtained.

In the same manner as in Production Example 47, the compounds of Production Example 47-1 to Production Example 47-3 shown in the table below were produced.

Production Example 48
To a solution of methyl 4- (tetrahydro-2H-pyran-2-yloxy) benzene (1.37 g) and 4-bromo-2-methylpyridine (1 g) in THF (20 mL) was added 1M LHMDS (11.6 mL) under ice cooling. In addition, the mixture was stirred overnight at room temperature. Water and EtOAc were added to the reaction solution for extraction. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2- (4-bromopyridin-2-yl) -1- [4- (tetrahydro-2H -Pyran-2-yloxy) phenyl] ethanone (1.91 g) was obtained.

Production Example 49
(Dimethoxymethyl) dimethylamine (1.53 g) was added to a solution of the compound of Production Example 35 (180 mg) in MeOH / DMF (1.8 mL / 1.98 mL). The reaction mixture was stirred at 25 ° C. for 18 hours and at 40 ° C. for 8 hours. To the reaction mixture was added 1M aqueous NaOH (698.7 μL) and the reaction mixture was stirred at room temperature overnight. The reaction solution was neutralized, diluted with water (100 mL), eluted with ODS column chromatography (pH 6.8 buffer, washed with water, 50% MeCN), concentrated under reduced pressure, and freeze-dried. 49 compounds (157 mg) were obtained.

Production Example 50
To a solution of tert-butyl 4-[(4,4-dimethylcyclohex-2-en-1-yl) oxy] piperidine-1-carboxylate (810 mg) in MeOH (8 mL) was added 10% Pd / C (50 % wet, 50 mg) was added, and catalytic reduction was performed at room temperature under 1 atm of hydrogen for 5 hours. The reaction mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-[(4,4-dimethylcyclohexyl) oxy] piperidine-1-carboxylate (500 mg) colorless. Obtained as an oil.

In the same manner as in Production Example 50, the compound of Production Example 50-1 shown in the table below was produced.

Production Example 51
A mixture of 4-bromo-2-chlorobenzoic acid (15 g), DIBOC (16.7 g), DMAP (390 mg), THF (230 mL), t-BuOH (75 mL) was stirred at room temperature for 24 hours. To the reaction solution was added sat. NaHCO ₃ aqueous solution, and the mixture was extracted with EtOAc (300 mL). The organic layer was washed successively with water, 0.1M aqueous hydrochloric acid and brine, dried over MgSO ₄ and concentrated under reduced pressure to give tert-butyl 4-bromo-2-chlorobenzoate (17 g) as an orange oil. Obtained.

Example 1
3- {1-[(9H-Fluoren-9-ylmethoxy) carbonyl] -1,2,3,6-tetrahydropyridin-4-yl} -4 '-[5- (trans-4-isobutoxycyclohexyl)- A mixture of 1,2,4-oxadiazol-3-yl] biphenyl-4-carboxylic acid (402 mg), HBTU (221.2 mg), DMF (6.00 mL), DIPEA (0.237 mL) was stirred at room temperature for 30 minutes did. The compound of Example No. 169 (578 mg) of International Publication WO99 / 40108 was added and stirred at room temperature for 5 hours. In TLC, it was confirmed that the active ester disappeared. Piperidine (709.3 mg) was added and stirred at room temperature for 30 minutes. EtOAc was added to the reaction solution, and the resulting precipitate was collected by filtration. Suspended in water and added until 1M NaOH water was dissolved. The mixture was purified by ODS (charged to 80 mL of ODS silica gel substituted with water, then eluted stepwise with 10, 20, 30, 40% MeCN water) and then lyophilized to give the compound of Example 1 (472 mg ) Was obtained as a white powder.

The compounds of Examples 2 to 6 were produced in the same manner as the method of Example 1.

Example 7
To a DMF solution (0.75 mL) of the compound of Production Example 42-1 (0.75 mL), 3-methoxybenzaldehyde (14 mg), AcOH (5 μL), NaBH (OAc) ₃ (15 mg) was added, and under a nitrogen atmosphere, Stir at room temperature for 15 hours. EtOAc was added to the reaction solution, and the resulting precipitate was collected by filtration. TFA (0.5 mL) was added to the obtained mixture at 0 ° C., and the mixture was stirred at the same temperature for 0.5 hour. The reaction mixture is slowly added to 1M NaOH aqueous solution (6.7 mL) -H ₂ O (200 mL) under ice-cooling, and purified as it is by ODS column chromatography (H ₂ O: MeCN = 80: 20 to 20:80). did. The target fraction of MeCN was distilled off under reduced pressure and then lyophilized to obtain the compound of Example 7.

The compounds of Examples 8 to 32 were produced in the same manner as in Example 7.

The compounds of Examples 33 to 36 were produced in the same manner as in Production Example 10.

Example 37
3- [1- (tert-Butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl] -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazol-6-yl} biphenyl-4-carboxylic acid (10.6 g), BOP (8.14 g), DMF (212 mL), DIPEA (d = 0.742, 7.01 mL) was stirred at room temperature for 1 hour. The compound of Example No. 169 (15.967 g) of WO99 / 40108 was added and stirred at room temperature overnight. The reaction mixture was added to EtOAc (3 L), and the resulting precipitate was collected by filtration, washed with IPE, and dried under reduced pressure for 3 hours. Under ice cooling, the powder obtained in TFA (d = 1.480, 130 mL) was added and stirred for 2 hours. CH ₂ Cl ₂ (1 L) was added to the reaction solution under ice-cooling, and Et ₃ N (d = 0.726, 320.8 mL) was slowly added dropwise taking care to keep the internal temperature at 15 ° C. or lower. The reaction solution was concentrated under reduced pressure, and the resulting oil was added to water (4 L) containing 1 M NaOH aqueous solution (30 mL) with stirring under ice cooling. Further, 1M NaOH aqueous solution (20 mL) was added to adjust pH = 11. This solution was purified using ODS column chromatography (washed with H ₂ O, MeCN: pH7 standard buffer solution = 20% to 42%). Fractions containing the desired product were diluted in water and dissolved by adding 1M NaOH aqueous solution. This solution was desalted using ODS column chromatography (washed with H ₂ O, MeCN: H ₂ O = 4: 1), concentrated under reduced pressure, and freeze-dried to give the compound of Example 37 (16.89 g). Obtained.

The compounds of Examples 38 to 153 and 295 were prepared in the same manner as in Example 37.

Example 154
The compound of Production Example 35 (100 mg), glyoxylic acid hydrate (30 mg) and MS3A (300 mg) were suspended in DMF (1.5 mL) and stirred overnight at room temperature. The reaction was diluted with MeOH, MS3A was filtered off and washed with MeOH. The filtrate and the washing solution were combined and concentrated under reduced pressure, EtOAc was added to the residue, and the precipitated powder was collected by filtration and washed with EtOAc. The powder was dried, suspended in CH ₂ Cl ₂ , and TFA was added under ice cooling. The mixture was stirred for 3 hours while warming to room temperature. Et ₃ N was added under ice cooling to stop the reaction. Water was added to the residue obtained by concentration under reduced pressure. Further, 1 M NaOH aqueous solution, 10% -MeCN / H ₂ O was added to the suspension and dissolved. The mixture was purified by ODS (conditions: 15 mL of ODS silica, charged, then eluted with buffer, 10%, 20%, 30%, 40% MeCN / buffer (10R each). The fraction was concentrated and diluted with H ₂ O After elution (eluent: H ₂ O, 10% MeCN / H ₂ O, 50% MeCN / H ₂ O in this order), elution was carried out to obtain the desired product (45 mg) as a white powder.

Example 155
A mixture of the compound of Production Example 33-55 (50.0 mg), HBTU (30.2 mg), DMF (750 μL), and DIPEA (d = 0.742, 37.2 μL) was stirred at room temperature for 1 hour. The compound of Production Example 20 (63.8 mg) of International Publication WO03 / 068807 was added and stirred at room temperature for 6 hours. EtOAc was added to the reaction solution, and the resulting precipitate was collected by filtration. The solid obtained by drying under reduced pressure was added to TFA (d = 1.480, 2.00 mL) under ice cooling and stirred for 3 hours. The reaction solution was added dropwise to 7% MeCN water (100 mL). The mixture was purified by ODS silica gel chromatography (charged to 20 mL of ODS silica gel replaced with water and then eluted stepwise with 0, 5, 10, 15, 20% pH 2.0 hydrochloric acid: MeCN system). Lyophilization was performed to obtain the compound of Example 155 (47.3 mg) as a yellow solid.

The compounds of Examples 156 to 164 were prepared in the same manner as in Example 155.

Example 165
Ethyl 3-bromopropionate (5.45 μL), powdered K ₂ CO ₃ (11.6 mg) and NaI (6.3 mg) were added to a solution of the compound of Example 55 (60 mg) in DMF (450 μL), and the mixture was stirred at room temperature for 4 days. Stir. EtOAc was added to the reaction mixture, and the resulting precipitate was collected by filtration to give a crude ethyl ester intermediate as a white powder (84.3 mg). The crude ethyl ester intermediate was dissolved in water (600 μL), 1M aqueous NaOH solution (420 μL) was added, and the mixture was stirred at room temperature for 2 hr. After neutralization with 1M hydrochloric acid, purification was performed by ODS silica gel chromatography (eluent; MeCN: pH6.86 buffer = 27.5: 72.5). Fractions containing the desired product were collected and diluted approximately 2-fold with water, then desalted by ODS column chromatography, and MeCN was concentrated under reduced pressure and lyophilized to obtain the compound of Example 165 (15.0 mg) as a white amorphous product. Got as.

Example 166
1,3-propane sultone (9 mg) was added to a DMF (750 μL) solution of the compound of Example 55 (100 mg), and the mixture was stirred at room temperature for 20 hours. 1,3-propane sultone (9 mg) was added, and the mixture was stirred at room temperature for 20 hours. 1,3-propane sultone (9 mg) was further added, and the mixture was warmed to 50 ° C. and stirred for 3 days. The reaction mixture was allowed to cool to room temperature, water (50 mL) was added, and the mixture was purified by ODS silica gel chromatography (eluent; MeCN: pH 6.86 buffer = 25: 75 to 27.5: 72.5). Fractions containing the desired product were collected, diluted with water approximately twice, and then desalted with ODS column chromatography.MeCN was concentrated under reduced pressure and lyophilized to obtain the compound of Example 166 (8.46 mg) as a white amorphous substance. Obtained.

Example 167
TFA was added to the compound of Production Example 10-19 (115 mg) and stirred at room temperature for 1 hour, and Et ₃ N was added under ice cooling. The mixed solution was concentrated under reduced pressure, and a 20% aqueous MeCN solution was added to form a suspension. A 1M NaOH aqueous solution was added to adjust the pH to about 9.5, and the solution was completely dissolved. This aqueous solution was purified by ODS column chromatography (eluent; MeCN: pH 6.8 buffer = 20: 80 to 80:20). The obtained aqueous solution was again subjected to ODS column chromatography to remove salts and replace the solvent with MeCN. The obtained solution was concentrated under reduced pressure, and the remaining aqueous solution was lyophilized to obtain the compound of Example 167 (89 mg) as a white powder.

The compounds of Examples 168 to 178 were prepared in the same manner as in Example 167.

Example 180
A 10% HCl / MeOH solution (1.48 mL) was suspended in a solution of the compound of Example 37 (50 mg) in MeOH (1.5 mL). The reaction mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting solid was pulverized by adding EtOAc. The precipitate was collected by filtration, washed with EtOAc, and dried to give the compound of Example 180 (29 mg).

The compounds of Examples 179 and 181 were prepared in the same manner as in Example 180.

Example 182
A mixture of the compound of Example 156 (50 mg), 1H-pyrazole-1-carboxamidine hydrochloride (12.9 mg), DMF (250 μL), DIPEA (d = 0.742, 24.6 μL) was stirred at room temperature overnight. MeCN was added to the reaction solution until water was added and dissolved. The mixture was purified by ODS silica gel chromatography (ODS silica gel 15 mL, eluent; hydrochloric acid water of 0% to 65% pH 2.0: MeCN system). Lyophilization was performed to obtain the compound of Example 182 (34.2 mg) as a white powder.

Example 183
To a mixture of the compound of Example 55 (103 mg), 1,4-dioxane-2,5-diol (17.3 mg), CHCl ₃ (3 mL), MeOH (1 mL), MS3A (154.5 mg), NaBH ₃ CN ( 10 mg) and AcOH (14 μL) were added. The mixture was stirred at room temperature for 3 hours. MS3A was filtered off and concentrated under reduced pressure. The residue was suspended in a solution of MeCN: H ₂ O = about 1:10, adjusted to pH 8-9 (pH test paper) with 1M NaOH, and dissolved. This solution was subjected to ODS medium pressure column chromatography (washing: MeCN: H ₂ O = 1: 9, MeCN: (pH 6.86 standard buffer solution) = 1: 9, elution: MeCN: (pH 6.86 standard buffer solution) = 1: 4, 3: 7). Fractions containing the desired product were collected, diluted approximately 1.5 times with H ₂ O, and ODS medium pressure column chromatography (washing solution: MeCN: H ₂ O = 1: 9, eluent; MeCN: H ₂ O = 4: 1) ) And then concentrated under reduced pressure. The fraction containing the desired product was concentrated under reduced pressure, and the residue containing water was lyophilized to obtain the compound of Example 183 (73.8 mg) as a powder.

The compounds of Examples 184 to 294 were prepared in the same manner as in Example 183. Of these, Example 199 was salted to obtain a hydrochloride.

The compounds of Examples and Production Examples shown in the table below were produced in the same manner as in the above Examples or Production Examples. For the production example compounds and the example compounds, structures, physicochemical data and production methods are shown, respectively. In the table, Pr represents the production example number and Ex represents the example number. Ref-Pr represents a production example number that can be produced by reference, and Ref-Ex represents an example number that can be produced by reference. However, in the Ref-Pr, an example number that can be manufactured by reference may be described, and in this case, the Ex number is described. In Ref-Ex, a production example number that can be produced by reference may be described, in which case it is indicated by a Pr number. The column of STR represents the structural formula. In the column of DAT, ¹ H-NMR and / or MS data are described. NMR1 = d ₆ -DMSO chemical shift values of ¹ H-NMR measured in _{(δ), NMR2 = d 6} -DMSO + D 2 O The chemical shift values of ¹ H-NMR measured in ([delta]), in NMR3 = CDCl3 ¹ shows the ¹ H-NMR chemical shift value (δ) measured in ( ¹ ). ESI and EI represent mass analysis values by electrospray ionization method and mass analysis values by electron ionization method, respectively, and mean positive or positive when ESI and EI data are not described. APCI indicates atmospheric pressure chemical ionization mass spectrometry, and APCI / ESI means mass spectrometry values measured simultaneously with APCI and ESI.

The compound of the formula (I) or a salt thereof has antifungal activity and has various infectious diseases such as dermatophytosis (e.g. ringworm), vermiculitis, candidiasis, geotrichumosis, sandy hair, Aspergillus , Penicillosis, sporotricosis, chromomises, coccidioidomycosis, histoplasmosis, blastosomiasis, paracoccidioidomycosis, pseudoaleseriasis, foot mycosis, fungal keratitis, otomycosis, pneumocystis, fungi It is useful for the prevention and / or treatment of blood pressure.

Claims (21)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof.
   

   

   
   Wherein R ¹ is -NH ₂ , -OH, -NH-lower alkylene-NH ₂ , -lower alkylene-NH-lower alkyl, -lower alkylene-N (lower alkyl) ₂ , -NH-lower alkylene- C (= O) OH or -NHCH (OH) C (= O) OH,
   R ² is -S (= O) ₂ OH, -CH ₂ CH (OH) CH ₂ OH, -lower alkylene-C (= O) OH, lower alkyl, or H,
   A ring is a nitrogen-containing heterocyclic group, aryl, or cycloalkyl,
   R ^A is H, -lower alkyl, -lower alkylene-NH ₂ , -lower alkylene-NH-lower alkyl, -lower alkylene-N (lower alkyl) ₂ , -lower alkylene-OH, -lower alkylene-O-lower Alkyl, -lower alkylene-C (= O) OH, -lower alkylene-S (= O) ₂ OH, -lower alkylene-S (= O) ₂ O-lower alkyl, -C (= O) O-lower alkyl , -C (= O) -lower alkylene-NH ₂ , -C (= O) -lower alkylene-NH-lower alkyl, -C (= O) -lower alkylene-N (lower alkyl) ₂ , -C (= O) -lower alkylene optionally substituted with —NH ₂ , —C (═NH) —NH ₂ , —CH (lower alkylene-OH) ₂ , or cycloalkyl,
   X is a single bond, lower alkylene, -NH-, or -N (lower alkyl)-
   R ^B and R ^C are the same or different, and H or halogen,
   Ring B is represented by the following formula (II), formula (III-a), or formula (III-b),
   

   

   
   A group represented by
   * Indicates the position at which the group bonds to X in formula (I), ** indicates the position at which the group bonds to R ^B in the formula (I),
   Ring D is a nitrogen-containing heteroaryl,
   R ^D represents the following formulas (IV) to (VI)
   

   

   
   Or a group represented by -LOR ¹⁰¹ ,
   L is lower alkylene, higher alkylene, -O-, -O-lower alkylene, or a single bond,
   E ring is a heterocyclic group,
   F ring and F1 ring are the same or different and each represents cycloalkyl,
   Fg ring is cycloalkyl or aryl,
   Efg ring is a heterocyclic group, cycloalkyl or aryl,
   R ^E is H, lower alkyl, -O-lower alkyl, or halogen,
   R ¹⁰¹ represents lower alkyl, -lower alkylene-cycloalkyl, or -higher alkylene-cycloalkyl,
   R ^Z1 or R ^Z2 is the same or different and is ^optionally substituted with H, halogen, halogen or lower alkyl, aryl, lower alkyl, higher alkyl, —O-lower alkyl, —O-higher alkyl, —O -Cycloalkyl, -O-aryl, -O-lower alkylene-aryl, -higher alkylene-O-lower alkyl, cycloalkyl, or -C (= O) O-lower alkylene-aryl. )
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the A ring is a monocyclic saturated heterocyclic group or a monocyclic unsaturated heterocyclic ring.
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the A ring is a 6-membered nitrogen-containing heterocycloalkyl.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein the ring D is a monocyclic nitrogen-containing heteroaryl or a condensed polycyclic nitrogen-containing heteroaryl.
5. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the D ring is a 5- to 6-membered monocyclic nitrogen-containing heteroaryl.
6. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the ring D is a 5-membered to 5-membered condensed polycyclic nitrogen-containing heteroaryl or a 5-membered to 6-membered condensed polycyclic nitrogen-containing heteroaryl. Salt.
7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the B ring is a group represented by the formula (II).
8. The compound according to any one of claims 1 to 3, wherein the ring B is a group represented by the formula (II), and the ring D is a monocyclic nitrogen-containing heteroaryl or a condensed polycyclic nitrogen-containing heteroaryl, or a compound thereof A pharmaceutically acceptable salt.
9. The compound according to any one of claims 1 to 3, wherein the B ring is a group represented by the formula (II), and the D ring is a 5-membered to 5-membered condensed polycyclic nitrogen-containing heteroaryl, or a pharmaceutical thereof A chemically acceptable salt.
10. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein B ring is a group represented by formula (II) and D ring is a 5- to 6-membered monocyclic nitrogen-containing heteroaryl. Salt.
11. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ^D is a group represented by the formula (V).
12. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ^D is a group represented by formula (VI).
13. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the E ring in R ^D is nitrogen-containing heterocycloalkyl.
14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the E ring in R ^D is a 6-membered nitrogen-containing saturated heterocycloalkyl.
15. Hydrogen sulfate 5-{(2R) -2-[(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-Amino-1-hydroxy-3 -Oxopropyl] -2,11,15-trihydroxy-6-[(1R) -1-hydroxyethyl] -9- (3- [1- (2-hydroxyethyl) -1,2,3,6- Tetrahydropyridin-4-yl] -4 '-{2- [4- (2-phenylethyl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazol-6-yl} [1,1'-biphenyl] -4-carboxamide) -16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipirolo [2,1-c: 2 ', 1 '-l] [1,4,7,10,13,16] hexaazacyclohenicosin-23-yl] -2-hydroxyethyl} -2-hydroxyphenyl ester,
    Hydrogen sulfate 5-{(2R) -2-[(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-Amino-1-hydroxy-3 -Oxopropyl] -2,11,15-trihydroxy-6-[(1R) -1-hydroxyethyl] -9- (3- [1- (2-hydroxyethyl) -1,2,3,6- Tetrahydropyridin-4-yl] -4 '-{5- [4- (2-phenylethyl) piperazin-1-yl] pyrimidin-2-yl} [1,1'-biphenyl] -4-carboxamide) -16 -Methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrolo [2,1-c: 2 ', 1'-l] [1,4,7,10,13, 16] hexaazacyclohenicosin-23-yl] -2-hydroxyethyl} -2-hydroxyphenyl ester,
    Hydrogen sulfate 5-[(2R) -2-{(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-Amino-1-hydroxy-3 -Oxopropyl] -9- {4 '-(5- {4-[(4,4-dimethylcyclohexyl) oxy] piperidin-1-yl} -1,2,4-oxadiazol-3-yl)- 3- [1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl] [1,1'-biphenyl] -4-carboxamide} -2,11,15-trihydroxy- 6-[(1R) -1-hydroxyethyl] -16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrolo [2,1-c: 2 ', 1' -l] [1,4,7,10,13,16] hexaazacyclohenicosin-23-yl} -2-hydroxyethyl] -2-hydroxyphenyl ester and N-{(2R, 6S, 9S, 11R, 14aS, 15S, 16S, 20S, 23S, 25aS) -20-[(1R) -3-Amino-1-hydroxy-3-oxopropyl] -2,11,15-trihydroxy-6-[(1R ) -1-hydroxyethyl] -23-[(1R) -1-hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethyl] -16-methyl-5,8,14,19,22,25- Hexa Xotetracosahydro-1H-dipyrolo [2,1-c: 2 ', 1'-l] [1,4,7,10,13,16] hexaazacyclohenicosin-9-yl} -4' -(5- {4- [2- (4-Ethoxyphenyl) ethyl] piperazin-1-yl} pyrimidin-2-yl) -3- (1,2,3,6-tetrahydropyridin-4-yl) [ A compound selected from the group consisting of 1,1′-biphenyl] -4-carboxamide or a pharmaceutically acceptable salt thereof.
    
16. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.
17. The pharmaceutical composition according to claim 16, which is a pharmaceutical composition for preventing or treating fungal infection.
18. Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for preventing or treating fungal infections.
19. Use of the compound according to claim 1 or a salt thereof for prevention or treatment of fungal infection.
20. The compound according to claim 1 or a salt thereof for the prevention or treatment of fungal infection.
21. A method for preventing or treating a fungal infection comprising administering an effective amount of the compound or salt thereof according to claim 1 to a subject.