TRIAZOLE DERIVATIVE

Info

Publication number: 20110269960
Type: Application
Filed: Jul 11, 2011
Publication Date: Nov 3, 2011
Applicant: TAISHO PHARMACEUTICAL CO., LTD. (Tokyo)
Inventors: Naoya ONO (Tokyo), Tetsuo Takayama (Tokyo), Fumiyasu Shiozawa (Tokyo), Hironori Katakai (Tokyo), Tetsuya Yabuuchi (Tokyo), Tomomi Ota (Tokyo), Makoto Yagi (Tokyo), Masakazu Sato (Tokyo)
Application Number: 13/180,011

Abstract

An object of the present invention is to provide a compound having an action of inhibiting binding between S1P and its receptor, Edg-1 (S1P1), and is useful as a pharmaceutical compound. A compound or a pharmaceutically acceptable salt thereof, which compound is represented by the formula below (where A represents an oxygen atom, a sulfur atom, a group represented by Formula —SO—, a group represented by Formula —SO2—, or the like, R1 represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, or the like, R1A represents a hydrogen atom or the like, R2 represents an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or the like, R3 represents an aryl group, R4 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms and optionally substituted with a carboxyl group, and R5 represents an alkyl group having 1-10 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an aryl group which is optionally substituted, or the like).

Description

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. application Ser. No. 12/278,054 filed Aug. 1, 2008, which is a National Stage of International Application No. PCT/JP2007/051951 filed Feb. 5, 2007, which claims priority to Japanese Application No. 2006/027799, filed Feb. 3, 2006. The contents of all of the prior applications are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to novel triazole derivatives which have an inhibitory effect on the binding between sphingosine-1-phosphate having various physiological actions and its receptor Edg-1 (Endothelial differentiation gene receptor type-1, S1P1). The present invention also relates to pharmaceutical preparations comprising these compounds as active ingredients, and synthetic intermediates for these compounds.

BACKGROUND ART

Sphingosine-1-phosphate (hereinafter referred to as “SIP”) is a physiologically active lipid which is generated when sphingolipids (typified by sphingomyelin) are metabolized in cells. SIP is known to have a wide variety of actions such as cell differentiation induction, cell growth stimulation, cell motility inhibition and apoptosis inhibition, and is also known to show physiological actions such as angiogenesis, bradycardia induction, inflammatory cell activation and platelet activation (Non-patent Document 1).

As SIP receptors, the following 5 subtypes have been reported: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4) and Edg-8(S1P5) (Non-patent Document 2).

Among these subtypes, Edg-1(S1P1) is highly expressed in immunocytes (e.g., T cells, dendritic cells) and vascular endothelial cells, suggesting that Edg-1 (S1P1) contributes deeply to SIP-stimulated T cell migration (Non-patent Document 3), mast cell migration (Non-patent Document 4), T and B cell egress from lymphoid organs (Non-patent Document 5) and angiogenesis (Non-patent Document 6), and is involved in autoimmune diseases such as Crohn's disease, irritable colitis, Sjogren's syndrome, multiple sclerosis and systemic lupus erythematosus, as well as other diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age-related macular degeneration, etc.

Thus, ligands for Edg-1(S1P1) would be effective for treatment or prevention of these diseases.

Edg-1(S1P1) ligands previously known include certain types of thiophene derivatives (Non-patent Document 7), phosphoric acid derivatives (Patent Documents 1 and 2, Nonpatent Documents 8 and 9) and thiazolidine derivatives (Patent Document 3), carboxylic acid derivatives (Patent Documents 4, 5, 6 and 8, Non-patent Documents 10 and 11), amino group-containing derivatives (Patent Document 7), and pyrrole derivatives (Patent Document 9).

Patent Document 1: WO2002-18395
Patent Document 2: JP 2003-137894 A
Patent Document 3: JP 2002-332278 A
Patent Document 4: WO2002-092068
Patent Document 5: WO2003-105771
Patent Document 6: WO2004-058149
Patent Document 7: WO2004-103279
Patent Document 8: WO2005-058848
Patent Document 9: WO2005-123677
Non-patent Document 1: J Biol Chem. 2004, 279: 20555, FASEB J 2002, 16: 625, Proceedings of the Japanese Society for Immunology 2003, 33: 2-J-W30-20-P
Non-patent Document 2: Pharmacol Res 2003, 47: 401
Non-patent Document 3: FASEB J 2002, 16:1874
Non-patent Document 4: J Exp Med 2004, 199: 959
Non-patent Document 5: Nature 2004, 427: 355
Non-patent Document 6: J Clin Invest 2000, 106: 951, Biocchim Biophys Acta 2002, 1582: 222
Non-patent Document 7: J Biol Chem 2004, 279: 13839
Non-patent Document 8: Bioorg Med Chem Lett 2003, 13: 3401
Non-patent Document 9: J Med Chem. 2004, 47: 6662
Non-patent Document 10: J Med Chem. 2005, 48: 6169
Non-patent Document 11: J Biol Chem. 2005; 280: 9833

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The present invention has as an object to provide a compound with a new skeletal structure, which compound has an action of inhibiting binding between S1P and its receptor Edg-1 (S1P₁) and is useful as a pharmaceutical product.

Means for Solving the Problems

The inventors of the present invention have diligently studied in an attempt to find ligand compounds for Edg-1 (S1P₁). As a result, they find that the object is attained with a triazole derivative of Formula (I) below or a pharmaceutically acceptable salt thereof (a feature is that R³in the formula is an optionally substituted aryl group). This finding has led to the accomplishment of the present invention. The triazole derivative of Formula (I) below with this feature is a completely new compound. Although compounds having an alkyl group corresponding to R³of Formula (I) are commercially available from Bionet as reagents, they differ in structure from that of the compound of the subject application, and pharmaceutical use of the compounds of Bionet has not been known at all.

The following are embodiments of the triazole derivatives of Formula (I) and compounds of Formula (II), which are intermediates of the triazole derivatives (hereinafter, all of them will be referred to as “compounds of the present invention”).

1. A compound represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
A represents:

- an oxygen atom,
- a sulfur atom,
- a group represented by Formula —SO—,
- a group represented by Formula —SO₂—,
- a group represented by Formula —CH₂—, or
- a group represented by Formula —NR⁶—, wherein R⁶represents
  a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
  R¹represents:
- a hydrogen atom,
- an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
  - a hydroxyl group,
  - a halogen atom,
  - an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and
  - a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,
- a cycloalkyl group having from 3 to 8 carbon atoms,
- an alkenyl group having from 2 to 8 carbon atoms,
- an alkynyl group having from 2 to 8 carbon atoms, or a phenyl group;
  R^1Arepresents:
- a hydrogen atom or
- an alkyl group having from 1 to 6 carbon atoms;
  R¹and R^1Aoptionally form, together with a carbon atom to which said R¹and R^1Aare attached, a cycloalkyl group having from 3 to 6 carbon atoms;
  R²represents:
- a hydrogen atom,
- an alkyl group having from 1 to 6 carbon atoms,
- an alkenyl group having from 2 to 8 carbon atoms,
- an alkynyl group having from 2 to 8 carbon atoms, or
- a cycloalkyl group having from 3 to 6 carbon atoms;
  R³represents an optionally substituted aryl group;
  R⁴represents:
- a hydrogen atom or
- an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a carboxyl group;
  R⁵represents:
- (i) an alkyl group having from 1 to 10 carbon atoms,
- (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
  - a cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group, and
  - a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms,
- (iii) a cycloalkyl group having from 3 to 8 carbon atoms,
- (iv) an alkenyl group having from 2 to 8 carbon atoms,
- (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
- (vi) an alkynyl group having from 2 to 8 carbon atoms,
- (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or
- (viii) an optionally substituted aryl group.
  2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein, in Formula (I):
  R¹represents:
- a hydrogen atom,
- an alkyl group having from 1 to 6 carbon atoms,
- an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,
- a cycloalkyl group having from 3 to 8 carbon atoms,
- an alkenyl group having from 2 to 8 carbon atoms,
- an alkynyl group having from 2 to 8 carbon atoms, or
- a phenyl group;
  R^1Arepresents a hydrogen atom;
  R²represents:
- an alkyl group having from 1 to 6 carbon atoms,
- an alkenyl group having from 2 to 8 carbon atoms,
- an alkynyl group having from 2 to 8 carbon atoms, or
- a cycloalkyl group having from 3 to 6 carbon atoms;
  R⁴represents:
- a hydrogen atom, or
- an alkyl group having from 1 to 6 carbon atoms;
  R⁵represents:
- (i) an alkyl group having from 1 to 10 carbon atoms,
- (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
  - a cycloalkyl group having from 3 to 8 carbon atoms, a phenyl group,
  - a naphthyl group,
  - a pyridyl group, and
  - a phenyl group substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms,
- (iii) a cycloalkyl group having from 3 to 8 carbon atoms,
- (iv) an alkenyl group having from 2 to 8 carbon atoms,
- (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
- (vi) an alkynyl group having from 2 to 8 carbon atoms,
- (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or
- (viii) an optionally substituted aryl group.
  3. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an oxygen atom or a group represented by Formula —NR⁶—.
  4. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an oxygen atom.
  5. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is a group represented by Formula —NH—.
  6. The compound of any one of Embodiments 1 and 3-5, or a pharmaceutically acceptable salt thereof, wherein:
  R¹represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
- a hydroxyl group,
- a halogen atom,
- an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group; and
- a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
  R^1Arepresents:
- a hydrogen atom; or
- an alkyl group having from 1 to 6 carbon atoms; and
  R¹and R^1Aoptionally form, together with a carbon atom to which said R¹and R^1Aare attached, a cycloalkyl group having from 3 to 6 carbon atoms.
  7. The compound of any one of Embodiments 1 and 3-5, or a pharmaceutically acceptable salt thereof, wherein:

R¹is:

an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or

a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and

R^1Ais a hydrogen atom.
8. The compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R¹is a methyl group or an ethyl group, and R^1Ais a hydrogen atom.
9. The compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R⁴is a hydrogen atom.
10. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R²is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms.
11. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R²is an ethyl group or a cyclopropyl group.
12. The compound of any one of Embodiments 1 and 3-11, or a pharmaceutically acceptable salt thereof, wherein R⁵is:

- (i) an alkyl group having from 1 to 10 carbon atoms,
- (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
  - a cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group, and
  - a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms;
- (iii) an alkenyl group having from 2 to 8 carbon atoms and optionally substituted with a phenyl group, or
- (iv) a phenyl group, a naphthyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a furanyl group, a benzothienyl group, an isoquinolinyl, an isoxazolyl group, a thiazolyl group, a benzothiadiazolyl group, a benzoxadiazolyl group, a dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group, an uracil group, a coumaryl group, a chromanyl group, a dihydroindolyl group, a tetrahydronaphthyl group, or a tetrahydroisoquinolinyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
  - an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
  - an alkenyl group having from 2 to 8 carbon atoms, a halogen atom,
  - an alkoxy group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
  - a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiadiazolyl group, and a pyrimidinyl group, each optionally substituted with a substituent(s) selected from Group X consisting of a methyl group, a trifluoromethyl group, a halogen atom, and a methylsulfanyl group,
  - an alkylthio group having from 1 to 6 carbon atoms,
  - an alkylsulfonyl group having from 1 to 6 carbon atoms,
  - a benzenesulfonyl group,
  - a morpholinosulfonyl group,
  - a morpholinocarbonylamino group,
  - an aminosulfonyl group,
  - an alkoxycarbonyl group having from 2 to 10 carbon atoms,
  - a morpholino group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms
  - a phenyl group optionally substituted with an alkoxy group(s) having from 1 to 6 carbon atoms,
  - a phenoxy group,
  - a pyridinecarbonyl group,
  - a pyridineoxy group,
  - a cyano group,
  - an alkanoyl group having from 2 to 7 carbon atoms and optionally substituted with a fluorine atom(s), and
  - an alkanoylamino group having from 2 to 7 carbon atoms.
    13. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R⁵is:

an alkyl group having from 1 to 10 carbon atoms and substituted with a cycloalkyl group having from 3 to 8 carbon atoms,

an alkyl group having from 1 to 10 carbon atoms and substituted with a naphthyl group,

an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,

a phenyl group or a naphthyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:

- an alkyl group having from 1 to 6 carbon atoms;
- a halogen atom,
- an alkoxy group having from 1 to 6 carbon atoms;
- a trifluoromethoxy group,
- a difluoromethoxy group,
- a trifluoromethyl group,
- an alkenyl group having from 1 to 6 carbon atoms,
- an alkylsulfonyl group having from 1 to 6 carbon atoms,
- an alkanoyl group having from 2 to 7 carbon atoms,
- an alkoxycarbonyl group having from 2 to 7 carbon atoms, and
- a cyano group,

a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a methoxycarbonyl group;

a furanyl group optionally selected from a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;

a thienyl group optionally substituted with a substituent (s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or

a benzothienyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.

14. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R⁵is:

an alkyl group having from 1 to 6 carbon atoms and substituted with a naphthyl group,

an alkenyl group having from 2 to 6 carbon atoms and substituted with a phenyl group;

an unsubstituted phenyl group,

a phenyl group substituted with 1 to 5 substituents selected from the group consisting of a methyl group, a methoxy group, and a halogen atom,

a phenyl group substituted with 1 to 3 substituents selected from the group consisting of:

- an alkyl group having from 1 to 6 carbon atoms,
- a halogen atom,
- a methoxy group,
- a trifluoromethoxy group,
- a difluoromethoxy group,
- a trifluoromethyl group,
- an alkenyl group having from 1 to 6 carbon atoms,
- a methylsulfonyl group,
- an acetyl group,
- a methoxycarbonyl group, and
- a cyano group,
- said phenyl group substituted at either 3 or 4 position or both;

a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of:

- a halogen atom,
- an alkyl group having from 1 to 6 carbon atoms,
- a cyano group, and
- an alkylsulfonyl group having from 1 to 6 carbon atoms, or

a benzothienyl group, a benzoxadiazolyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, an indanyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom. 15. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R⁵is:

a phenyl group substituted at 3 and 4 positions each with a halogen atom, or

a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano group.

16. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R³is a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl group, each optionally substituted with 1 to 3 substituents selected from the group consisting of the following substituents:

an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),

a cycloalkyl group having from 3 to 8 carbon atoms,

a halogen atom,

an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of a fluorine atom, a phenyl group, an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and a morpholino group;

a phenoxy group,

a phenyl group,

a carboxyl group,

an alkoxycarbonyl group having from 2 to 10 carbon atoms,

a hydroxyl group,

a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,

a nitrogen-containing monocylic unsaturated hydrocarbon group,

a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,

a piperazino group optionally substituted with a substituent(s) selected from the group consisting of:

- an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
- a formyl group,
- an alkanoyl group having from 2 to 7 carbon atoms,
- a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
- an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, and
- an alkylsulfonyl group having from 1 to 6 carbon atoms, and

Formula —NR⁷R⁸, wherein:

- R⁷and R⁸each represent:
- a hydrogen atom,
- an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
- an alkanoyl group having from 1 to 6 carbon atoms,
- a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
- a morpholinocarbonyl group,
- an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
- an alkylsulfonyl group having from 1 to 6 carbon atoms, or
- R⁷and R⁸optionally form, together with the nitrogen atom to which said R⁷and R⁸are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  17. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R³is:

a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,

a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or

a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,

an unsubstituted phenyl group, or

a substituted phenyl group (A), (B), or (C) below:

(A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of:

- an alkyl group having from 1 to 6 carbon atoms,
- a cycloalkyl group having from 3 to 8 carbon atoms,
- an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
- a halogen atom,
- a trifluoromethoxy group,
- a phenoxy group,
- a phenyl group,
- a 1-pyrrolyl group, and
- —NR^AR^B, wherein each of R^Aand R^Bis an alkyl group having from 1 to 6 carbon atoms, or R^Aand R^Boptionally form, together with the nitrogen atom to which said R^Aand R^Bare attached, a 3- to 5-membered saturated hydrocarbon ring,

wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms;

(B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of:

- a hydroxyl group,
- an alkyl group having from 1 to 6 carbon atoms, and
- an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,

wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom; and

(C) a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below, said phenyl group further optionally substituted at 4 position with a halogen atom:

- (i) a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
- (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group,
- (iii) a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
- (iv) a piperazino group, optionally substituted with an alkanoyl group having from 2 to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
  - an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and
  - a morpholino group, and
- (v) Formula —NR⁷R⁸, wherein:
  - R⁷and R⁸each represent:
  - a hydrogen atom,
  - an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms, an alkanoyl group having from 1 to 6 carbon atoms,
  - a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
  - a morpholinocarbonyl group,
  - an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
  - an alkylsulfonyl group having from 1 to 6 carbon atoms, or
- R⁷and R⁸optionally form, together with the nitrogen atom to which said R⁷and R⁸are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  18. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R³is a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below, said phenyl group further optionally substituted at 4 position with a halogen atom:

(i) a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,

(ii) a nitrogen-containing monocylic unsaturated hydrocarbon group,

(iii) a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,

(iv) a piperazino group, optionally substituted with an alkanoyl group having from 2 to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:

- an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and
- a morpholino group, and

(v) Formula —NR⁷R⁸, wherein:

- R⁷and R⁸each represent:
- a hydrogen atom,
- an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
- an alkanoyl group having from 1 to 6 carbon atoms,
- a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
- a morpholinocarbonyl group,
- an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
- an alkylsulfonyl group having from 1 to 6 carbon atoms, or

R⁷and R⁸optionally form, together with the nitrogen atom to which said R⁷and R⁸are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.

19. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R³is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom.
20. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R³is a 6-indolyl group.
21. A pharmaceutical preparation, comprising the compound of any one of Embodiments 1-20 or a pharmaceutically acceptable salt thereof.
22. The pharmaceutical preparation of Embodiment 21, which is for treatment of an autoimmune disease, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, or age-related macular degeneration.
23. A compound represented by Formula (II)

or a salt thereof, wherein R¹, R^1A, R², and R³are as defined in Embodiment 1, and A′ represents an oxygen atom or NH.
24. The compound of Embodiment 23, or a salt thereof, wherein, in Formula (II):
A′ represents an oxygen atom;
R¹represents:

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms,

an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,

a cycloalkyl group having from 3 to 8 carbon atoms,

an alkenyl group having from 2 to 8 carbon atoms,

an alkynyl group having from 2 to 8 carbon atoms, or

a phenyl group;

R^1Arepresents a hydrogen atom; and
R²represents:

an alkyl group having from 1 to 6 carbon atoms,

an alkenyl group having from 2 to 8 carbon atoms,

an alkynyl group having from 2 to 8 carbon atoms, or

a cycloalkyl group having from 3 to 6 carbon atoms.

25. The compound of Embodiment 23, or a salt thereof, wherein, in Formula (II):
A′ represents NH;
R¹represents:

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms,

an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,

a cycloalkyl group having from 3 to 8 carbon atoms,

an alkenyl group having from 2 to 8 carbon atoms,

an alkynyl group having from 2 to 8 carbon atoms, or

a phenyl group;

R^1Arepresents a hydrogen atom; and
R²represents:

an alkyl group having from 1 to 6 carbon atoms,

an alkenyl group having from 2 to 8 carbon atoms,

an alkynyl group having from 2 to 8 carbon atoms, or

a cycloalkyl group having from 3 to 6 carbon atoms.

26. The compound of Embodiment 23, or a salt thereof, wherein:
R¹represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:

a hydroxyl group,

a halogen atom,

an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and

a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;

R^1Arepresents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; and
R¹and R^1Aoptionally form, together with a carbon atom to which said R¹and R^1Aare attached, a cycloalkyl group having from 3 to 6 carbon atoms.
27. The compound of Embodiment 23, or a salt thereof, wherein:
R¹is an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and
R^1Ais a hydrogen atom.
28. The compound of any one of Embodiments 23-25, or a salt thereof, wherein R¹is a methyl group or an ethyl group, and R^1Ais a hydrogen atom.
29. The compound of any one of Embodiments 23-28, or a salt thereof, wherein R²is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 8 carbon atoms.
30. The compound of any one of Embodiments 23-28, or a salt thereof, wherein R²is an ethyl group or a cyclopropyl group.
31. The compound of any one of Embodiments 23-30, or a salt thereof, wherein:

R³is a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl group, each optionally substituted with 1 to 3 substituents selected from the group consisting of the following substituents:

an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),

a cycloalkyl group having from 3 to 8 carbon atoms,

a halogen atom,

an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of a fluorine atom, a phenyl group, an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and a morpholino group, a phenoxy group,

a phenyl group,

a carboxyl group,

an alkoxycarbonyl group having from 2 to 10 carbon atoms,

a hydroxyl group,

a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms;

a nitrogen-containing monocylic unsaturated hydrocarbon group,

a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,

a piperazino group optionally substituted with a substituent(s) selected from the group consisting of:

- an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
- a formyl group,
- an alkanoyl group having from 2 to 7 carbon atoms,
- a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
- an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, and
- an alkylsulfonyl group having from 1 to 6 carbon atoms; and

Formula —NR⁷R⁸, wherein:

- R⁷and R⁸each represent:
- a hydrogen atom,
- an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
- an alkanoyl group having from 1 to 6 carbon atoms,
- a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
- a morpholinocarbonyl group,
- an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
- an alkylsulfonyl group having from 1 to 6 carbon atoms, or

R⁷and R⁸optionally form, together with the nitrogen atom to which said R⁷and R⁸are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.

32. The compound of any one of Embodiments 23-30, or a salt thereof, wherein R³is:

a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;

a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;

a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms;

an unsubstituted phenyl group; or

a substituted phenyl group (A), (B), or (C) below:

(A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of:

- an alkyl group having from 1 to 6 carbon atoms,
- a cycloalkyl group having from 3 to 8 carbon atoms,
- an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
- a halogen atom,
- a trifluoromethoxy group,
- a phenoxy group,
- a phenyl group,
- a 1-pyrrolyl group, and
- —NR^AR^B, wherein each of R^Aand R^Bis an alkyl group having from 1 to 6 carbon atoms, or R^Aand R^Boptionally form, together with the nitrogen atom to which said R^Aand R^Bare attached, a 3- to 5-membered saturated hydrocarbon ring,

wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms;

(B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of:

- a hydroxyl group,
- an alkyl group having from 1 to 6 carbon atoms, and
- an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,

wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom; and

(C) a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below, said phenyl group further optionally substituted at 4 position with a halogen atom:

- (i) a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
- (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group,
- (iii) a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
- (iv) a piperazino group, optionally substituted with an alkanoyl group having from 2 to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
  - an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms; and
  - a morpholino group, and
- (v) Formula —NR⁷R⁸, wherein:
  - R⁷and R⁸each represent:
    - a hydrogen atom,
    - an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms;
    - an alkanoyl group having from 1 to 6 carbon atoms,
    - a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
    - a morpholinocarbonyl group,
    - an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
    - an alkylsulfonyl group having from 1 to 6 carbon atoms, or
  - R⁷and R⁸optionally form, together with the nitrogen atom to which said R⁷and R⁸are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.

The present invention is described in detail as follows.

The term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The term “alkyl group having from 1 to 6 carbon atoms” refers to a linear or branched alkyl group containing 1 to 6 carbon atoms. Examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a n-hexyl group.

The term “cycloalkyl group having from 3 to 8 carbon atoms” refers to a cycloalkyl group containing 3 to 8 carbon atoms. Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The term “alkenyl group having from 2 to 8 carbon atoms” refers to a linear or branched alkenyl group containing 2 to 8 carbon atoms. Examples include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1,3-butadienyl group, a 2-methylallyl group, a 2-methyl-propenyl group, a 2-pentenyl group, and a 3-methyl-but-2-enyl group.

The term “alkynyl group having from 2 to 8 carbon atoms” refers to a linear or branched alkynyl group containing 2 to 8 carbon atoms. Examples include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 1-methyl-prop-2-ynyl group, a 2-pentynyl group, and a 4-pentynyl group.

The term “alkoxy group having from 1 to 6 carbon atoms” refers to a linear or branched alkoxy group containing 1 to 6 carbon atoms. Examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.

The term “alkyl group having from 1 to 10 carbon atoms” refers to a linear or branched alkyl group containing 1 to 10 carbon atoms. Examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, and a n-hexadecyl group.

The term “alkylthio group having from 1 to 6 carbon atoms” refers to a linear or branched alkylthio group containing 1 to 6 carbon atoms. Examples include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, and a hexylthio group.

The term “alkylsulfonyl group having from 1 to 6 carbon atoms” refers to a linear or branched alkylsulfonyl group containing 1 to 6 carbon atoms. Examples include a methanesulfonyl group, an ethanesulfonyl group, a propane-2-sulfonyl group, and a hexanesulfonyl group.

The term “alkoxycarbonyl group having from 2 to 10 carbon atoms” refers to a linear or branched alkoxycarbonyl group containing 2 to 10 carbon atoms. Examples include alkanoyl group having from 2 to 7 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group and a t-butoxycarbonyl group, as well as an octyloxycarbonyl group.

The term “alkanoyl group having from 2 to 7 carbon atoms” refers to a linear or branched alkanoyl group containing 2 to 7 carbon atoms. Examples include an acetyl group, a propanoyl group, a butanoyl group, and a hexanoyl group.

The term “alkanoyl group having from 1 to 6 carbon atoms” refers to a linear or branched alkanoyl group containing 1 to 6 carbon atoms. Examples include a formyl group, an acetyl group, a propanoyl group, and a butanoyl group.

The phrase “amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms” is intended to include, for example, an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a hexylamino group, a dimethylamino group, a diethylamino group, a diisopropylamino group, and a dihexylamino group.

The phrase “aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms” is intended to include, for example, a sulfamoyl group, a dimethylaminosulfonyl group, and a diethylaminosulfonyl group.

The phrase “carbamoyl group optionally substituted with an alkyl group(s) having from 1 to 4 carbon atoms” is intended to include a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, and a propylcarbamoyl group.

The phrase “piperazino group which may be substituted” or “optionally substituted piperazino group” refers to a piperazino group which may be substituted (preferably on its nitrogen atom) with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (wherein said alkyl group may be substituted with an amino group which may be substituted with one or two alkyl groups each having 1-6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having 1-6 carbon atoms), a formyl group, an alkanoyl group having 2-7 carbon atoms, a carbamoyl group which may be substituted with one or two alkyl groups each having 1-4 carbon atoms, an aminosulfonyl group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, and an alkylsulfonyl group having 1-6 carbon atoms. Specific examples include a piperazino group, a methylpiperazino group, an isopropylpiperazino group, a dimethylaminoethylpiperazino group, and an acetylpiperazino group.

The term “monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s)” means a 3- to 9-membered monocylic saturated hydrocarbon group containing one or two nitrogen atoms as ring-forming atoms and substituted at a ring carbon atom. Examples of the monocylic saturated hydrocarbon group include aziridinyl groups, azetidinyl groups, pyrrolidinyl groups, and piperidinyl groups (e.g., 4-piperidinyl groups).

The term “nitrogen-containing monocyclic unsaturated hydrocarbon group” refers to a 5- or 6-membered unsaturated ring containing 1 to 3 nitrogen atoms as its ring members. Examples include a pyrrolyl group (e.g., a pyrrol-1-yl group), an imidazol-1-yl group (e.g., an imidazolyl group), a pyrazolyl group, a triazol-4-yl group (e.g., a [1,2,4]triazol-4-yl group), and a pyridyl group.

The 3- to 5-membered saturated hydrocarbon ring formed by R^Aand R^Btogether with the nitrogen atom to which R^Aand R^Bare attached is intended to include an aziridinyl group, an azetidinyl group, and a pyrrolidinyl group.

The 3- to 8-membered saturated hydrocarbon ring formed by R⁷and R⁸(or R^Cand R^D) together with the nitrogen atom to which R⁷and R⁸(or R^Cand R^D) are attached is intended to include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group.

The term “aryl group” as used herein refers to an aromatic hydrocarbon group, a partially saturated aromatic hydrocarbon group, an aromatic heterocyclic group, or a partially saturated aromatic heterocyclic ring. The aromatic hydrocarbon group refers to, for example, an aromatic hydrocarbon group containing 6-14 carbon atoms, including a phenyl group, a naphthyl group, and an anthryl group.

The partially saturated aromatic hydrocarbon group refers to a group obtained by partial saturation of a polycyclic aromatic hydrocarbon group having 6-14 carbon atoms. Examples include a tetrahydronaphthyl group and an indanyl group.

The aromatic heterocyclic group refers to a monocylic or polycyclic aromatic heterocyclic group containing 2-13 carbon atoms and having 1-6 hetero atoms (e.g., oxygen, sulfur and/or nitrogen atoms). Examples include a thienyl group, a furanyl group, a pyrrolyl group, an isothiazolyl group, an isoxazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a benzothienyl group, a benzofuranyl group, an indolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, a quinolinyl group, an isoquinolinyl group, a benzoxadiazolyl group, a benzothiadiazolyl group, and a pyrazolopyrimidinyl group (e.g., a 5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl group).

The partially saturated aromatic heterocyclic ring refers to a heterocyclic ring obtained by partial saturation of a polycyclic aromatic heterocyclic group. Such a heterocyclic ring may be substituted with an oxo group. Examples include a dihydroquinolinonyl group:

a dihydrobenzofuranyl group, a dihydrobenzodioxinyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzoxazolyl group, and a dihydrobenzoxazinyl group.

In a case where such an aryl group is substituted, substituents for the aryl group include those listed below and the aryl group can be substituted with 1 to 5 of these substituents:

a halogen atom, a cyano group, a nitro group, a sulfamoyl group, a hydroxyl group, a carboxyl group, an alkyl group having 1-6 carbon atoms, a trifluoromethyl group, a methoxycarbonylethyl group, an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a phenyl group, an alkylamino group having 1-6 carbon atoms, a dialkylamino group having 2-12 carbon atoms, or a morpholino group), a trifluoromethoxy group, a difluoromethoxy group, a cyanoethoxy group,

an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms,

a cycloalkyl group having 3-8 carbon atoms, an alkanoyl group having 2-7 carbon atoms, a trifluoroacetyl group, an alkoxycarbonyl group having 2-10 carbon atoms,

a phenyl group (the phenyl group is optionally substituted with an alkanoyl group having 2-7 carbon atoms or an alkoxy group having 1-6 carbon atoms),

a phenoxy group optionally substituted with an alkoxy group having 1-6 carbon atoms,

a pyrazolyl group, a 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl group, a methylpyrimidinyl group, a 2-methylsulfanyl-pyrimidin-4-yl groups, an oxazolyl group (e.g., oxazol-5-yl group), an isooxazol-5-yl group, a 5-trifluoromethyl-isooxazol-3-yl group, a pyridyloxy group (e.g., 4-pyridyloxy group), a pyridinecarbonyl group, a benzoyl group, a pyrrolyl group (e.g., pyrrol-1-yl group), an imidazolyl group (e.g., imidazol-1-yl group), a thiazolyl group, a [1,2,3]thiadiazol-4-yl group, a triazolyl group (e.g., [1,2,4]triazol-4-yl group), an alkylthio group having 1-6 carbon atoms (e.g., methylthio group), an alkylsulfonyl group having 1-6 carbon atoms (e.g., methanesulfonyl group), a benzenesulfonyl group, a pyrrolidinesulfonyl group, a morpholinylsulfonyl group, a 4-piperidinyl group optionally substituted with an alkyl group having 1-6 carbon atoms, a morpholino group optionally substituted with an alkyl group having 1-6 carbon atoms, a piperazino group substituted with an alkyl group having 1-6 carbon atoms or an alkyl group having 1-6 carbon atoms and substituted with a dimethylamino group, or a group represented by Formula —NR⁷R⁸, where R⁷and R⁸each represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an alkoxy group having 1-6 carbon atoms or a dimethylamino group), an alkanoyl group having 1-6 carbon atoms, a carbamoyl group, a carbamoyl group substituted with an alkyl group(s) having 1-4 carbon atoms, a morpholinocarbonyl group, a dimethylaminosulfonyl group, or an alkylsulfonyl group having 1-6 carbon atoms, or R⁷and R⁸optionally form, together with the nitrogen atom to which R⁷and R⁸are attached, to form a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a dimethylenedioxy group, an oxo group, or a hydroxyl group, (e.g., acetamide groups, dimethylamino groups, methylureido groups, butylureido groups, trimethylureido groups, morpholinylcarbonylamino), a methoxyethylureido group, a pyridylethoxycarbonylamino group.

The term “pharmaceutically acceptable salt” refers to a salt with an alkali metal, an alkaline earth metal, ammonium or an alkylammonium, or a salt with a mineral acid or an organic acid. Examples include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an aluminum salt, a triethylammonium salt, an acetate salt, a propionate salt, a butyrate salt, a formate salt, a trifluoroacetate salt, a maleate salt, a tartrate salt, a citrate salt, a stearate salt, a succinate salt, an ethylsuccinate salt, a lactobionate salt, a gluconate salt, a glucoheptate salt, a benzoate salt, a methanesulfonate salt, an ethanesulfonate salt, a 2-hydroxyethanesulfonate salt, a benzenesulfonate salt, a paratoluenesulfonate salt, a lauryl sulfate salt, a malate salt, an aspartate salt, a glutamate salt, an adipate salt, a salt with cysteine, a salt with N-acetylcysteine, a hydrochloride salt, a hydrobromide salt, a phosphate salt, a sulfate salt, a hydroiodide salt, a nicotinate salt, an oxalate salt, a picrate salt, a thiocyanate salt, an undecanoate salt, a salt with an acrylate polymer, and a salt with a carboxyvinyl polymer.

The compounds of the present invention may have stereoisomers including optical isomers, diastereoisomers and geometrical isomers. All of these stereoisomers and mixtures thereof also fall within the scope of the present invention. Some of the compounds and intermediates of the present invention may also exist, e.g., as keto-enol tautomers.

As shown in Test Example below, the compounds of the present invention show strong activity in an action of inhibiting binding between SIP and its receptor, Edg-1 (S1P1). Thus, the compounds are expected to have preventive or therapeutic effects on autoimmune, diseases, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.

Preferred embodiments of the compound of the present invention are described as follows.

A preferred example of A is an oxygen atom or —NR⁶— (it is preferable that R⁶be hydrogen). A more preferred example of A is an oxygen atom.

A preferred example of R¹is an alkyl group having 1-6 carbon atoms which may be substituted with a halogen atom(s), or a benzyl group which may be substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having 1-6 carbon atoms. More preferred is a methyl group, an ethyl group, or a benzyl group which may be substituted with a halogen atom(s), and even more preferred is a methyl group.

A preferred example of R^1Ais a hydrogen atom.

Preferred examples of R²are an ethyl group and a cyclopropyl group.

A preferred example of R⁴is a hydrogen atom.

In a preferred embodiment, R³is: a optionally substituted phenyl group; a 2-naphthyl group (the naphthyl group is optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having 1-6 carbon atoms); a 3-pyrazolyl group (the pyrazolyl group is optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom); or a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group (preferably a 6-indolyl group), each optionally substituted with an alkyl group(s) having 1-6 carbon atoms (preferably a methyl group).

The “optionally substituted phenyl group” in the preferred embodiment of R³includes unsubstituted phenyl groups and substituted phenyl groups (A)-(C) below:

(A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having 1-4 carbon atoms, a morpholino group, and a phenyl group), a halogen atom, a trifluoromethoxy group, a phenoxy group, a phenyl group, a 1-pyrrolyl group, and —NR^AR^B(R^Aand R^Bare alkyl groups each having 1-6 carbon atoms, or R^Aand R^Boptionally form, together with the nitrogen atom to which R^Aand R^Bare attached, a 3- to 5-membered saturated hydrocarbon ring), which phenyl group substituted at 4 position is optionally further substituted at 3 position with a substituent selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, and an alkoxy group having 1-6 carbon atoms;
(B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of a hydroxyl group, an alkyl group having 1-6 carbon atoms, and an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having 1-4 carbon atoms, a morpholino group, and a phenyl group), which phenyl group substituted at 3 position is optionally further substituted with one or two alkyl groups each having 1-6 carbon atoms, or is optionally further substituted at 4 position with a halogen atom; and
(C) a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below and, in some cases, optionally further substituted at 4 position with a halogen atom, which nitrogen-containing groups preferably have a tertiary nitrogen and are attached to the phenyl group at a nitrogen atom:

- (i) a monocylic saturated hydrocarbon group having 2-7 carbon atoms, having a nitrogen atom(s) as a ring atom(s), and substituted with a phenyl group at a carbon atom (the saturated hydrocarbon group is optionally substituted with an alkyl group(s) having 1-6 carbon atoms) (e.g., a piperidinyl group optionally substituted with an alkyl group(s) having 1-6 carbon atoms, such as a 4-piperidinyl group);
- (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group (e.g., a pyrrolyl group, an imidazolyl group);
- (iii) a morpholinyl group optionally substituted with an alkyl group(s) having 1-6 carbon atoms, such as a morpholino group;
- (iv) an optionally substituted piperazino group (e.g., a piperazino group optionally substituted (preferably on a nitrogen atom constituting a ring) with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having 1-4 carbon atoms, and a morpholino group), and an alkanoyl group having 2-7 carbon atoms); and
- (v) Formula —NR⁷R⁸, in which R⁷and R⁸each represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an amino group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having 1-6 carbon atoms), an alkanoyl group having 1-6 carbon atoms, a carbamoyl group optionally substituted with one or two alkyl groups each having 1-4 carbon atoms, a morpholinocarbonyl group, an aminosulfonyl group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, or an alkylsulfonyl group having 1-6 carbon atoms, or R⁷and R⁸optionally form, together with the nitrogen atom to which R⁷and R⁸are attached, a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.

It is preferable that Formula —NR⁷R⁸in item (v) above be —NR^CR^Das defined below.

R^Cand R^Deach represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an amino group optionally substituted with one or two alkyl groups each having 1-4 carbon atoms, a hydroxyl group, or an alkoxy group having 1-4 carbon atoms), a formyl group, an acetyl group, an aminocarbonyl group, a dimethylaminosulfonyl group, or a methylsulfonyl group, or R^Cand

R^Doptionally form, together with the nitrogen atom to which R^Cand R^Dare attached, a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.

In an especially preferred embodiment, R³is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom, a 6-indolyl group, and nitrogen-containing groups (i), (iv), and (v) shown in item (C) above, which phenyl group substituted with a substituent selected from the above group is optionally further substituted at 4 position with a halogen atom.

In a preferred embodiment, R⁵is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a cycloalkyl group having 3-8 carbon atoms; an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a phenyl group or a naphthyl group (preferably 2-naphthyl group) each optionally substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms, an alkanoyl group having 2-7 carbon atoms, an alkoxycarbonyl group having 2-7 carbon atoms, and a cyano group; a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a methoxycarbonyl group; a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom; a thienyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or a benzothienyl group (preferably a 2-benzothienyl group), a phenyl group condensed with a 5- to 7-membered saturated hydrocarbon ring which may contain one or two oxygen atoms as ring-forming atoms (e.g., a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group), a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group (preferably 5-benzothiadiazolyl groups), each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom.

In a preferred embodiment of R⁵, examples of the “phenyl group which is optionally substituted” include an unsubstituted phenyl group, a phenyl group substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), an alkoxy group having 1-6 carbon atoms (preferably a methoxy group), and a halogen atom, and a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms (preferably a methoxy group), a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group), a methoxycarbonyl group, an acetyl group, and a cyano group, preferably a halogen atom, a methyl group, and a methoxy group, and more preferably a halogen atom.

In a preferred embodiment of R⁵, an example of the “naphthyl group which is optionally substituted” is a naphthyl group optionally substituted with a substituent(s) (preferably 1-3 substituents) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group). More preferably, it is a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group. Examples in a case of a 2-naphthyl group include an unsubstituted 2-naphthyl group and a 2-naphthyl group substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (substituted at any position, preferably at 5, 7 and/or 8 position) and other substituents (substituted at 5, 7 and/or 8 position). Examples in a case of a 1-naphthyl group include an unsubstituted 1-naphthyl group and a 1-naphthyl group substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (substituted at any position) and other substituents, preferably a halogen atom (substituted preferably at 4 position).

In an especially preferred embodiment, R⁵is a phenyl group substituted at 3 and 4 positions with a halogen atom, an unsubstituted 2-naphthyl group, and a 2-naphthyl group substituted at 5, 7 and/or 8 position with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group.

The following are combinations of R³and R⁵that are especially preferred. In a case in which R³is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom, R⁵is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a substituted phenyl group (e.g., a phenyl group substituted with 1-5 methyl groups, a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 a carbon atom (preferably a methyl group, an ethyl group, a propyl group), a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms (preferably a vinyl group), a methoxycarbonyl group, an acetyl group, and a cyano group; a benzothienyl group; a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group); a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of a methyl group and a methoxycarbonyl group; a thienyl group substituted with an alkyl group(s) having 1-6 carbon atoms (preferably a methyl group); a benzodioxolyl group; a dihydrobenzodioxynyl group; a dihydrobenzofuranyl group; a tetrahydronaphthyl group; an indanyl group; or a benzothiadiazolyl group (preferably a 5-benzothiadiazolyl group).

In a case in which R³is a 6-indolyl group, R⁵is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a phenyl group which is optionally substituted (e.g., an unsubstituted phenyl group, a phenyl group substituted with 1-5 methyl groups, a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group, an ethyl group, a propyl group), a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms (preferably a vinyl group), a methoxycarbonyl group, an acetyl group, and a cyano group); a benzothienyl group; a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group); a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a methoxycarbonyl group; or a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, or a benzothiadiazolyl group (preferably, 5-benzothiadiazolyl group), each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom.

In a case in which R³is of the embodiment shown in item (C) above, R⁵is: an alkyl group having 1-6 carbon atoms and substituted with a cycloalkyl group having 3-8 carbon atoms; an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a optionally substituted phenyl group (e.g., an unsubstituted phenyl group, a phenyl group substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom, a phenyl group substituted at 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group), a methoxycarbonyl group, an acetyl group, and a cyano group; a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group); a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a methoxycarbonyl group; a thienyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom; or a benzothienyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group (preferably a 5-thiadiazolyl group), a benzoxadiazolyl group, or a benzothiadiazolyl group (preferably a 5-benzothiadiazolyl group), each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom.

A preferred optically-active compound of the present compound having R^1Abeing a hydrogen atom has the structure below.

The compound of the present invention can be synthesized by, for instance, the method described below.

(where R¹, R^1A, R², R³, and R⁵are as defined above, R′ represents an alkyl group having 1-6 carbon atoms, R″ represents a protecting group for an amino group, which protecting group is stable under a basic condition (e.g., a t-butoxycarbonyl group, a benzyloxycarbonyl group), L represents a leaving group (e.g., a halogen atom, such as a chlorine atom, a bromine atom, and an iodine atom, an alkylsulfonyloxy group, such as an a methanesulfonyloxy group and a p-toluenesulfonyloxy group, an arylsulfonyloxy group, a 2-oxo-1-oxazolyl group), and A¹represents an oxygen atom, a sulfur atom, or a group represented by —NR⁶—, where R⁶represents a hydrogen atom or an alkyl group having 1-6 carbon atoms.)

In the present invention, a compound having A being an oxygen atom, a sulfur atom, or a group represented by —NR⁶— can be synthesized by, for instance, the method shown in Scheme 1.

The compound represented by Formula (b) can be obtained by allowing the compound represented by Formula (a) to react with hydrazine in a solvent or in the absence of a solvent. The amount of the hydrazine used is generally 1-30 equivalent weight with respect to Compound (a), preferably 5-30 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include alcohols such as methanol and ethanol. The reaction temperature is generally a room temperature to a solvent reflux temperature. The reaction time is generally 12-24 hours, but it depends on the reaction temperature and starting compounds.

The compound represented by Formula (d) can be obtained by allowing the compound represented by Formula (b) to react with the compound represented by Formula (c) in a solvent or in the absence of a solvent. The amount of the compound represented by Formula (c) to be used is generally 1-3 equivalent weight with respect to the compound represented by Formula (b), preferably 1.1-1.5 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. For instance, alcohols, such as methanol and ethanol, and halogenated hydrocarbons, such as dichloromethane and chloroform, are preferably used. The reaction temperature is generally a room temperature to a solvent reflux temperature. The reaction time is generally 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.

The compound represented by Formula (e) can be obtained by allowing the compound of Formula (d) to react with a base in a solvent or in the absence of a solvent to cyclize. The base to be used includes alkali metal hydroxides such as NaOH and KOH, and alkali metal salts such as NaHCO₃and K₂CO₃. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (d), preferably 1.1-1.5 equivalent weight. If a solvent is necessary, the following can be used as the solvent: water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran (THF), and mixed solvents thereof. The reaction temperature is generally a room temperature to a solvent reflux temperature. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.

The compound represented by Formula (g) can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (e) to react with the compound represented by Formula (f) in the presence of a base. The amount of the compound represented by Formula (f) to be used is generally 1-5 equivalent weight, preferably 1.1-1.5 equivalent weight, with respect to the compound represented by Formula (e). The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO₃and K₂CO₃, and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (e), preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N′-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.

The compound represented by Formula (h) can be obtained by allowing the compound represented by Formula (g) to react with an oxidant in a solvent. Examples of the solvent to be used include organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid, inorganic or organic peroxides such as hydrogen peroxide, hydrogen peroxide urea adduct/phthalic anhydride, tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate, Oxone (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl, iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane addition complex. The amount of the oxidant used is 2-10 equivalent weight with respect to the compound represented by Formula (g), preferably 2-3 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C.-40° C. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (i) or a salt of the compound can be obtained by subjecting the compound represented by Formula (h) to deprotection of an amino group in a solvent under a conventional condition, e.g., allowing it to react with an acid. Examples of the acid used include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) and organic acids (e.g., trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid). The amount of the acid used is 1-50 equivalent weight with respect to the compound represented by Formula (h). The reaction temperature is 0° C. to a solvent reflux temperature, preferably a room temperature to 40° C. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (k) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (i) to react with the compound represented by Formula (j) (where A¹represents an oxygen atom, a sulfur atom, or a group represented by Formula —NR⁶—, and R³is as defined above) in the presence of a base and, when necessary, forming a salt. The amount of the compound of Formula (j) to be used is generally 1-5 equivalent weight with respect to the compound represented by Formula (i), preferably 1-3 equivalent weight. Examples of the base used include alkali metal salts, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, dimsyl sodium, sodium hydride, sodium amide, tert-butoxypotassium, and tert-butoxysodium, amines, such as triethylamine, diisopropylamine, pyrrolidine, and piperidine, sodium acetate, and potassium acetate. The amount of the base used is generally 1-10 equivalent weight with respect to the compound represented by Formula (i), preferably 1-3 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, and it can be carried out under ordinary pressure, increased pressure, microwave irradiation, or the like. The reaction solvent to be used includes ethers such as dioxane and THF, DMF, DMA, DMPU, RMPA, or the like, or mixed solvents thereof. The reaction time is generally a period of 1-12 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (m) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (k) to react with the compound represented by Formula (l) in the presence of a base and, when necessary, forming a salt. The amount of the compound represented by Formula (l) used is 1-5 equivalent weight with respect to the compound represented by Formula (k), preferably 1-1.2 equivalent weight. The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO₃and K₂CO₃, or amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (k), preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

(where R¹, R^1A, R², R³, R⁴, R⁵, R′, R″, A, and L are as defined above, R⁴¹is the same as R⁴excluding the hydrogen atom).

In the present invention, a compound having A represented by Formula —SO— or Formula —SO₂— can be synthesized by the method shown in Scheme 2.

The compound represented by Formula (m2), the compound represented by Formula (m3), or pharmaceutically acceptable salts of the compounds can be obtained by allowing, among the compounds obtained in Scheme 1 and represented by Formula (m), the compound represented by Formula (m1) having A¹being a sulfur atom to react with an oxidant and, when necessary, forming a salt. Examples of the oxidant to be used include organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid, inorganic or organic peroxides such as hydrogen peroxide, hydrogen peroxide urea adduct/phthalic anhydride, tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate, Oxone (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl, iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane addition complex. The amount of the oxidant used is 1-10 equivalent weight with respect to the compound represented by Formula (m1), preferably 1-3 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is −78° C. to a solvent reflux temperature, preferably 0°-40° C. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

In the present invention, a compound having A represented by —CH₂— can be synthesized by the method shown in Scheme 3.

The compound represented by Formula (o) can be obtained by allowing the compound represented by Formula (a) to react with the compound represented by Formula (n) (R²is as defined above) in a solvent or in the absence of a solvent. The amount of the compound represented by Formula (n) to be used is 1-10 equivalent weight with respect to the compound represented by Formula (a), preferably 1-1.2 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include alcohols such as methanol and ethanol. The reaction temperature is generally a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C. The reaction time is generally a period of 12-24 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (p) can be obtained by allowing the compound represented by Formula (o) to react with a Lawesson's reagent in a solvent or in the absence of a solvent. The amount of the Lawesson's reagent used is 1-5 equivalent weight with respect to the compound represented by Formula (o), preferably 1-1.2 equivalent weight. The reaction solvent to be used includes ethers such as dioxane and THF, and mixed solvents thereof. The reaction temperature is a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C. The reaction time is generally 1-12 hours, but it depends on the reaction temperature and starting compounds.

The compound represented by Formula (r) can be obtained by allowing the compound represented by Formula (p) to react with the compound represented by Formula (q) in the presence of a mercury compound. The amount of the compound represented by Formula (q) to be used is 1-10 equivalent weight with respect to the compound represented by Formula (p), preferably 1-1.2 equivalent weight. Examples of the mercury compound include HgCl₂and Hg(OAc)₂. The amount of the mercury compound used is 1-10 equivalent weight with respect to the compound represented by Formula (p), preferably 1-1.2 equivalent weight. The solvent to be used includes acetonitrile, THF, dioxane, and the like. The reaction temperature is a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C. The reaction time is generally a period of 12-48 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (k1) or a salt of the compound can be obtained by subjecting the compound represented by Formula (r) to deprotection of an amino group in a solvent under a conventional condition, e.g., allowing it to react with an acid. Examples of the acid include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) and organic acids (e.g., trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid). The amount of the acid used is 1-50 equivalent weight with respect to the compound represented by Formula (r). The reaction temperature is 0° C. to a solvent reflux temperature, preferably a room temperature to 40° C. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (m4) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (k1) to react with the compound represented by Formula (l) in the presence of a base and, when necessary, forming a salt. The amount of the compound represented by Formula (l) to be used is 1-5 equivalent weight with respect to the compound represented by Formula (k1), preferably 1-1.2 equivalent weight. The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO₃and K₂CO₃, and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base is 1-10 equivalent weight, preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

The compound represented by Formula (u) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (m5) to react with the compound represented by Formula (s) in the presence of a base and, when necessary, forming a salt. The amount of the compound represented by Formula (s) to be used is generally 1-10 equivalent weight with respect to the compound represented by Formula (m5), preferably 1.1-1.5 equivalent weight. The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO₃and K₂CO₃, and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (m5), preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N′-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.

Further, a functional group can be introduced to R³by carrying out protection, deprotection, functional group transformation in the process described above.

For use as pharmaceutical preparations, the compounds of the present invention may be supplemented with commonly used excipients, extenders, pH regulators, solubilizers and so on, and then formulated using standard techniques into tablets, granules, pills, capsules, powders, solutions, suspensions, injections, etc. The pharmaceutical preparations thus obtained can be administered as oral or parenteral formulations.

The compound of the present invention can be administered to an adult patient at a dose of 1-1000 mg per day in several separated doses. This dosage can be increased or reduced according to a type of a disease, an age, a weight, and a symptom of a patient, or the like.

Advantageous Effect of the Invention

As the Test Example described below shows, it is found that the compounds of the present invention are strong Edg-1 (S1P₁) ligands.

BEST MODE FOR CARRYING OUT THE INVENTION

The following describes the present invention in more detail, with reference to Examples and the Test Example.

Example 1 3,4-Dichloro-N—{(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]ethyl}benzenesulfonamide (Compound 12)

(R)-(1-Hydrazinocarbonyl-2-ethyl)carbamic acid t-butyl ester

(1) Hydrazine monohydrate (30 ml) was added to a solution of N-(t-butoxycarbonyl)-D-alanine methyl ester (41.8 g) in methanol (180 ml), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the resulting crude crystal was washed with a mixed solvent of hexane and ethyl acetate (1:1, 300 ml) and then dried to give the titled compound as a colorless powder (32.6 g).

¹H NMR (300 MHz, DMDO-d₆) δ ppm: 1.14 (d, J=7.2 Hz, 3H), 1.37 (s, 9H), 3.30-4.09 (m, 3H), 6.70-6.90 (m, 1H), 8.96 (br s, 1H)

(R)-2-(N-(t-Butoxycarbonyl)amino)propionyl)-N-ethylhydrazinecarbothioamide

(2) Ethyl isothiocyanate (14.6 ml) was added to a solution of the compound (30.8 g) of Example 1-(1) in ethanol (152 ml), and the mixture was heated under reflux for two hours. Then, the mixture was cooled to room temperature, and the resulting crystal was filtered. The filtrate was concentrated, and the resulting residue was purified by silica-gel chromatography with a mixed solvent of ethyl acetate and chloroform to give the titled compound as a colorless amorphous substance (43.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 0.98-1.28 (m, 6H), 1.40 (s, 9H), 3.25-3.65 (m, 2H), 3.77-3.95 (m, 1H), 7.20-7.39 (m, 1H), 7.45-7.60 (m, 1H), 9.25 (s, 1H), 10.00 (s, 1H)

[(R)-1-(4-Ethyl-5-mercapto-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester

(3) One mol/l aqueous sodium hydroxide (218 ml) was added to a mixed solution of the compound (42.1 g) of Example 1-(2) in methanol (120 ml) and dioxane (240 ml), and the mixture was heated under reflux for three hours. The reaction solution was concentrated, and an aqueous hydrochloric acid (2N, 100 ml) was added. The mixture was extracted with a mixed solution of ethyl acetate, chloroform, and methanol (10:10:1, 500 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was washed with a mixed solvent of hexane and ethyl acetate (1:1, 300 ml) and then dried to give the titled compound as a white solid (29.22 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.21 (t, J=7.1 Hz, 3H), 1.30-1.50 (m, 3H), 1.39 (s, 9H), 3.82-4.05 (m, 2H), 4.72-4.88 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 13.60 (br s, 1H

[(R)-1-(4-Ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester

(4) Diisopropylamine (17.4 ml) and MeI (7.7 ml) were added to a solution of the compound (28.12 g) of Example 1-(3) in THF (200 ml), and the mixture was stirred at room temperature for one hour. Thereafter, the resulting crystal was filtered. The filtrate was concentrated, and the resulting crude crystal was washed with a mixed solvent of hexane and ethyl acetate (3:1, 200 ml) and then dried to give the titled compound as a white powder (29.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.21 (t, J=7.0 Hz, 3H), 1.38 (s, 9H), 1.45 (t, J=7.0 Hz, 3H), 2.62 (s, 3H), 3.80-4.00 (m, 2H), 4.85-4.92 (m, 1H), 7.52 (d, J=8.5 Hz, 1H)

[(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester

(5) With ice cooling, m-chloroperbenzoic acid (43.0 g) was added in four portions to a solution of the compound (21.0 g) of Example 1-(4) in chloroform (293 ml), and the mixture was stirred at room temperature for three hours and thereafter at 40° C. for one hour. Na₂S₂O₃(12.9 g) and 1 mol/l aqueous sodium hydroxide (300 ml) were added to the reaction solution to separate the organic layer, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica-gel flush column chromatography with a mixed solvent of hexane and ethyl acetate, and then recrystallized with hexane and chloroform to give the titled compound as a white powder (17.2 g).

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.44 (s, 9H), 1.49 (t, J=7.1 Hz, 3H), 1.67 (t, J=6.8 Hz, 3H), 3.53 (s, 3H), 4.25-4.59 (m, 2H), 4.92-5.20 (m, 2H)

(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine trifluoroacetic acid salts

(6) Trifluoroacetic acid (121 ml) was added to the compound (100.0 g) obtained in Example 1-(5), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to give the titled compound as a white powder (103.8 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.37 (t, J=7.2 Hz, 3H), 1.59 (d, J=6.8 Hz, 3H), 3.65 (s, 3H), 4.21-4.50 (m, 2H), 4.72-4.90 (m, 1H), 8.69 (br s, 3H)

(1R)-1-(4-Ethyl-5(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl)ethylamine

(7) In a pressure-resistant screw cap test tube,

N,N′-dimethylpropyleneurea (DMPU) (5 mL), 4-fluorophenol (1.01 g) and cesium carbonate (2.94 g) were added to the compound (1.00 g) obtained in Example 1-(6), and the mixture was stirred at 200° C. for one hour. The mixture was brought to room temperature, and saturated aqueous sodium chloride was added. The mixture was extracted with ethyl acetate (100 ml×5). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH SiO₂, hexane/ethyl acetate=50/50 to 20/80, chloroform/methanol=30/1) to give the titled compound (brown oil compound, 0.586 g).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.41 (t, J=7.3 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 3.95-4.23 (m, 3H), 6.90-7.15 (m, 2H), 7.30-7.44 (m, 2H)

3,4-Dichloro-N-{(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]ethyl}benzenesulfonamide (Compound 12)

(8) Triethylamine (0.93 mL, 6.64 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.45 mL, 2.88 mmol) were added at room temperature to a solution of the compound (0.554 g) of Example 1-(7) in THF (10 mL), and the mixture was stirred at room temperature for 2.5 hours. Then, ethyl acetate was added. The organic layer was washed with 1N aqueous hydrochloric acid and thereafter with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO₂, hexane/ethyl acetate=50/50 to 10/90) and then recrystallized (ethyl acetate-hexane) to give 0.447 g of the titled compound (Compound 12) as a colorless powder.

Melting point: 190.0° C. to 192.0° C.

Example 2 N-[(1R)-1-(4-Ethyl-5(4-methylphenylamino)-4H-[1,2,4]triazol-3-yl)ethyl]3,4-dichlorobenzenesulfonamide (Compound 61)

(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine

(1) To the compound (4.30 g) obtained in Example 1-(6), n-BuNH₂(20 ml) was added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and the resulting crude product was purified by NH silica-gel chromatography with a mixed solvent of methanol and chloroform (methanol/chloroform=10%) to give the titled compound as a colorless crystal (2.737 g).

¹H NMR (200 MHz, CDCl₃) δ ppm: 1.53 (t, J=7.3 Hz, 3H), 1.65 (d, J=6.8 Hz, 3H), 3.53 (s, 3H), 4.14-4.58 (m, 3H)

[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-methylphenylamine

(2) The compound (437 mg) obtained in Example 2-(1), DMPU (2.0 mL), 4-toluidine (257 mg), and NaH (240 mg, 60-72 wt % oily) were put in a pressure-resistant screw cap test tube. The mixture was stirred at 200° C. for 1.0 hour and then brought to room temperature, and 10% methanol/chloroform was added to the reaction solution. The reaction solution was filtered through NH silica gel and then concentrated, and the resulting brown oily substance was purified by column chromatography (NH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=5%) to give the titled compound (brown oil compound, 224 mg).

¹H NMR (200 MHz, CDCl₃) δ ppm: 1.31 (t, J=7.3 Hz, 3H), 1.60 (d, J=6.6 Hz, 3H), 2.28 (s, 3H), 3.60-4.30 (m, 3H), 6.96-7.02 (m, 4H)

N-[(1R)-1-(4-Ethyl-5(4-methylphenylamino)-4H-[1,2,4]triazol-3-yl)ethyl]3,4-dichlorobenzenesulfonamide (Compound 61)

A solution of 3,4-dichlorobenzenesulfonyl chloride (154 μl) in THF (2.0 ml) was added at room temperature to a solution of the compound (220 mg) of Example 2-(2) and triethylamine (0.249 ml) in THF (9.0 ml), and the mixture was stirred at room temperature for five hours. The insoluble matter was filtered off, and the resulting residue was concentrated. The resulting crude product was purified by OH silica-gel column chromatography (elution solvent: ethyl acetate/hexane=50-99%) and then recrystallized (ethyl acetate-hexane) to give 160 mg of the titled compound (Compound 61) as a pale yellow powder.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.18 (t, J=7.1 Hz, 3H), 1.30 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.87-4.03 (m, 2H), 4.63-4.72 (m, 1H), 7.00-7.12 (m, 2H), 7.35-7.45 (m, 2H), 7.74 (dd, J=8.6, 1.9 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.57-8.66 (m, 1H)

Melting point: 93.0° C. to 99.0° C.

Example 3 3,4-Dichloro-N—[(R)-1-(4-ethyl-5(4-methylbenzenesulfenyl)-4H-[1,2,4]triazol-3-yl)-ethyl]-benzenesulfonamide (Compound 55)

(R)-1-(4-Ethyl-5(4-methylphenylsulfanyl)-4H-[1,2,4]triazol-3-yl)-ethylamine

(1) The compound (5.00 g, 15.1 mmol) obtained in Example 1-(6), DMF (50 mL), 4-methylbenzenethiol (3.74 g, 30.1 mmol), and cesium carbonate (14.7 g, 45.1 mmol) were put in a pressure-resistant screw cap test tube. The mixture was stirred at 150° C. for four hours and thereafter brought back to room temperature, and a mixed solvent of chloroform/methanol (10/1) was added. The insoluble matter was filtered off. The filtrate was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (NH SiO₂, hexane/ethyl acetate=50/50 to 10/90, chloroform/methanol=40/1) to give 3.01 g of the titled compound (colorless oily compound).

¹H NMR (600 MHz, CDCl₃) δ ppm 1.21 (t, J=7.3 Hz, 3H), 1.59 (d, J=6.4 Hz, 3H), 2.31 (s, 3H), 4.00-4.18 (m, 3H), 7.06-7.14 (m, 2H), 7.26-7.30 (m, 2H)

3,4-Dichloro-N—[(R)-1-(4-ethyl-5(4-methylbenzenesulfanyl)-4H-[1,2,4]triazol-3-yl)-ethyl]-benzenesulfonamide (Compound 55)

(2) Starting from the compound obtained in Example 3-(1), the same procedure as used in Example 1-(8) was repeated to give the titled compound.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.08 (t, J=7.3 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H), 2.28 (s, 3H), 3.90-4.11 (m, 2H), 4.78 (q, J=6.9 Hz, 1H), 7.17-7.23 (m, 4H), 7.67-7.74 (m, 1H), 7.81-7.88 (m, 1H), 7.92-7.94 (m, 1H), 8.77 (s, 1H)

Yield: 46%, Melting point: 141.0° C. to 143.0° C.

Example 4 3,4-Dichloro-N—[(R)-1-[4-ethyl-5(4-methylbenzenesulfonyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 57)

To a solution of the compound (0.300 g) of Example 3-(2) in chloroform (6 mL), m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for one hour. Then, a further portion of m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for 15 hours. Thereafter, a further portion of m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for two hours. Then, ethyl acetate was added, and the organic layer was washed with 5% aqueous Na₂S₂O₃solution and thereafter with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO₂, hexane/ethyl acetate=70/30 to 40/60) and then recrystallized (ethyl acetate-hexane) to give 0.196 g of the titled compound (Compound 57) (colorless powdered compound). ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.25-1.35 (m, 6H), 2.45 (s, 3H), 4.23-4.40 (m, 2H), 4.78-4.86 (m, 1H), 7.52-7.56 (m, 2H), 7.62-7.67 (m, 1H), 7.78-7.82 (m, 1H), 7.86-7.94 (m, 3H)

Melting point: 164.0° C. to 165.0° C.

Example 5 3,4-Dichloro-N—[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 56)

((R)-1-Ethylcarbamoyl-ethyl)-carbamic acid t-butyl ester

(1) EtNH₂(10 ml, 70% aqueous solution) was added to N-(t-butoxycarbonyl)-D-alanine methyl ester (4.76 g) in methanol (20 ml), and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (acidic OH SiO₂, chloroform/ethyl acetate=10-50%) to give 3.96 g of the titled compound (colorless amorphous substance).

¹H NMR (200 MHz, CDCl₃) δ ppm: 1.12 (t, J=7.2 Hz, 3H), 1.35 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 3.18-3.37 (m, 2H), 4.00-4.20 (m, 1H), 4.90-5.10 (m, 1H), 6.04-6.22 (m, 1H)

((R)-1-Ethylthiocarbamoyl-ethyl)-carbamic acid t-butyl ester

(2) A Lawesson's reagent (8.89 g) was added to a solution of the compound (3.96 g) of Example 5-(1) in THF (92 ml), and the mixture was stirred at room temperature for one hour and thereafter at 50° C. for 30 minutes. The reaction solution was cooled to room temperature, and the insoluble matter was filtered off. Then, the resulting residue was concentrated. The resulting crude product was purified by column chromatography (acidic OH SiO₂, chloroform/ethyl acetate=10-50%) and thereafter by NH silica-gel column chromatography (ethyl acetate/hexane=50%) to give the titled compound (3.75 g) as a colorless powder.

¹H NMR (200 MHz, CDCl₃) δ ppm: 1.26 (t, J=7.2 Hz, 3H), 1.38-1.52 (m, 3H), 1.45 (s, 9H), 3.60-3.77 (m, 2H), 4.36-4.53 (m, 1H), 5.10-5.32 (m, 1H), 7.99-8.24 (m, 1H)

[(R)-1-[4-Ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-carbamic acid t-butyl ester

(3) Hg (OAc)₂(2.43 g) was added to a solution of the compound (1.61 g) obtained in Example 5-(2) and 4-methylphenylacetic acid hydrazide (1.25 g) in CH₃CN (30 mL), and the mixture was stirred at room temperature for 42 hours. Ethyl acetate was added to the reaction solution, and the insoluble matter was filtered off through celite. The filtrate was washed with 1N aqueous KHSO₄solution and thereafter with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO₂, ethyl acetate/hexane=50-100%, methanol/chloroform=1/1) (neutral OH SiO₂, methanol/chloroform=1/10) to give 0.530 g of the titled compound (colorless amorphous substance).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.04 (t, J=7.3 Hz, 3H), 1.41 (s, 9H), 1.61 (d, J=6.9 Hz, 3H), 2.30 (s, 3H), 3.73-3.90 (m, 2H), 4.06-4.20 (m, 2H), 4.85-4.94 (m, 1H), 5.11-5.17 (m, 1H), 7.09 (s, 4H)

(R)-1-[4-Ethyl-5-(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethylamine

(4) Trifluoroacetic acid (5 mL) was added to a solution of the compound (0.496 g) of Example 5-(3) in chloroform (5 mL), and the mixture was stirred at room temperature for 18 hours. Aqueous sodium hydroxide (1.0N) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent, whereby 0.148 g of the titled compound was obtained as a colorless oily compound.

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.09 (t, J=7.3 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H), 2.30 (s, 3H), 3.74-3.94 (m, 2H), 4.01-4.20 (m, 3H), 7.10 (s, 4H)

3,4-Dichloro-N—[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 56)

(5) Triethylamine (0.25 mL) and 3,4-dichlorobenzenesulfonyl chloride (0.707 mL) were added to a solution of the compound (0.144 g) of Example 5-(4) in THF (3 mL), and the mixture was stirred at room temperature for 3.5 hours. Then, 2N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO₂, chloroform/methanol=50/1 to 10/1) and then recrystallized (ethyl acetate-hexane) to give 0.100 g of the titled compound (Compound 56) as a colorless powdered compound.

¹H NMR (600 MHz, DMSO-D6) δ ppm: 0.91 (t, J=7.1 Hz, 3H), 1.26 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.77-3.92 (m, 2H), 4.00 (s, 2H), 4.60-4.70 (m, 1H), 7.03-7.12 (m, 4H), 7.64-7.68 (m, 1H), 7.79-7.82 (m, 1H), 7.89-7.91 (m, 1H), 8.64 (s, 1H)

Melting point: 189.0° C. to 191.0° C.

Example 6 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-N-methyl-benzenesulfonamide (Compound 115)

K₂CO₃(78 mg) and MeI (0.022 ml) were added at room temperature to a solution of Compound 12 (150 mg) of Example 1 in dimethylformamide (2.0 ml), and the mixture was stirred at room temperature for three hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform=1/4). The resulting organic layer was washed with saturated aqueous sodium chloride, dried (MgSO₄), filtered, and evaporated under reduced pressure to remove the solvent. After eluting the residue with a mixed solvent of ethyl acetate and hexane, the resulting elute was purified by column chromatography (acidic OH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=0-10%) and then recrystallized (ethyl acetate-hexane) to give 111 mg of the titled compound as a colorless powdered compound.

Melting point: 125.5° C. to 126.5° C.

Example 7 3,4-Dichloro-N—((R)-1-[5-[3-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 87)

3-(1,4-Dioxa-8-aza-spiro[4.5]decen-8-yl)-phenol

(1) In a pressure-resistant screw cap test tube, 3-bromophenol (1.50 g), 1,4-dioxa-8-azaspiro[4,5]decan (1.49 g), Pd₂(dba)₃(0.079 g), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.082 g), and LiN(TMS)₂(20% in THF, 18 mL) were put, and the mixture was stirred at 65° C. for 7.5 hours. Ethyl acetate was added, and the organic layer was washed with 1N aqueous hydrochloric acid and thereafter with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO₂, hexane/ethyl acetate=70/30 to 60/40) to give 1.96 g of the titled compound (brown oil).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.79-1.83 (m, 4H), 3.27-3.35 (m, 4H), 3.98 (s, 4H), 4.86 (s, 1H), 6.28 (dd, J=8.0, 2.5 Hz, 1H), 6.41 (t, J=2.3 Hz, 1H), 6.51 (dd, J=8.5, 2.5 Hz, 1H), 7.08 (t, J=8.3 Hz, 1H)

(R)-1-[5-[3-(1,4-Dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethylamine

(2) Starting from the compound obtained in Example 7-(1) in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 58%).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.38 (t, J=7.3 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.77-1.83 (m, 4H), 3.27-3.36 (m, 4H), 3.95-4.06 (m, 6H), 4.14 (q, J=6.9 Hz, 1H), 6.70-6.75 (m, 2H), 6.97 (t, J=2.3 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H)

3,4-Dichloro-N—((R)-1-[5-[3-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 87)

(3) Starting from the compound obtained in Example 7-(2), the same procedure as used in Example 1-(8) was repeated to give the titled compound (colorless powder, yield 64%).

Melting point: 174.0° C. to 179.0° C.

Example 8 3,4-Dichloro-N—((R)-1-[4-ethyl-5-[3-(4-oxo-piperidin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 88)

To a solution of the compound (0.981 g) of Example 7 in THF (10 mL), 2N aqueous hydrochloric acid (8.4 mL) was added, and the mixture was stirred at room temperature for one hour. Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 50° C. for six hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO₂, ethyl acetate) and then recrystallized (chloroform-hexane) to give the titled compound (0.572 g, colorless powder).

Melting point: 188.5° C. to 190.5° C.

Example 9 3,4-Dichloro-N—((R)-1-[4-ethyl-5-[3-(4-hydroxy-piperidin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 93)

NaBH₄(0.021 g) was added at 0° C. to a solution of the compound (0.150 g) of Example 8 in methanol (3.0 ml), and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO₄, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH SiO₂, methanol/chloroform=1/50 to 1/10) and then recrystallized (ethyl acetate-hexane) to give 0.113 g of the titled compound (Compound 93) as a colorless powder.

Melting point: 167.5° C. to 169.5° C.

Example 10 N—[(R)-1-[5-(3-Amino-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 82)

3-[5-((R)-1-Amino-ethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl amine

(1) Starting from 3-aminophenol in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 99%). ¹H NMR (600 MHz, CDCl₃) δ ppm: 1.37 (t, J=7.1 Hz, 3H), 1.58 (d, J=6.9 Hz, 3H), 3.96-4.05 (m, 2H), 4.15 (q, J=6.7 Hz, 1H), 6.45-6.50 (m, 1H), 6.62-6.67 (m, 1H), 6.71-6.75 (m, 1H), 7.11 (t, J=8.0 Hz, 1H)

N—[(R)-1-[5-(3-Amino-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 82)

(2) Triethylamine (4.16 ml) and 3,4-dichlorobenzenesulfonyl chloride (3.73 g) were added to a solution of the compound (3.69 g) of Example 10-(1) in THF (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (NH SiO₂, methanol/chloroform) and recrystallized (ethyl acetate/hexane) to give 3.60 g of the titled compound (Compound 82) (colorless powdered compound).

Melting point: 142.0° C. to 145.0° C.

Example 11 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-pyrrol-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 86)

To a solution of the compound (700 mg) of Example 10 in AcOH (4.6 ml), 2,5-dimethoxy-tetrahydrofuran (375 μl) was added, and the mixture was stirred at 130° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Thereafter, water was added, and the mixture was extracted with methanol/chloroform (1/4). Then, the organic layer was washed with saturated aqueous sodium chloride, dried over MgSO₄, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO₂, ethyl acetate/hexane=33-100%, methanol/chloroform=5%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 86) (173 mg, colorless powdered compound).

Melting point: 176.0° C. to 177.0° C.

Example 12 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-formylamino-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 90)

A mixture of the compound (300 mg) obtained in Example 10-(2) and ethyl formate (1.1 ml) was stirred at 105° C. for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (acidic OH SiO₂, ethyl acetate/hexane=50-100%, methanol/chloroform=5%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 90) (81 mg, colorless powder).

Melting point: 168.0° C. to 170.0° C.

Example 13 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-ureido-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 91)

A mixture of the compound (300 mg) obtained in Example 10-(2), potassium cyanate (65 mg), AcOH (1.0 ml), and water (0.5 ml) was stirred at room temperature for one hour. Water was added, and the mixture was extracted with methanol/chloroform (1/4). The organic layer was dried over MgSO₄, filtered, and evaporated to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=0-3%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 91) (273 mg, colorless powder).

Melting point: 137.0° C. to 138.0° C.

Example 14 3,4-Dichloro-N—((R)-1-[5-[3-(3,3-dimethylureido)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 97)

Dimethylcarbamyl chloride (146 μl) was added to a solution of the compound (300 mg) of Example 10-(2) and triethylamine (368 μl) in chloroform (1.1 ml), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=0-3%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 97) (93 mg, colorless powder).

Melting point: 158.0° C. to 159.0° C.

Example 15 3,4-Dichloro-N—((R)-1-[4-ethyl-5-[3-(3-ethylureido)-phenoxy]4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 92)

Ethyl isocyanate (63 μl) was added to a solution of the compound (300 mg) of Example 10-(2) in chloroform (1.1 ml), and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=0-3%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 92) (228 mg, colorless powder).

Melting point: 118.0° C. to 120.0° C.

Example 16 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-methanesulfonylamino-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 102)

Methanesulfonyl chloride (114 mg) was added to a solution of the compound (300 mg) of Example 10-(2) in pyridine (1.32 ml), and the mixture was stirred at room temperature for three hours. Hydrochloric acid (1.0 N) was added, and the mixture was extracted with methanol/chloroform (1/4). The organic layer was dried over Na₂SO₄, filtered, and concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=0-5%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 102) (281 mg, colorless powder).

Melting point: 117.0° C. to 118.0° C.

Example 17 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 114)

(R)-1-[5-(3-Benzyloxy-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethylamine

(1) Starting from 3-benzyloxyphenol in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 84%).

¹H NMR (600 MHz, CDCl₃), δ ppm: 1.39 (t, J=7.3 Hz, 3H), 1.60 (d, J=6.4 Hz, 3H), 3.96-4.09 (m, 2H), 4.17 (q, J=6.9 Hz, 1H), 5.06 (s, 2H), 6.79-6.84 (m, 1H), 6.91-6.96 (m, 1H), 7.04-7.08 (m, 1H), 7.22-7.46 (m, 6H)

3-[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenol

(2) A suspension of the compound (1.5 g) of Example 17-(1) and Pd(OH)₂/C (150 mg, Pd 20 wt %) in methanol (4.0 ml) was stirred at room temperature for a day under a hydrogen atmosphere (approximately 1 atmospheric pressure). The reaction mixture was filtered through celite and evaporated to remove the solvent. The resulting crude product was purified by column chromatography (NH SiO₂, methanol/chloroform=0-25%) to give the titled compound (gray amorphous substance, 323 mg).

¹H NMR (600 MHz, DMSO-d₆), 8 ppm: 1.23 (t, J=7.3 Hz, 3H), 1.54 (d, J=6.9 Hz, 3H), 3.82-4.09 (m, 2H), 4.60 (q, J=6.0 Hz, 1H), 6.61-6.69 (m, 2H), 6.70-6.77 (m, 1H), 7.14-7.21 (m, 1H), 8.28-9.11 (m, 2H), 9.43-10.55 (m, 1H)

3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 114)

(3) Triethylamine (0.225 ml) and 3,4-dichlorobenzenesulfonyl chloride (198 mg) were added at room temperature to a solution of the compound (200 mg) of Example 17-(2) in THF (2.0 ml), and the mixture was stirred at room temperature for 12 hours. The mixture was evaporated to remove the solvent, and KOH (104 mg), ethanol (4.0 ml), and water (4.0 ml) were added to the resulting crude product. The mixture was stirred at 120° C. for 40 minutes, and then cooled to room temperature. HCl (1.0 N) was added, and the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform=1/4), dried (MgSO₄), filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO₂, ethyl acetate/hexane=30-70%) and then recrystallized (methanol/chloroform/hexane) to give 37 mg of the titled compound (Compound 114) as a colorless powder.

Melting point: 185.0° C. to 186.0° C.

Example 18 3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]triazol-3-yloxy]benzoic acid t-butyl ester (Compound 118)

3-[(5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-benzoic acid t-butyl ester

(1) Starting from 3-hydroxybenzoic acid t-butyl ester in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (colorless and oily, yield 24%).

¹H NMR (600 MHz, CDCl₃), 8 ppm: 1.43 (t, J=7.1 Hz, 3H), 1.58-1.62 (m, 12H), 4.01-4.13 (m, 2H), 4.18 (q, J=6.6 Hz, 1H), 7.42-7.46 (m, 1H), 7.61-7.65 (m, 1H), 7.82-7.85 (m, 1H), 7.87-7.91 (m, 1H)

3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]triazol-3-yloxy]benzoic acid t-butyl ester (Compound 118)

(2) Starting from the compound obtained in Example 18-(1), the same procedure as used in Example 1-(8) was repeated to give the titled compound (colorless powder, yield 68%).

¹H NMR (600 MHz, CDCl₃), 8 ppm: 1.38 (t, J=7.3 Hz, 3H), 1.51 (d, J=6.9 Hz, 3H), 1.58 (s, 9H), 3.93-4.01 (m, 2H), 4.29-4.35 (m, 1H), 7.43-7.48 (m, 1H), 7.50-7.60 (m, 3H), 7.64-7.69 (m, 1H), 7.81-7.89 (m, 2H), 7.90-7.94 (m, 1H)

Example 19 3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-benzoic acid (Compound 113)

Trifluoroacetic acid (0.12 ml) was added to a solution of the compound (260 mg) of Example 18 in chloroform (12.0 ml), and the mixture was stirred at room temperature for five days. The mixture was evaporated to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH SiO₂, ethyl acetate/hexane=50-99%, methanol/chloroform=0-20%) and then recrystallized (methanol/chloroform/hexane) to give the titled compound (Compound 113) (101 mg, colorless powder).

Melting point: 183.0° C. to 185.0° C.

N—[(R)-1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-4-methoxybenzenesulfonamide (Compound 175)

To a solution of the compound (12.5 mg) of Example 1-(7) in THF (0.3 ml), triethylamine (25 μl) was added, and then a solution of 4-methoxybenzenesulfonylchloride (15.5 mg) in THF (0.3 ml) was added. The mixture was stirred at room temperature for two hours. PSA (product name: VARIAN Inc. polymer supported amine, 1.4 meq/g) (75 μl) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The insoluble matter was filtered off, and the resulting residue was evaporated to remove the solvent. The resulting crude product was purified by silica-gel column chromatography (acidic OH SiO₂, ethyl acetate/hexane=50-100%, methanol/chloroform=10%) to give 10.7 mg of the titled compound (Compound 175) as a colorless powder.

APCI MS (M−H)−: 419, APCI MS (M+H)+: 421

Example 21 3,4-Dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 45)

(1) The following compound was obtained by the same procedure as used in Example 1-(7) (the procedure will be specifically described below).

(R)-1-[4-Ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethylamine

In a pressure-resistant screw cap test tube, N,N′-dimethylpropyleneurea (DMPU) (4.0 ml), 3-(4-methyl-piperazin-1-yl)-phenol (500 mg), and cesium carbonate (2.21 g) were added to the compound (750 mg) obtained in Example 1-(6), and the mixture was stirred at 160° C. for three hours. The mixture was brought to room temperature, and saturated aqueous sodium chloride was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH SiO₂, chloroform/methanol=50/1-30/1) to give the titled compound (yellow oily compound, 427 mg).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.40 (t, J=7.3 Hz, 3H), 1.59 (d, J=6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J=6.9 Hz, 1H), 6.71-6.80 (m, 2H), 6.99-7.03 (m, 1H), 7.20-7.25 (m, 1H)

(2) The following compound was obtained by the same procedure as used in Example 1-(8) (the procedure will be specifically described below).

3,4-Dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 45)

Triethylamine (0.41 mL) and 3,4-dichlorobenzenesulfonyl chloride (0.232 mL) were added at room temperature to a solution of the compound (427 mg) of Example 21-(1) in THF (8.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (NH SiO₂, chloroform/methanol=50/1-30/1) and then recrystallized (ethyl acetate-hexane) to give 280 mg of the titled compound (Compound 45) as a colorless powder.

Melting point: 194.0° C. to 196.0° C.

Example 22 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 64)

(1) The following compound was obtained by the same procedure as used in Example 1-(7) (the procedure will be specifically described below).

(R)-1-[4-Ethyl-5-(1H-indol-6-yloxy)-4H-[1,2,4]triazol-3-yl]-ethylamine

In a pressure-resistant screw cap test tube, N,N″-dimethylpropyleneurea (DMPU) (5.0 ml), 1H-indol-6-ol (601 mg), and cesium carbonate (2.94 g) were added to the compound (1.00 g) obtained in Example 1-(6), and the mixture was stirred at 200° C. for one hour and then brought to room temperature. Saturated aqueous sodium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO₄), filtered, and evaporated under reduced pressure to remove the solvent. Then, the resulting crude product was purified by column chromatography (NH SiO₂, chloroform/methanol=50/1-30/1) to give the titled compound (yellow oily compound, 750 mg).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.42 (t, J=7.1 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 3.98-4.10 (m, 2H), 4.15 (q, J=6.7 Hz, 1H), 6.30-6.39 (m, 1H), 6.87-7.00 (m, 2H), 7.39-7.52 (m, 2H), 9.55 (s, 1H)

(2) The following compound was obtained by the same procedure as used in Example 1-(8) (the procedure will be specifically described below).

3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 64)

Triethylamine (0.77 mL) and 3,4-dichlorobenzenesulfonyl chloride (1.02 g) were added at room temperature to the compound (748 mg) of Example 22-(1) in THF (10.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (NH SiO₂,chloroform/methanol=30/1) and then recrystallized (CHCl₃/MeOH/hexane) to give 815 mg of the titled compound (Compound 64) as a colorless powder.

Melting point: 223.0° C. to 224.0° C.

Example 23 N—[(S)-2-Benzyloxy-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 695)

Starting from (R)-2-amino-3-benzyloxy-propionic acid methyl ester in place of N-(t-butoxycarbonyl)-D-alanine methyl ester used in Example 1-(1), the same procedure as used in Example 1 was repeated to give the titled compound (Compound 695) as a colorless powder.

¹H NMR (200 MHz, CDCl₃) δ ppm: 1.31 (t, J=7.3 Hz, 3H), 3.65-4.03 (m, 4H), 4.35 (s, 2H), 4.67 (q, J=7.9 Hz, 1H), 7.03-7.39 (m, 10H), 7.68 (dd, J=8.8, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)

Example 24 3,4-Dichloro-N—[(S)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2-hydroxyethyl]-benzenesulfonamide (Compound 696)

AlCl₃(49 mg) and PhNMe₂(148 mg) were added to a solution of the compound (69 mg) of Example 23 in CH₂Cl₂(2.0 ml), and the mixture was stirred at room temperature for one hour. Then, AcOEt was added, and the mixture was washed with 1N hydrochloric acid and thereafter with saturated aqueous sodium chloride. The organic layer was dried (Na₂SO₄), filtered, and evaporated under reduced pressure to remove the solvent. Then, the resulting crude product was purified by column chromatography (OH SiO₂, AcOEt/hexane=2/1) to give 54 mg of the titled compound (Compound 696) as a colorless powder.

¹H NMR (200 MHz, CDCl₃) δ ppm: 1.41 (t, J=7.5 Hz, 3H), 3.62 (dd, J=4.8, 11.8 Hz, 1H), 3.88 (dd, J=4.8, 11.8 Hz, 1H), 4.05 (q, J=7.5 Hz, 2H), 4.51-4.60 (m, 1H), 7.04-7.13 (m, 2H), 7.23-7.31 (m, 3H), 7.53 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)

Example 25 3,4-Dichloro-N—[(S)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2-fluoroethyl]-benzenesulfonamide (Compound 689)

A solution of diethylaminosulfurtrifluoride (DAST) (16 mg) in CH₂Cl₂(1.0 ml) was added at 0° C. to a solution of the compound (45 mg) of Example 24 in CH₂Cl₂(2.0 ml), and the mixture was stirred at the same temperature for one hour. The reaction solution was added to saturated aqueous sodium bicarbonate, and the mixture was extracted with AcOEt. The organic layer was dried (Na₂SO₄) and filtered evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (OH SiO₂, AcOEt/hexane=30-50%) to give 6 mg of the titled compound (Compound 696) as a pale yellow powder.

¹H NMR (200 MHz, CDCl₃) δ ppm 1.39 (t, J=7.5 Hz, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.45-4.86 (m, 3H), 6.98 (br, 1H), 7.05-7.36 (m, 4H), 7.48 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)

Example 26 3,4-Dichloro-N-[1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]-2,2,2-trifluoroethyl]-benzenesulfonamide (Compound 687)

4-Ethyl-5-mercapto-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester

(1) To a solution of diethyl formate (48.64 g) in MeOH (100 ml), a solution of hydrazine monohydrate (16.33 g) in MeOH (100 ml) was added dropwise at −5° C. over 1.5 hours, and ethylisothiocyanate (29.00 g) was added at the same temperature. The mixture was warmed to room temperature and stirred overnight. The insoluble matter was filtered off, and the resulting residue was evaporated to remove the solvent. The resulting solid was washed with a mixed solution of hexane/AcOEt (1/1) and dried, and the resulting white powder (55.30 g) was added to an aqueous solution (228 ml) of NaOH (913 mg). The mixture was stirred at 70° C. for four hours, at room temperature overnight, and then at 100° C. for seven hours. The reaction mixture was concentrated to approximately ⅓, and then a saturated aqueous NH₄Cl solution (300 ml) was added. The resulting white precipitate was filtered and dried to give the titled compound (15.06 g) as a colorless powder.

¹H NMR (200 MHz, CDCl₃) δ ppm 1.38 (t, J=6.6 Hz, 3H), 1.45 (t, J=6.5 Hz, 3H), 4.40-4.57 (m, 4H), 11.58-11.84 (m, 1H)

4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester

(2) Starting from the compound obtained in Example 26-(1), the same procedure as used in Example 1-(4) was repeated to give the titled compound as a light yellow solid (yield 84%).

¹H NMR (200 MHz, CDCl₃) δ ppm 1.31-1.50 (m, 6H), 2.80 (s, 3H), 4.31 (q, J=7.2 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H)

4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester

(3) Starting from the compound obtained in Example 26-(2), the same procedure as used in Example 1-(5) was repeated to give the titled compound as a light yellow solid (yield 84%).

¹H NMR (200 MHz, CDCl₃) δ ppm 1.48 (t, J=7.1 Hz, 3H), 1.53 (t, J=7.2 Hz, 3H), 3.60 (s, 3H), 4.53 (q, J=7.1 Hz, 2H), 4.75 (q, J=7.2 Hz, 2H)

4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester

(4) To a suspension of NaH (1.236 g, oil free) in THF (68 ml), 4-fluorophenol (4.62 g) was added at 0° C., and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0° C., and a solution of the compound (8.49 g) of Example 26-(3) in THF (20 ml) was added. The mixture was stirred at room temperature for 30 minutes and thereafter at 70° C. for 1.5 hours. The temperature was cooled to room temperature, and then the reaction mixture was added to a saturated aqueous NH₄Cl solution (500 ml). The mixture was extracted with AcOEt (500 ml) and washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO₄), filtered, and concentrated, and the resulting crude product was purified by column chromatography (OH acid SiO₂, AcOEt/hexane=10-99%) to give the titled compound (5.144 g, light yellow solid).

¹H NMR (200 MHz, CDCl₃) δ ppm 1.35-1.52 (m, 6H), 4.36 (q, J=7.2 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 7.02-7.18 (m, 2H), 7.28-7.48 (m, 2H)

4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-carbaldehyde

(5) DiBAl—H (0.99 M, toluene solution, 36.1 ml) was added at −5° C. to a solution of the compound (5.00 g) of Example 26-(4) in THF (50 ml), and the mixture was stirred at the same temperature for three hours. Then, 1N-hydrochloric acid was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO₄), filtered, and concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO₂, AcOEt/hexane=5-40%) to give the titled compound (2.22 g, colorless and oily).

¹H NMR (600 MHz, CDCl₃) δ ppm ppm 1.44 (t, J=7.3 Hz, 3H), 4.37 (J=7.3 Hz, 2H), 7.10-7.17 (m, 2H), 7.36-7.40 (m, 2H)

4-Methylbenzene sulfonic acid 4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-ylmethyleneamide

(6) A solution of the compound (1.00 g) obtained in Example 26-(5), 4-methylbenzene sulfonic acid amide (660 mg), and cesium carbonate (1.39 g) in chloroform (21 ml) was stirred at 45° C. for nine hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The resulting residue was purified by silica-gel chromatography (neutral OH silica gel, elution solvent: AcOEt/hexane 0-30%) to give the titled compound (630 mg) as a pale yellow solid.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.30 (t, J=7.1 Hz, 3H), 2.42 (s, 3H), 4.27-4.43 (m, 2H), 7.07-7.15 (m, 2H), 7.31-7.39 (m, 4H), 7.57-7.62 (m, 2H), 8.85 (s, 1H)

N-[1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]2,2,2-trifluoroethyl]-4-methylbenzamide

(7) Under an argon atmosphere, a solution of (trifluoromethyl)trimethyl silane (120 μl) in THF (5.0 ml) was added at −35° C. to a suspension of the compound (200 mg) of Example 26-(6) and tetramethylfluoride (60 mg) in THF (5.0 ml), and the mixture was stirred at the same temperature for an hour and a half. A further portion of tetramethylfluoride (60 mg) and thereafter a further portion of (trifluoromethyl)trimethyl silane (60 mg) were added to the reaction solution at the same temperature, and the mixture was stirred at the same temperature for two hours and warmed to −10° C., and a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by silica-gel column chromatography (neutral —OH silica gel, AcOEt/hexane 0-40%) to give the titled compound (219 mg) as a pale yellow oily substance.

¹H NMR (600 MHz, CDCl₃) δ ppm 1.32 (t, J=7.3 Hz, 3H), 2.40 (s, 3H), 3.80-3.87 (m, 2H), 4.86-4.92 (m, 1H), 5.59 (d, J=8.3 Hz, 1H), 7.06-7.13 (m, 2H), 7.27-7.31 (m, 2H), 7.32-7.37 (m, 2H), 7.53-7.59 (m, 2H)

1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2,2,2,-trifluoroethylamine

(8) HCl (4N, dioxane solution, 1.25 ml) was added at room temperature to a solution of the compound (215 mg) of Example 26-(7) in methanol (5.0 ml), and the mixture was stirred at 85° C. for two hours. The reaction solution was concentrated, and the resulting residue was purified by silica-gel column chromatography (NH SiO₂, AcOEt/hexane 0-50%) to give the titled compound (82 mg) as a colorless oily substance.

(600 MHz, CDCl₃) δ ppm: 1.43 (t, J=7.3 Hz, 3H), 3.97-4.11 (m, 2H), 4.47-4.54 (m, 1H), 7.06-7.12 (m, 2H), 7.35-7.40 (m, 2H)

3,4-Dichloro-N-[1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2,2,2-trifluoroethyl]-benzenesulfonamide (Compound 687)

(9) Starting from the compound (79 mg) obtained in Example 26-(8), the same procedure as used in Example 1-(8) was repeated to give the titled compound (3 mg) as a light yellow oily substance.

(600 MHz, CDCl₃) δ ppm: 1.43 (t, J=7.1 Hz, 3H), 3.91-4.07 (m, 2H), 5.06-5.13 (m, 1H), 7.07-7.16 (m, 2H), 7.29-7.35 (m, 2H), 7.50-7.57 (m, 1H), 7.67-7.74 (m, 1H), 7.90 (s, 1H)

Example 27 N—((R)-1-[5-[3-(4-Acetylpiperazin-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-3,4-dichlorobenzenesulfonamide (Compound 697)

(R)-1-[4-Ethyl-5-(3-piperazin-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethylamine

(1) In a pressure-resistant screw cap test tube, DMPU (10 ml), 3-piperazinylphenol (1.34 g), and Cs₂CO₃(6.13 g) were added to the compound (2.08 g) obtained in Example 1-(6), and the mixture was stirred at 200° C. for 40 minutes. It was cooled to room temperature and then concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (NH SiO₂, AcOEt to MeOH/CHCl₂=1/50) to give the titled compound (yellow oily compound, 1.17 g).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.40 (t, J=7.1 Hz, 3H), 1.59 (d, J=6.9 Hz, 3H), 2.98-3.04 (m, 4H), 3.14-3.19 (m, 4H), 3.97-4.09 (m, 2H), 4.13-4.18 (m, 1H), 6.70-6.80 (m, 2H), 6.97-7.03 (m, 1H), 7.21-7.26 (m, 1H)

1-(4-[3-[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone

(2) AcCl (0.24 ml) was added at −30° C. to a solution of the compound (1.06 g) of Example 27-(1) and Et₃N (1.4 ml) in THF (20 ml), and the mixture was stirred at the same temperature for two hours. Then, the mixture was warmed to room temperature and then stirred for another five hours. The reaction mixture was concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO₂, MeOH/CHCl₃=1/5) to give a mixture (315 mg, colorless solid) of the titled compound and triethylamine hydrochloride.

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.35 (t, J=7.3 Hz, 3H), 1.72 (d, J=6.4 Hz, 3H), 2.12 (s, 3H), 3.14-3.23 (m, 4H), 3.57-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.87-4.10 (m, 2H), 4.57-4.66 (m, 1H), 6.70-6.81 (m, 2H), 6.95-6.99 (m, 1H), 7.21-7.26 (m, 1H)

N—((R)-1-[5-[3-(4-Acetylpiperazin-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-3,4-dichlorobenzenesulfonamide (Compound 697)

(3) Water was added to a mixture (307 mg) of 1-(4-[3-[5-((R)-1-aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone obtained in Example 27-(2) and triethylamine hydrochloride, 3,4-dichlorobenzenesulfonyl chloride (0.13 ml), and K₂CO₃(355 mg). The mixture was stirred at room temperature for 15 hours. The precipitated solid was filtered and purified by column chromatography (NH SiO₂, MeOH/CHCl₃=1/50) to give the titled compound (Compound 697) (117 mg, colorless syrup).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.38 (t, J=7.3 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H), 2.14 (s, 3H), 3.14-3.27 (m, 4H), 3.56-3.64 (m, 2H), 3.72-3.80 (m, 2H), 3.88-4.01 (m, 2H), 4.58-4.68 (m, 1H), 5.98-6.06 (m, 1H), 6.72-6.82 (m, 2H), 6.95-7.01 (m, 1H), 7.25-7.30 (m, 1H), 7.51-7.57 (m, 1H), 7.65-7.73 (m, 1H), 7.89-7.97 (m, 1H)

Example 28 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-piperazin-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 683),

A mixture of the compound (107 mg) obtained in Example 27-(3), NaOH (105 mg), water (2.0 ml), and EtOH (4.0 ml) was stirred at 80° C. for one hour and then stirred at 100° C. for 18 hours. The mixture was cooled to room temperature and then extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO₄), filtered, and concentrated. The resulting crude product was purified by column chromatography (NH SiO₂, MeOH/CHCl₂=1/30) and then recrystallized (AcOEt/hexane) to give the titled compound (Compound 683) (55 mg, colorless powder).

¹H NMR (600 MHz, DMSO-d₆) δ ppm: 1.24 (t, J=7.3 Hz, 3H), 1.31 (d, J=6.9 Hz, 3H), 2.77-2.86 (m, 4H), 3.03-3.10 (m, 4H), 3.81-3.99 (m, 2H), 4.67-4.75 (m, 1H), 6.56-6.62 (m, 1H), 6.76-6.85 (m, 2H), 7.19-7.27 (m, 1H), 7.69-7.77 (m, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.93-7.97 (m, 1H)

Melting point: 175.0° C. to 178.0° C.

The compounds shown in Table 1 were obtained using the corresponding starting compounds and the procedures shown in Examples 1 to 28.

The compounds obtained in the Examples above are also shown in Table 1 together with the other compounds.

Test Example 1 (S1P₁Binding Assay

Using a human Edg-1 (S1P₁) gene transferred HEK-293 cell strain membrane fraction, the Edg-1 (S1P₁) binding inhibiting action of the compounds of the present invention was determined in accordance with the method described in the literature (Science. 2002, 296: 346) (showing a binding of Kd=0.15 nM, Bmax=2.5 fmol/μg to [³³P]-S1P). The membrane fraction was obtained by treating the cells with a solubilizing buffer (1 mM Tris/HCl, pH 7.2) for 10 minutes on ice, centrifuging at 1000×g for 5 minutes to remove insoluble fractions, and then centrifuging at 40000×g for 30 minutes at 4° C. The resulting membrane fraction was dissolved in a binding buffer (20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 15 mM NaF, 2 mM deoxypyridoxine, 4 mg/mL fatty acid-free BSA), and then [³³P]-S1P (manufactured by ARC, final concentration 0.1 nM) and a DMSO solution (final concentration of the compound 10⁻⁵M, final concentration of DMSO 0.1%) of the test compound were added. Thereafter, the mixture was stirred and then treated for one hour at 30° C. Using a harvester, the membrane fraction was harvested onto unifilter-96 GF/C filter (manufactured by Perkin Elmer), washing was carried out four times with the binding buffer, and the filter was dried. Twenty five μL Microscint 0 (manufactured by Perkin Elmer) was added, and radioactivity was measured using Top Count NXT (manufactured by Packard) to calculate the amount (A) of [³³P]-S1P bound to the membrane fraction at the time when the compound was added.

The same procedure was carried out in the absence of the test compound, and the amount (B) of [³³P]-S1P bound was calculated. Further, the same procedure was carried out in the absence of the test compound by use of HEK-293 cells to which no Edg-1 (S1P₁) gene was introduced, and the background amount (C) of [³³P]-S1P bound was calculated.

The Edg-1 (S1P₁) binding inhibition rates of the compound calculated using the following equation are shown in Table 1.

Inhibition rate(%)=[1−(A−C)/(B−C)]×100

Further, concentrations (IC₅₀) at the time when binding in the absence of the test compound was inhibited by 50% were calculated. The membrane system binding assay was carried out in the presence of test compounds with various concentrations, and the Edg-1 (S1P₁) binding inhibition rates were calculated using the equation above. Then, IC₅₀values were calculated using Origin (Lightstone Corp.), a software for data analysis.

The compounds below each had an IC₅₀value of 35 nM or lower and showed particularly strong activity.

Compounds 5, 13, 16, 18, 21, 23, 25, 26, 32, 35, 37, 43, 46, 64, 69, 76, 101, 102, 109, 122, 123, 125, 131, 134, 141, 142, 145, 665.

The following compounds had an IC₅₀value of 10 nM or below, and showed even stronger activity.

Compounds 24, 39, 40, 70, 75, 87, 93, 94, 107, 111, 112, 121, 132, 133, 137, 138, 139, 140, 147, 151, 663, 666, 667, 669, 671, 681, 683, 690.

Specific IC₅₀values of the individual compounds are as follows (unit: nM).

Compound 3: 4.2. Compound 7: 35.5. Compound 8: 18.5. Compound 10: 17.5. Compound 11: 8.9. Compound 12: 20.0. Compound 14: 6.4. Compound 15: 32.5. Compound 22: 14.0. Compound 28: 3.1. Compound 34: 2.0. Compound 36: 17.5. Compound 38: 11.7. Compound 42: 22.0. Compound 45: 4.2. Compound 46: 28.5. Compound 49: 6.0. Compound 61: 39.0. Compound 73: 2.2. Compound 74: 15.0. Compound 83: 8.1. Compound 88: 5.4. Compound 99: 25.0. Compound 100: 18.5. Compound 105: 2.9. Compound 108: 18.0. Compound 120:1.7. Compound 129: 20.0. Compound 130: 2.9. Compound 136: 8.1. Compound 143: 7.3. Compound 144: 7.9. Compound 146: 12.0. Compound 148: 1.9. Compound 149: 7.8. Compound 670: 5.2. Compound 678: 10.2. Compound 680:1.4. Compound 688: 1.5. Compound 691: 2.6. Compound 692: 5.1. Compound 694: 2.9. Compound 698: 2.3.

TABLE 1 Binding assay (membrane) Compound Melting % inhibition number Chemical structure point (° C.) (10 μM) Compound 1 182.0-184.0 100.8 Compound 2 134.0-138.0 97.8 Compound 3 183.5-187.5 98.7 Compound 4 198.5-200.5 95.7 Compound 5 160.0-161.0 97.3 Compound 6 180.0-190.0 98.2 Compound 7 159.5-161.5 99.4 Compound 8 179.0-179.5 100.1 Compound 9 145.0-148.0 100.3 Compound 10 182.5-184.5 99.8 Compound 11 155.0-160.0 98.5 Compound 12 190.0-192.0 99.2 Compound 13 152.0-156.0 102.0 Compound 14 161.0-162.5 99.5 Compound 15 200.0-205.0 102.7 Compound 16 125.0-127.0 101.3 Compound 17 129.5-131.5 95.4 Compound 18 189.0-194.0 102.1 Compound 19 145.0-150.0 97.9 Compound 20 118.0-120.0 97.4 Compound 21 146.5-149.5 96.7 Compound 22 163.0-167.5 95.4 Compound 23 173.0-176.0 96.7 Compound 24 172.5-173.0 101.0 Compound 25 155.0-156.0 97.5 Compound 26 159.0-164.0 97.9 Compound 27 163.0-168.0 100.1 Compound 28 165.0-170.0 104.4 Compound 29 177.0-178.5 101.4 Compound 30 212.0-216.0 100.4 Compound 31 143.0-146.0 101.2 Compound 32 147.0-148.0 104.1 Compound 33 173.5-174.5 100.8 Compound 34 192.5-195.5 106.1 Compound 35 156.0-159.0 100.4 Compound 36 125.0-130.0 102.2 Compound 37 145.0-147.0 100.3 Compound 38 148.5-150.0 104.8 Compound 39 176.0-178.0 98.5 Compound 40 155.5-156.5 105.6 Compound 41 166.0-170.0 92.0 Compound 42 176.5-179.5 102.4 Compound 43 182.5-185.0 99.8 Compound 44 140.0-145.5 100.1 Compound 45 194.0-196.0 106.0 Compound 46 247.0-250.0 94.6 Compound 47 191.0-192.0 102.3 Compound 48 195.5-196.5 96.7 Compound 49 198.0-199.0 102.5 Compound 50 129.0-130.0 92.9 Compound 51 148.5-150.5 99.9 Compound 52 203.0-205.0 100.2 Compound 53 172.0-173.0 86.8 Compound 54 192.0-193.0 104.1 Compound 55 141.0-143.0 80.6 Compound 56 189.0-191.0 88.3 Compound 57 164.0-165.0 Compound 58 181.0-183.0 99.7 Compound 59 169.5-170.5 94.3 Compound 60 192.5-195.0 98.9 Compound 61 93.0-99.0 102.2 Compound 62 186.0-188.5 83.5 Compound 63 216.5-217.5 104.7 Compound 64 223.0-224.0 100.8 Compound 65 201.0-202.0 105.3 Compound 66 183.0-190.0 93.4 Compound 67 182.0-188.0 95.5 Compound 68 212.0-223.0 100.9 Compound 69 119.0-120.5 103.2 Compound 70 144.0-146.0 96.5 Compound 71 126.0-135.0 99.3 Compound 72 198.0-200.5 99.0 Compound 73 185.0-187.0 103.3 Compound 74 218.5-227.0 104.9 Compound 75 177.0-179.0 95.0 Compound 76 151.5-153.5 99.2 Compound 77 123.0-127.0 99.7 Compound 78 178.0-179.0 90.7 Compound 79 190.0-195.0 103.7 Compound 80 164.0-165.0 87.6 Compound 81 160.0-165.0 93.2 Compound 82 142.0-145.0 100.8 Compound 83 170.0-173.0 100.7 Compound 84 160.0-165.0 100.5 Compound 85 133.0-134.0 100.0 Compound 86 176.0-177.0 106.7 Compound 87 174.0-179.0 99.9 Compound 88 188.5-190.5 99.5 Compound 89 101.0-103.0 90.3 Compound 90 168.0-170.0 99.0 Compound 91 137.0-138.0 90.6 Compound 92 118.0-120.0 92.1 Compound 93 167.5-169.5 99.9 Compound 94 190.0-192.0 106.4 Compound 95 205.0-208.5 92.4 Compound 96 191.0-194.0 78.7 Compound 97 158.0-159.0 93.0 Compound 98 143.0-144.0 100.4 Compound 99 103.0-105.5 102.4 Compound 100 109.9 Compound 101 142.0-143.0 100.9 Compound 102 117.0-118.0 104.2 Compound 103 146.5-147.5 91.2 Compound 104 187.0-187.5 95.2 Compound 105 121.0-123.0 104.4 Compound 106 132.0-134.0 110.2 Compound 107 159.0-162.0 103.8 Compound 108 175.0-180.0 101.3 Compound 109 152.0-153.0 103.5 Compound 110 187.5-188.5 103.6 Compound 111 204.0-205.0 108.7 Compound 112 171.0-173.0 99.2 Compound 113 183.0-185.0 74.2 Compound 114 185.0-186.0 94.5 Compound 115 125.5-126.5 81.8 Compound 116 192.0-195.0 83.1 Compound 117 153.5-155.5 87.1 Compound 118 Compound 119 Compound 120 211.5-216.5 93.03 Compound 121 195.5-198.5 103.45 Compound 122 167.0-170.0 81.93 Compound 123 162.0-165.0 97.12 Compound 124 178.5-180.0 97.44 Compound 125 253.5-254.5 94.28 Compound 126 176.5-178.0 91.80 Compound 127 94.44 Compound 128 182.5-183.5 90.70 Compound 129 96.0-104.0 96.79 Compound 130 107.0-114.0 98.87 Compound 131 102.0-110.5 97.35 Compound 132 95.0-104.0 99.52 Compound 133 164.0-169.5 101.11 Compound 134 108.5-114.5 101.47 Compound 135 188.5-192.0 100.63 Compound 136 100.0-106.0 96.51 Compound 137 173.5-177.0 101.74 Compound 138 167.5-169.0 99.58 Compound 139 174.0-177.0 101.46 Compound 140 110.0-119.0 101.57 Compound 141 169.0-173.0 104.70 Compound 142 183.0-184.0 98.11 Compound 143 144.0-145.0 99.89 Compound 144 187.0-188.0 99.38 Compound 145 150.0-152.0 101.30 Compound 146 121.0-122.0 101.65 Compound 147 141.0-143.0 102.74 Compound 148 154.5-155.5 102.47 Compound 149 212.0-214.5 100.70 Compound 1 191.5-196.0 93.40 Compound 2 252.0-255.0 102.84 Binding assay APCI APCI (membrane) Compound MS MS % inhibition number Chemical Structure (M − H)⁻ (M + H)⁺ (10 μM) Compound 152 467 469 Compound 153 446 448 Compound 154 431 433 92.3 Compound 155 389 391 59.9 Compound 156 467, 469 469, 471 106.6 Compound 157 445 447 74.6 Compound 158 467, 469 469, 471 Compound 159 461 463 Compound 160 467, 469 469, 471 96.9 Compound 161 551, 553 553, 554 Compound 162 423 425 109.3 Compound 163 414 416 Compound 164 465 467 Compound 165 414 416 72.9 Compound 166 493 495 Compound 167 451 453 113.3 Compound 168 457 459 68.4 Compound 169 457 459 Compound 170 449 451 76.0 Compound 171 341 343 Compound 172 417 419 92.0 Compound 173 407 409 97.2 Compound 174 431 433 52.5 Compound 175 419 421 102.7 Compound 176 327 329 Compound 177 467 469 55.3 Compound 178 467 469 Compound 179 439 441 83.0 Compound 180 467 469 94.6 Compound 181 479 481 50.4 Compound 182 514 517 109.3 Compound 183 415 417 92.8 Compound 184 491, 493 493, 495 97.3 Compound 185 515 517 Compound 186 403 405 86.8 Compound 187 403 405 Compound 188 457 459 106.6 Compound 189 403 405 99.7 Compound 190 473 475 87.9 Compound 191 415 417 96.9 Compound 192 403 405 95.2 Compound 193 530 532 Compound 194 540 542 80.7 Compound 195 417 419 90.1 Compound 196 479 481 65.6 Compound 197 535 537 Compound 198 441 443 Compound 199 408 410 Compound 200 465 467 Compound 201 450 452 84.3 Compound 202 421 423 Compound 203 447 449 Compound 204 457 459 Compound 205 465 467 Compound 206 431 433 85.4 Compound 207 491, 493 493, 495 107.7 Compound 208 445 447 80.2 Compound 209 457 459 91.4 Compound 210 437 439 Compound 211 423 425 Compound 212 525 527 69.7 Compound 213 457 459 101.9 Compound 214 437 439 102.1 Compound 215 419 421 91.4 Compound 216 503, 505 505, 507 88.9 Compound 217 461 463 57.5 Compound 218 497, 499 499, 501 74.7 Compound 219 421 423 70.8 Compound 220 459 461 93.7 Compound 221 433 435 69.2 Compound 222 473 475 Compound 223 414 416 90.8 Compound 224 481 483 Compound 225 491, 493 493, 495 Compound 226 457 459 80.4 Compound 227 425 427 51.4 Compound 228 449 451 53.9 Compound 229 441 443 Compound 230 407 409 Compound 231 423 425 65.1 Compound 232 431 433 68.7 Compound 233 455 457 87.1 Compound 234 495, 497 497, 499 50.6 Compound 235 481, 483 483, 485 82.9 Compound 236 448 450 Compound 237 443 445 64.8 Compound 238 425 427 Compound 239 525 527 Compound 240 459 461 82.5 Compound 241 425 427 95.8 Compound 242 485, 487 487, 489 85.9 Compound 243 459 461 90.0 Compound 244 503, 505 505, 507 94.6 Compound 245 459 461 89.3 Compound 246 471 473 Compound 247 493 495 Compound 248 471 473 104.9 Compound 249 581, 583 583, 585 Compound 250 425 427 Compound 251 491 493 59.0 Compound 252 407 409 82.8 Compound 253 480 482 Compound 254 453 455 75.1 Compound 255 471 473 86.4 Compound 256 443 445 85.2 Compound 257 545, 547 547, 549 78.2 Compound 258 462 464 67.9 Compound 259 437 439 Compound 260 545, 547 547, 549 74.1 Compound 261 432 434 73.6 Compound 262 417 419 79.6 Compound 263 455 457 82.6 Compound 264 455 457 95.9 Compound 265 503, 505 505, 507 59.1 Compound 266 425 427 99.0 Compound 267 441 443 89.6 Compound 268 443 445 99.9 Compound 269 485, 487 487, 489 91.5 Compound 270 535, 537 537, 539 73.0 Compound 271 535, 537 537, 539 57.1 Compound 272 421 423 104.3 Compound 273 421 423 71.6 Compound 274 441 443 53.5 Compound 275 485, 487 487, 489 107.1 Compound 276 501, 503 503, 505 94.4 Compound 277 535, 537 537, 539 Compound 278 477 479 Compound 279 421 423 79.6 Compound 280 441 443 87.3 Compound 281 475 477 Compound 282 495 497 Compound 283 482 484 Compound 284 404 406 Compound 285 419 421 Compound 286 409 411 60.6 Compound 287 456 455 Compound 288 394 396 Compound 289 447 449 105.6 Compound 290 424 426 Compound 291 447 449 Compound 292 447 449 106.9 Compound 293 431 433 Compound 294 395 397 50.8 Compound 295 462 464 Compound 296 469 471 Compound 297 478 480 Compound 298 543 545 Compound 299 519 521 Compound 300 423 425 82.1 Compound 301 449 451 78.8 Compound 302 538 540 Compound 303 491 493 77.4 Compound 304 517 519 Compound 305 561 563 Compound 306 431 433 60.2 Compound 307 457 459 94.4 Compound 308 490 492 Compound 309 490 492 Compound 310 494 496 Compound 311 447 449 76.5 Compound 312 461 463 Compound 313 437 439 Compound 314 502 504 52.2 Compound 315 440 442 Compound 316 525 527 Compound 317 535, 537 537, 539 Compound 318 535, 537 537, 539 78.9 Compound 319 535, 537 537, 539 61.7 Compound 320 390 392 Compound 321 475 477 Compound 322 539 541 Compound 323 445 447 77.9 Compound 324 445 447 81.8 Compound 325 488 490 Compound 326 487 469 Compound 327 452 454 92.3 Compound 328 410 412 85.2 Compound 329 488, 490 490, 492 100.8 Compound 330 466 468 81.6 Compound 331 488, 490 490, 492 59.8 Compound 332 482 484 Compound 333 488, 490 490, 492 102.2 Compound 334 572, 574 574, 576 Compound 335 444 446 106.1 Compound 336 435 437 56.8 Compound 337 486 488 Compound 338 435 437 69.2 Compound 339 514 516 62.8 Compound 340 472 474 100.0 Compound 341 478 480 92.8 Compound 342 478 480 53.6 Compound 343 470 472 86.5 Compound 344 362 364 Compound 345 438 440 90.4 Compound 346 428 430 89.2 Compound 347 452 454 50.1 Compound 348 440 442 109.1 Compound 349 348 350 Compound 350 488 490 75.0 Compound 351 488 490 Compound 352 460 462 88.5 Compound 353 488 490 92.3 Compound 354 500 502 Compound 355 536 538 98.8 Compound 356 436 438 95.6 Compound 357 512, 514 514, 516 106.1 Compound 358 536 538 Compound 359 424 426 95.7 Compound 360 424 426 Compound 361 424 426 96.9 Compound 362 494 496 95.1 Compound 363 436 438 96.2 Compound 364 424 426 87.5 Compound 365 551 553 Compound 366 561 563 63.2 Compound 367 438 440 94.3 Compound 368 500 502 60.5 Compound 369 556 558 Compound 370 462 464 Compound 371 429 431 Compound 372 471 473 106.3 Compound 373 442 444 Compound 374 468 470 Compound 375 478 480 Compound 376 486 488 Compound 377 452 454 73.9 Compound 378 466 468 71.6 Compound 379 478 480 89.2 Compound 380 458 460 Compound 381 444 446 Compound 382 546 548 66.9 Compound 383 478 480 83.6 Compound 384 458 460 88.1 Compound 385 462 464 98.0 Compound 386 440 442 84.0 Compound 387 524, 526 526, 528 63.5 Compound 388 482 484 65.8 Compound 389 518, 520 520, 522 88.0 Compound 390 442 444 65.9 Compound 391 480 482 80.4 Compound 392 566, 568 568, 570 73.6 Compound 393 454 456 79.7 Compound 394 494 496 Compound 395 435 437 79.1 Compound 396 502 504 Compound 397 512, 514 514, 516 Compound 398 478 480 84.7 Compound 399 446 448 Compound 400 470 472 75.3 Compound 401 462 464 Compound 402 428 430 Compound 403 444 446 72.5 Compound 404 452 454 60.2 Compound 405 476 478 61.4 Compound 406 516, 518 518, 520 56.3 Compound 407 502, 504 504, 506 68.2 Compound 408 469 471 Compound 409 464 466 74.7 Compound 410 446 448 Compound 411 546 548 Compound 412 480 482 82.5 Compound 413 446 448 95.3 Compound 414 506, 508 508, 510 92.5 Compound 415 480 482 91.5 Compound 416 524, 526 526, 528 83.2 Compound 417 480 482 90.8 Compound 418 492 494 Compound 419 514 516 Compound 420 602, 604 604, 606 61.0 Compound 421 446 448 Compound 422 512 514 83.1 Compound 423 428 430 87.8 Compound 424 501 503 Compound 425 474 476 90.1 Compound 426 492 494 92.3 Compound 427 464 466 86.5 Compound 428 566, 568 568, 570 81.4 Compound 429 483 485 71.1 Compound 430 458 460 50.0 Compound 431 566, 568 568, 570 80.5 Compound 432 453 455 84.2 Compound 433 438 440 93.8 Compound 434 476 478 79.5 Compound 435 476 478 94.6 Compound 436 524, 526 526, 528 67.5 Compound 437 446 448 97.3 Compound 438 462 464 71.6 Compound 439 464 466 98.1 Compound 440 502, 504 504, 506 88.4 Compound 441 506, 508 508, 510 63.0 Compound 442 556, 558 558, 560 70.1 Compound 443 556, 558 558, 560 55.7 Compound 444 442 444 100.2 Compound 445 442 444 55.6 Compound 446 462 464 75.8 Compound 447 506, 508 508, 510 95.5 Compound 448 522, 524 524, 526 81.1 Compound 449 556, 558 558, 560 Compound 450 498 500 Compound 451 442 444 76.8 Compound 452 462 464 68.9 Compound 453 496 498 Compound 454 516 518 Compound 455 503 505 Compound 456 425 427 Compound 457 440 442 Compound 458 430 432 83.8 Compound 459 474 476 Compound 460 482 484 53.2 Compound 461 468 470 99.7 Compound 462 445 447 Compound 463 468 470 Compound 464 468 470 87.9 Compound 465 452 454 Compound 466 416 418 51.1 Compound 467 483 485 59.9 Compound 468 490 492 56.2 Compound 469 499 501 Compound 470 564 566 Compound 471 540 542 Compound 472 444 446 55.3 Compound 473 470 472 74.5 Compound 474 559 561 Compound 475 512 514 51.8 Compound 476 482 484 Compound 477 452 454 58.1 Compound 478 478 480 87.0 Compound 479 511 513 Compound 480 511 513 Compound 481 515 517 Compound 482 468 470 87.4 Compound 483 482 484 Compound 484 523 525 65.3 Compound 485 461 463 Compound 486 546 548 Compound 487 556, 558 558, 560 Compound 488 556, 558 558, 560 62.5 Compound 489 556, 558 558, 560 Compound 490 411 413 Compound 491 496 498 Compound 492 560 562 Compound 493 466 468 83.1 Compound 494 466 468 66.0 Compound 495 547 549 Compound 496 526 528 Compound 497 511 513 103.6 Compound 498 469 471 84.0 Compound 499 547, 549 549, 551 108.9 Compound 500 525 527 90.2 Compound 501 547, 549 549, 551 61.7 Compound 502 541 543 75.5 Compound 503 547, 549 549, 551 116.0 Compound 504 631, 633 633, 635 53.5 Compound 505 503 505 108.0 Compound 506 494 496 83.2 Compound 507 545 547 84.8 Compound 508 494 496 Compound 509 573 575 87.0 Compound 510 531 533 113.5 Compound 511 537 539 98.6 Compound 512 537 539 60.7 Compound 513 529 531 96.6 Compound 514 421 423 Compound 515 497 499 108.9 Compound 516 487 489 106.7 Compound 517 511 513 69.6 Compound 518 499 501 110.8 Compound 519 407 409 Compound 520 547 549 69.9 Compound 521 547 549 Compound 522 519 521 98.4 Compound 523 547 549 113.5 Compound 524 559 561 83.0 Compound 525 595 597 110.9 Compound 526 571, 573 573, 575 111.8 Compound 527 595 597 52.1 Compound 528 483 485 106.2 Compound 529 483 485 Compound 530 537 539 114.7 Compound 531 483 485 100.1 Compound 532 553 555 99.2 Compound 533 495 497 Compound 534 483 485 100.8 Compound 535 610 612 Compound 536 620 622 50.3 Compound 537 497 499 96.7 Compound 538 559 561 97.1 Compound 539 615 617 Compound 540 521 523 64.3 Compound 541 488 490 65.5 Compound 542 545 547 50.1 Compound 543 530 532 111.8 Compound 544 501 503 53.9 Compound 545 527 529 50.7 Compound 546 537 539 55.8 Compound 547 545 547 Compound 548 511 513 96.7 Compound 549 525 527 89.2 Compound 550 537 539 103.6 Compound 551 517 519 76.1 Compound 552 503 505 67.2 Compound 553 605 607 106.6 Compound 554 537 539 116.5 Compound 555 517 519 102.0 Compound 556 499 501 104.8 Compound 557 583, 585 585, 587 107.3 Compound 558 541 543 64.8 Compound 559 577, 579 579, 581 79.3 Compound 560 501 503 74.4 Compound 561 539 541 92.4 Compound 562 513 515 93.3 Compound 563 553 555 64.1 Compound 564 494 496 105.4 Compound 565 561 563 Compound 566 571, 573 573, 575 88.7 Compound 567 537 539 101.6 Compound 568 505 507 71.1 Compound 569 529 531 75.0 Compound 570 521 523 77.4 Compound 571 487 489 55.7 Compound 572 503 505 96.5 Compound 573 511 513 86.3 Compound 574 575, 577 577, 579 86.9 Compound 575 561, 563 563, 565 103.7 Compound 576 528 530 81.4 Compound 577 523 525 92.4 Compound 578 505 507 Compound 579 605 607 87.6 Compound 580 539 541 89.2 Compound 581 505 507 99.9 Compound 582 565, 567 567, 569 106.0 Compound 583 539 541 108.9 Compound 584 583, 585 585, 587 96.2 Compound 585 539 541 103.0 Compound 586 551 553 87.9 Compound 587 573 575 60.0 Compound 588 551 553 109.3 Compound 589 661, 663 663, 665 80.2 Compound 590 505 507 62.3 Compound 591 571 573 77.5 Compound 592 487 489 95.8 Compound 593 560 562 65.9 Compound 594 533 535 84.0 Compound 595 551 553 93.7 Compound 596 523 525 100.3 Compound 597 625, 627 627, 629 97.3 Compound 598 542 544 89.5 Compound 599 517 519 80.6 Compound 600 625, 627 627, 629 100.5 Compound 601 512 514 100.4 Compound 602 497 499 106.7 Compound 603 535 537 106.8 Compound 604 535 537 109.4 Compound 605 583, 585 535, 587 83.4 Compound 606 505 507 107.8 Compound 607 521 523 Compound 608 523 525 108.6 Compound 609 565, 567 567, 569 93.1 Compound 610 615, 617 617, 619 91.2 Compound 611 615, 617 617, 619 63.9 Compound 612 501 503 114.0 Compound 613 501 503 90.9 Compound 614 521 523 77.8 Compound 615 565, 567 567, 569 110.3 Compound 616 581, 583 583, 585 99.9 Compound 617 615, 617 617, 619 77.5 Compound 618 557 559 65.4 Compound 619 497 499 114.2 Compound 620 501 503 88.4 Compound 621 521 523 95.4 Compound 622 555 557 58.9 Compound 623 575 577 Compound 624 562 564 Compound 625 484 486 Compound 626 499 501 61.1 Compound 627 489 491 90.0 Compound 628 533 535 64.4 Compound 629 541 543 101.1 Compound 630 527 529 107.4 Compound 631 504 506 95.2 Compound 632 527 529 59.9 Compound 633 527 529 111.2 Compound 634 511 513 51.0 Compound 635 475 477 68.7 Compound 636 542 544 85.7 Compound 637 549 551 50.6 Compound 638 558 560 Compound 639 623 625 Compound 640 599 601 59.5 Compound 641 503 505 85.2 Compound 642 529 531 85.5 Compound 643 618 620 Compound 644 571 573 93.0 Compound 645 597 599 Compound 646 641 643 Compound 647 511 513 99.0 Compound 648 537 539 107.8 Compound 649 570 572 64.7 Compound 650 570 572 Compound 651 574 576 Compound 652 527 529 91.9 Compound 653 541 543 Compound 654 582 584 71.7 Compound 655 605 607 Compound 656 615, 617 617, 619 Compound 657 615, 617 617, 619 94.9 Compound 658 615, 617 617, 619 80.4 Compound 659 470 472 Compound 660 555 557 Compound 661 619 621 Compound 662 525 527 95.4 Binding assay (membrane) Compound Melting % inhibition number Chemical structure point (° C.) (10 μM) Compound 663 210.0-217.0 99.5 Compound 664 218.0-221.5 85.4 Compound 665 197.0-201.0 100.3 Compound 666 143.5-144.5 97.9 Compound 667 207.0-208.0 99.2 Compound 668 98.6 Compound 669 131.5-132.5 100.3 Compound 670 214.5-218.0 100.8 Compound 671 100.6 Compound 672 102.7 Compound 673 62.0 Compound 674 97.0 Compound 675 96.6 Compound 676 92.6 Compound 677 60.8 Compound 678 97.4 Compound 679 104.0 Compound 680 169.5-170.5 100.1 Compound 681 189.0-189.5 100.2 Compound 682 228.0-228.5 76.6 Compound 683 175.0-178.0 100.5 Compound 684 169.5-171.5 Compound 685 255.0-260.0 65.1 Compound 686 220.5-221.0 92.7 Compound 687 80.1 Compound 688 192.0-193.0 100.5 Compound 689 92.7 Compound 690 198.0-200.0 102.2 Compound 691 180.0-182.0 98.5 Compound 692 227.0-229.0 98.5 Compound 693 158.0-161.0 97.7 Compound 694 189.0-191.0 106.0 Compound 695 Compound 696 Compound 697 Compound 698 99.8

In Table 1, some of the compounds have two data on APCI MS (M−H)− and APCI MS (M+H)+, because two peaks were detected due to isotopes of a chlorine atom or a bromine atom.

For the compounds listed below, ¹H-NMR data is shown.

Compound 100: (600 MHz, DMSO-d₆) δ ppm: 1.21 (t, J=7.1 Hz, 3H) 1.27 (d, J=6.9 Hz, 3H) 3.22 (s, 6H) 3.40-3.50 (m, 8H) 3.77-3.93 (m, 2H) 4.68 (q, J=6.9 Hz, 1H) 6.34 (dd, J=7.3, 2.29 Hz, 1H) 6.52 (dd, J=8.3, 2.29 Hz, 1H) 6.56 (t, J=2.3 Hz, 1H) 7.12 (t, J=8.3 Hz, 1H) 7.70 (dd, J=8.3, 2.3 Hz, 1H) 7.85 (d, J=8.3 Hz, 1H) 7.92 (d, J=1.8 Hz, 1H) 8.66 (s, 1H).

Compound 119: (600 MHz, CDCl₃) δ ppm: 1.34 (t, J=7.3 Hz, 3H), 1.50 (d, J=7.3 Hz, 3H), 3.89-3.98 (m, 2H), 4.59-4.65 (m, 1H), 5.06 (s, 2H) 6.37-6.42 (m, 1H), 6.80-6.95 (m, 2H), 7.01-7.04 (m, 1H), 7.24-7.36 (m, 2H), 7.36-7.44 (m, 4H), 7.49-7.53 (m, 1H), 7.67-7.73 (m, 1H), 7.93-7.96 (m, 1H).

Compound 127: (600 MHz, CDCl₃) δ ppm: 1.38 (t, J=7.1 Hz, 3H), 1.49 (d, J=6.9 Hz, 3H), 2.41 (s, 3H), 3.93-4.02 (m, 2H), 4.59-4.65 (m, 1H), 5.47 (d, J=9.6 Hz, 1H), 7.05-7.10 (m, 2H), 7.31-7.37 (m, 3H), 7.61-7.64 (m, 1H), 7.80-7.82 (m, 1H).

Compound 129: (600 MHz, DMSO-d₆) δ ppm: 1.21-1.29 (m, 6H), 2.29 (s, 6H), 3.83-4.01 (m, 2H), 4.61 (q, J=6.4 Hz, 1H), 6.43-6.47 (m, 1H), 6.89-6.93 (m, 1H), 7.34-7.40 (m, 3H), 7.52-7.60 (m, 3H), 8.24 (s, 1H), 11.18 (s, 1H).

Compound 130: (600 MHz, DMSO-d₆) δ ppm: 1.22 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 3.87-4.02 (m, 2H), 4.70 (q, J=6.8 Hz, 1H), 6.43-6.45 (m, 1H), 6.77-6.80 (m, 1H), 7.28-7.30 (m, 1H), 7.36-7.38 (m, 1H), 7.50-7.53 (m, 1H), 7.67-7.75 (m, 2H), 7.83-7.86 (m, 1H), 8.04-8.07 (m, 1H), 8.12-8.19 (m, 2H), 8.45-8.47 (m, 1H), 8.52 (s, 1H), 11.16 (s, 1H).

Compound 131: (600 MHz, DMSO-d₆) δ ppm: 1.28 (t, J=7.1 Hz, 3H), 1.35 (d, J=6.9 Hz, 3H), 2.36 (s, 3H), 3.89-4.03 (m, 2H), 4.64-4.72 (m, 1H), 6.44-6.46 (m, 1H), 6.87-6.90 (m, 1H), 7.36-7.38 (m, 2H), 7.53-7.57 (m, 1H), 7.82-7.84 (m, 1H), 7.88-7.91 (m, 1H), 8.77 (s, 1H), 11.18 (s, 1H).

Compound 132: (600 MHz, DMSO-d₆) δ ppm: 1.23-1.31 (m, 6H), 2.39 (s, 3H), 3.85-4.02 (m, 2H), 4.69 (q, J=6.9 Hz, 1H), 6.43-6.47 (m, 1H), 6.88-6.92 (m, 1H), 7.36-7.39 (m, 2H), 7.53-7.60 (m, 2H), 7.64-7.68 (m, 1H), 7.77-7.80 (m, 1H), 8.51 (s, 1H), 11.18 (s, 1H).

Compound 134: (600 MHz, DMSO-d₆) δ ppm: 1.29 (t, J=7.3 Hz, 3H), 1.36 (d, J=6.9 Hz, 3H), 3.89-4.05 (m, 2H), 4.67-4.73 (m, 1H), 6.44-6.46 (m, 1H), 6.86-6.90 (m, 1H), 7.35-7.39 (m, 2H), 7.54-7.57 (m, 1H), 7.83-7.88 (m, 1H), 7.91-7.94 (m, 1H), 9.01 (s, 1H), 11.17 (s, 1H).

Compound 136: (600 MHz, DMSO-d₆) δ ppm: 1.23-1.31 (m, 6H), 3.85-4.02 (m, 2H), 4.72 (q, J=6.9 Hz, 1H), 6.44-6.47 (m, 1H), 6.87-6.91 (m, 1H), 7.34-7.39 (m, 2H), 7.52-7.57 (m, 1H), 7.97-8.05 (m, 4H), 8.74 (s, 1H), 11.17 (s, 1H).

Compound 150: (200 MHz, CDCl₃) δ ppm: 0.94 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H), 1.30 (t, J=7.3 Hz, 3H), 2.00-2.20 (m, 1H), 2.37 (s, 3H), 3.70-3.88 (m, 2H), 4.10 (dd, J=6.9, 9.4 Hz, 1H), 6.71 (d, J=9.4 Hz, 2H), 7.12-7.22 (m, 4H), 7.40 (d, J=8.4 Hz, 1H), 7.65 (dd, J=2.2, 8.4 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H).

Compound 668: (600 MHz, DMSO-d₆) ppm: 1.19-1.25 (m, 6H), 2.22 (s, 3H), 2.41-2.46 (m, 4H), 2.49-2.54 (m, 3H), 3.11-3.17 (m, 4H), 3.83-3.99 (m, 2H), 4.65-4.71 (m, 1H), 6.47-6.51 (m, 1H), 6.77-6.82 (m, 2H), 7.17-7.22 (m, 1H), 7.51-7.55 (m, 1H), 7.77-7.84 (m, 2H), 8.01-8.10 (m, 2H), 8.38-8.51 (m, 2H).

Compound 671: (200 MHz, CDCl₃) δ ppm: 0.89 (t, J=7.5 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 1.70-2.06 (m, 2H), 2.42 (s, 3H), 2.66 (bs, 4H), 3.29 (t, J=5.1 Hz, 4H), 3.68-3.92 (m, 2H), 4.38 (dd, J=7.0, 15.4 Hz, 1H), 6.50 (bs, 1H), 6.56 (dd, J=2.0, 8.1 Hz, 1H), 6.72 (dd, J=2.0, 8.4 Hz, 1H), 6.89 (t, J=2.0 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.94 (d, J=2.0, 9.0 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.4 (d, J=2.0 Hz, 1H).

Compound 672: (200 MHz, CDCl₃) δ ppm: 1.33 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.41 (s, 3H), 2.57-2.70 (m, 4H), 3.16-3.33 (m, 6H), 3.91 (q, J=7.3 Hz, 2H), 4.52-4.69 (m, 3H), 5.08 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.2, 8.6 Hz, 2H), 6.81 (d, J=9.0 Hz, 1H), 6.97 (t, J=2.2 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.62-7.68 (m, 2H).

Compound 673: (200 MHz, CDCl₃) δ ppm: 1.31 (t, J=7.0 Hz, 3H), 1.33 (s, 6H), 1.49 (d, J=7.0 Hz, 3H), 1.80 (t, J=6.6 Hz, 2H), 2.39 (s, 3H), 2.59 (t, J=5.0 Hz, 4H), 2.79 (t, J=7.0 Hz, 2H), 3.25 (t, J=5.0 Hz, 4H), 3.90 (q, J=7.0 Hz, 2H), 4.48-4.65 (m, 1H), 5.07 (d, J=9.5 Hz, 1H), 6.73 (dd, J=2.4, 8.1 Hz, 2H), 6.82 (d, J=9.2 Hz, 1H), 6.97 (t, J=2.4 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.51-7.57 (m, 2H).

Compound 674: (200 MHz, CDCl₃) δ ppm: 1.34 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.21 (quint, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.59 (t, J=4.6 Hz, 4H), 3.25 (t, J=4.6 Hz, 4H), 3.93 (q, J=7.3 Hz, 2H), 4.27 (dd, J=6.0, 11.6 Hz, 4H) 4.51-4.66 (m, 1H), 5.15 (d, J=9.5 Hz, 1H), 6.74 (dd, J=2.2, 8.4 Hz, 1H), 7.07-7.13 (m, 2H), 7.23 (t, J=8.1 Hz, 1H), 7.38 (dd, J=2.4, 8.1 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H).

Compound 675: (200 MHz, CDCl₃) δ ppm: 1.36 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.39 (s, 3H), 2.59 (t, J=5.0 Hz, 4H), 3.26 (t, J=5.0 Hz, 4H), 3.95 (q, J=7.3 Hz, 2H), 4.50-4.68 (m, 1H), 5.18 (d, J=9.5 Hz, 1H), 6.05 (s, 2H), 6.74 (dd, J=2.4, 8.1 Hz, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.98 (t, J=2.4 Hz, 1H), 7.19-7.27 (m, 2H), 7.42 (dd, J=1.8, 8.1 Hz, 1H).

Compound 676: (200 MHz, CDCl₃) δ ppm: 1.27-1.33 (m, 15H), 1.47 (d, J=6.8 Hz, 3H), 2.43 (s, 3H), 2.61-2.72 (m, 4H), 3.25-3.33 (m, 4H), 3.90 (q, J=7.5 Hz, 2H), 4.57 (dd, J=6.8, 9.2 Hz, 1H), 5.13 (d, J=9.2 Hz, 1H), 6.70-6.79 (m, 2H), 6.99 (t, J=2.2 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.57 (dd, J=2.0, 8.1 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H).

Compound 677: (200 MHz, CDCl₃) δ ppm: 1.32 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.22 (s, 3H), 2.38 (s, 3H), 2.56-2.63 (m, 4H), 3.14-3.30 (m, 6H), 3.84-4.10 (m, 4H), 4.53-4.64 (m, 1H), 5.25 (d, J=9.5 Hz, 1H), 6.71-6.79 (m, 2H), 7.01 (t, J=2.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.69 (dd, J=2.0, 8.4 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H).

Compound 678: (200 MHz, CDCl₃) δ ppm: 1.32 (t, J=7.3 Hz, 3H), 1.46 (d, J=6.8 Hz, 3H), 2.11 (quint, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.58 (t, J=5.0 Hz, 4H), 2.94 (t, J=7.5 Hz, 4H), 3.25 (t, J=5.0 Hz, 4H), 3.92 (q, J=7.3 Hz, 2H), 4.52-4.67 (m, 1H), 5.15 (d, J=10.0 Hz, 1H), 6.73 (dd, J=2.2, 8.1 Hz, 2H), 6.98 (t, J=2.2 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.62 (dd, J=2.2, 7.9 Hz, 1H), 7.67 (s, 1H).

Compound 679: (600 MHz, DMSO-d₆) δ ppm: 1.24 (t, J=7.1 Hz, 3H), 1.29 (d, J=6.9 Hz, 3H), 2.22 (s, 3H), 2.40-2.46 (m, 4H), 3.12-3.16 (m, 4H), 3.81-3.97 (m, 2H), 4.64-4.72 (m, 1H), 6.53-6.58 (m, 1H), 6.60-6.65 (m, 1H), 6.77-6.82 (m, 2H), 7.20 (t, J=8.3 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.94-7.99 (m, 1H), 8.17-8.23 (m, 2H), 8.54-8.61 (m, 1H).

Compound 698: (600 MHz, CDCl₃) δ ppm: 1.33 (t, J=7.1 Hz, 3H), 1.43 (d, J=6.9 Hz, 3H), 2.11 (s, 3H), 3.10-3.20 (m, 4H), 3.53-3.59 (m, 2H), 3.67-3.74 (m, 2H), 3.89-4.00 (m, 2H), 4.67 (q, J=7.1 Hz, 1H), 6.65-6.75 (m, 2H), 6.94-6.97 (m, 1H), 7.21-7.25 (m, 1H), 7.46-7.50 (m, 1H), 7.69-7.73 (m, 1H), 7.80-7.84 (m, 1H), 7.95-7.99 (m, 1H), 8.29-8.34 (m, 1H), 8.45-8.47 (m, 1H).

The following describes exemplary methods of preparing starting materials used to produce the compounds of the present application.

Reference Examples 1-3

Starting from the corresponding amine in place of 1,4-dioxa-8-azaspiro[4,5]decane used in Example 7-(1), the same procedure as used in Example 7-(1) was repeated to give the titled compounds.

Reference Example 1 3-((2R,6S)-2,6-Dimethylmorpholine-4-yl)-phenol

Brown oily substance, yield 71%

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.24 (d, J=6.0 Hz, 6H), 2.36-2.45 (m, 2H), 3.37-3.46 (m, 2H), 3.73-3.83 (m, 2H), 5.01 (s, 1H), 6.28-6.33 (m, 1H), 6.36-6.38 (m, 1H), 6.46-6.51 (m, 1H), 7.10 (t, J=8.0 Hz, 1H)

Reference Example 2 3-[4-(2-Dimethylaminoethyl)-piperazin-1-yl]-phenol

Yellow oily substance, yield 12%

¹H NMR (600 MHz, CDCl₃) δ ppm: 2.29 (s, 6H), 2.48-2.57 (m, 4H), 2.57-2.64 (m, 4H), 3.11-3.16 (m, 4H), 6.24-6.30 (m, 1H), 6.32-6.37 (m, 1H), 6.42-6.49 (m, 1H), 7.04-7.09 (m, 1H)

Reference Example 3 3-[(2-Dimethylaminoethyl)-methyl-amino]-phenol

Brown oily substance, yield 42%

¹H NMR (600 MHz, CDCl₃) δ ppm: 2.27 (s, 6H), 2.44-2.50 (m, 2H), 2.87 (s, 3H), 3.37-3.44 (m, 2H), 6.09-6.16 (m, 2H), 6.19-6.24 (m, 1H), 7.01 (t, J=8.0 Hz, 1H)

Reference Example 4 3-(4-Isopropyl-piperazin-1-yl)-phenol

Acetone (1.95 g) and NaBH(OAc)₃(7.12 g) were added to a solution of 3-piperazin-1-yl-phenol (2.00 g) in THF (40 ml), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO₄) and filtered to give the titled compound (1.48 g, colorless powder).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.11 (d, J=6.4 Hz, 6H), 2.68-2.72 (m, 4H), 2.71-2.78 (m, 1H), 3.15-3.23 (m, 4H), 6.28-6.32 (m, 1H), 6.36 (t, J=2.3 Hz, 1H), 6.50 (dd, J=8.3, 2.3 Hz, 1H), 7.09 (t, J=8.3 Hz, 1H)

Reference Example 5 3-(1-Isopropylpiperidin-4-yl)-phenol

Starting from 3-piperidin-4-yl-phenol in place of 3-piperazin-1-yl-phenol used in Reference Example 4, the same procedure as used in Reference Example 4 was repeated to give the titled compound (yield 31%, colorless powder).

¹H NMR (600 MHz, CDCl₃) δ ppm: 1.16 (d, J=6.4 Hz, 6H), 1.76-1.86 (m, 2H), 1.91-2.01 (m, 2H), 2.31-2.50 (m, 3H), 2.92-3.02 (m, 1H), 3.08-3.19 (m, 2H), 6.66-6.72 (m, 2H), 6.74-6.79 (m, 1H), 7.11 (t, J=7.8 Hz, 1H)

Reference Example 6 4-Fluoro-3-(4-methyl-piperazin-1-yl)-phenol

4-Benzyloxy-2-chloro-1-fluorobenzene

(1) A suspension of 3-chloro-4-fluorophenol (2.00 g), benzyl chloride (1.88 ml), and potassium carbonate (2.82 g) in dimethylformamide (10 ml) was stirred at room temperature for three hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO₄), filtered, and concentrated, and the resulting residue was purified by silica-gel column chromatography (OH SiO₂, AcOEt/hexane=0-10%) to give the titled compound (2.00 g) as a light yellow oily substance.

¹H NMR (600 MHz, CDCl₃) δ ppm: 5.01 (s, 2H), 6.77-6.86 (m, 1H), 6.96-7.09 (m, 2H), 7.30-7.46 (m, 5H)

1-(5-Benzyloxy-2-fluorophenyl)-4-methyl-piperazine

(2) Under an argon atmosphere at room temperature, the compound (7.5 g) obtained in Reference Example 6-(1) and thereafter a solution of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-1 phosphino-bicyclo[3,3,3]-undecane (1.1 g) in toluene (320 ml) were added to tris dibenzylidenedipalladium (1.45 g) and t-butoxysodium (4.26 g). Then, a solution of N-methylpiperazine (1.02 g) in toluene (20 ml) was added at room temperature, and the mixture was stirred at 100° C. for 60 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica-gel column chromatography (NH SiO₂, AcOEt/hexane=0-30%) to give the titled compound (2.27 g) as a yellow oily substance.

¹H NMR (600 MHz, CDCl₃) δ ppm: 2.35 (s, 3H), 2.55-2.63 (m, 4H), 3.06-3.15 (m, 4H), 5.00 (s, 2H), 6.46-6.51 (m, 1H), 6.56-6.59 (m, 1H), 6.89-6.95 (m, 1H), 7.29-7.45 (m, 5H)

4-Fluoro-3-(4-methylpiperazin-1-yl)-phenol

(3) A suspension of the compound (2.48 g) obtained in Reference Example 6-(2) and palladium hydroxide (10%, 250 mg) in methanol (30 ml) was stirred under a hydrogen atmosphere at 65° C. for two hours and a half and thereafter at room temperature for overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. The resulting residue was purified by silica-gel column chromatography (NH SiO₂, AcOEt/hexane=0-99%, methanol/chloroform=0-10%). Thereafter, the resulting compound was purified again by silica-gel column chromatography (OH SiO₂, methanol/chloroform=0-10%) to give the titled compound (877 mg) as an ocher solid.

¹H NMR (600 MHz, DMSO-d₆) δ ppm: 2.21 (s, 3H), 2.39-2.48 (m, 4H), 2.89-2.99 (m, 4H), 6.26-6.31 (m, 1H), 6.35-6.39 (m, 1H), 6.84-6.91 (m, 1H), 9.20 (s, 1H)

The following describes an exemplary method of producing an intermediate represented by Formula (II) of the present application.

Starting from the corresponding starting materials, the same procedures as shown in Examples 1-(1) to 1-(7), Examples 2-(1) and 2-(2), Examples 7-(1) and 7-(2), Examples 17-(1) and 17-(2), Example 18-(1), Example 21-(1), Example 22-(1), Example 23-(1), and Examples 26-(1) to 26-(8) were repeated, followed by salt formation as needed to obtain compounds or salts of the compounds which are intermediates useful in producing the compound of Formula (I) of the present application. The resulting intermediates are shown in Table 2 together with the intermediates obtained in the Examples above.

TABLE 2 Compound number Chemical structure ¹H NMR Intermediate 1 (200 MHz, CDCl₃) δ ppm: 1.25 (t, J = 7.3 Hz, 3H), 3.12 (dd, J = 13.3, 8.6 Hz, 1H), 3.38 (dd, J = 13.3, 6.1 Hz, 1H), 3.60-4.30 (m, 3H), 7.10-7.46 (m, 10H) Intermediate 2 (600 MHz, DMSO-d6) δ ppm: 1.29 (t, J = 7.3 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 2.30 (s, 3H), 3.96- 4.09 (m, 3H), 7.15-7.30 (m, 4H) Intermediate 3 (600 MHz, DMSO-d6) δ ppm: 1.33 (t, J = 7.1 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H), 2.23 (s, 3H), 4.00- 4.12 (m, 3H), 7.10-7.40 (m, 4H) Intermediate 4 (600 MHz, DMSO-d6) δ ppm: 1.22-1.30 (m, 3H), 1.41-1.48 (m, 3H), 2.33 (s, 3H), 3.83-4.10 (m, 3H), 7.04-7.14 (m, 3H), 7.26-7.37 (m, 1H) Intermediate 5 (600 MHz, CDCl₃) δ ppm: 1.46 (t, J = 7.1 Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H), 4.05-4.25 (m, 3H), 6.81- 7.32 (m, 4H) Intermediate 6 (200 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.6 Hz, 3H), 3.87-4.26 (m, 3H), 7.14- 7.26 (m, 1H), 7.30-7.45 (m, 4H) Intermediate 7 (600 MHz, CDCl₃) δ ppm: 1.35-1.45 (m, 3H), 1.53- 1.62 (m, 3H), 3.95-4.20 (m, 3H), 7.27-7.40 (m, 4H) Intermediate 8 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.1 Hz, 3H), 1.60(d, J = 6.9 Hz, 3H). 3.90-4.25 (m, 3H), 7.15-7.50 (m, 4H) Intermediate 9 (600 MHz, DMSO-d6) δ ppm: 1.14 (t, J = 7.3 Hz, 3H), 2.30 (s, 3H), 3.00 (dd, J = 13.3, 7.3 Hz, 1H), 3.19 (dd, J = 13.3, 6.9 Hz, 1H), 3.77-3.98 (m, 2H), 4.11 (t, J = 7.1 Hz, 1H), 7.13-7.139 (m, 9H) Intermediate 10 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.4 Hz, 3H). 1.57 (d, J = 6.8 Hz, 3H), 3.80 (s, 3H), 3.95-4.20 (m, 3H), 6.82-6.97 (m, 2H), 7.21-7.34 (m, 2H) Intermediate 11 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.4 Hz, 3H), 3.95-4.23 (m, 3H), 6.90-7.15 (m, 2H), 7.30-7.44 (m, 2H) Intermediate 12 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.4 Hz, 3H), 1.60 (d, J = 6.8 Hz, 3H), 3.98-4.21 (m, 3H), 7.26-7.65 (m, 3H) Intermediate 13 (600 MHz, CDCl₃) δ ppm: 1.40 (t, J = 7.1 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H), 2.24 (s, 3H), 2.25 (s, 3H), 3.95- 4.23 (m, 3H), 7.00-7.19 (m, 3H) Intermediate 14 (200 MHz, CDCl₃) δ ppm: 1.05-2.03 (m, 16 H), 2.32- 2.65 (m, 1 H), 3.87-4.29 (m, 3 H), 700-7.46 (m, 4 H) Intermediate 15 (200 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 7.0 Hz, 3 H), 3.87 (s, 6 H), 3.96-4.27 (m, 3 H), 6.82-6.88 (m, 2 H), 6.97 (d, J = 2.6 Hz, 1 H) Intermediate 16 (600 MHz, CDCl₃) δ ppm: 1.42 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.4 Hz, 3 H), 3.80 (s, 3 H), 3.82 (s, 6 H), 3.99-4.12 (m, 2 H), 4.13-4.19 (m, 1 H), 6.63 (s, 2 H) Intermediate 17 (600 MHz, CDCl₃) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.12 (s, 3 H), 2.26 (s, 6 H), 3.96-4.07 (m, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.97 (s, 2 H) Intermediate 18 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.30 (s, 6 H), 3.94-4.08 (m, 2 H) 4.15 (q, J = 6.9 Hz, 1 H), 6.81 (s, 1 H), 6.95 (s, 2 H) Intermediate 19 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7 .3 Hz, 3 H), 1.63 (d, J = 6.9 Hz, 3 H), 3.81 (s, 6 H), 4.00-4.12 (m, 2 H), 4.20 (q, J = 6.7 Hz, 1 H), 6.33 (s, 1 H), 6.59 (s, 2 H) Intermediate 20 (600 MHz, CDCl₃) δ ppm: 0.96-0.98 (m, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.43-1.52 (m, 2 H), 1.56 (d, J = 6.9 Hz, 3 H), 1.71-1.78 (m, 2H), 3.93 (t, J = 6.4 Hz, 2 H), 3.97-4.08 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.85- 6.89 (m, 2 H) 7.23-7.28 (m, 2 H) Intermediate 21 (600 MHz, CDCl₃) δ ppm: 1.42 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 3.99-4.13 (m, 2H), 4.17 (q, J = 6.9 Hz, 1H), 6.98-7.05 (m, 4H), 7.07-7.13 (m, 1H), 7.29-7.39 (m, 4H) Intermediate 22 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7 .1 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H), 3.99-4.10 (m, 2H), 4.16 (q, J =6.9 Hz, 1H), 5.05 (s, 2H). 6.94-7.00 (m, 2H). 7.25- 7.31 (m, 2H), 7.31-7.35 (m, 1H), 7.36-7.41 (m, 2H), 7.41-7.44 (m, 2H) Intermediate 23 (600 MHz, CDCl₃), δ ppm: 1.23 (t, J = 7.6 Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.4 Hz, 3 H), 2.64 (q, J = 7.5 Hz, 2 H), 3.98-4.11 (m, 2H), 4.16 (q, J = 6.9 Hz, 1 H), 7.16-7.31 (m, 4 H) Intermediate 24 (600 MHz, CDCl₃), δ ppm: 0.94 (t, J =7.3 Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.54-1.67 (m, 5 H), 2.53- 2.61 (m, 2 H), 3.94-4.10 (m, 2 H), 4.17 (q, J = 6.4 Hz, 1 H), 7.12-7.31 (m, 4 H) Intermediate 25 (600 MHz, , CDCl₃) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.35 (s, 3 H), 3.96-4.09 (m, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 7.14 (dd, J = 8.7, 3.7 Hz, 1 H), 7.27 (d, J = 3.2 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 1 H) Intermediate 26 (600 MHz, , CDCl₃) δ ppm: 1.40 (t, J = 7.3 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H), 3.99-4.10 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.30-6.33 (m, 2 H), 6.99-7.03 (m, 2 H), 7.34-7.38 (m, 2 H), 7.41-7.44 (m, 2 H) Intermediate 27 (600 MHz, , CDCl₃) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.94 (s, 6 H), 3.95-4.07 (m, 2 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.52 (dd, J = 8.7, 2.8 Hz, 1 H), 6.60 (dd, J = 8.7, 2.3 Hz, 1 H), 6.72 (t, J = 2.3 Hz, 1 H), 7.18 (t, J = 8.3 Hz, 1 H) Intermediate 28 (600 MHz, CDCl₃) δ ppm 1..43 (t, J = 7.1 Hz, 3H), 1.60 (d, J = 6.9 Hz, 3H), 4.02-4.13 (m, 2H), 4.19 (q, J = 6.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.40-7.48 (m, 4H), 7.55-7.62 (m, 4H) Intermediate 29 (600 MHz, CDCl₃) δ ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 4.00-4.12 (m, 2H), 4.17-4.23 (m, 1H), 7.19-7.23 (m, 1H), 7.37-7.42 (m, 2H) Intermediate 30 (600 MHz, CDCl₃) δ ppm: 1.42 (t, J = 7.1 Hz, 3H), 1.60 (d, J = 6.4 Hz, 3H), 4.01-4.13 (m, 2H), 4.17(q, J = 6.4 Hz, 1H), 7.13-7.18 (m, 1H), 7.30-7.34 (m, 1H), 7.51-7.54 (m, 1H) Intermediate 31 (600 MHz, CDCl₃), δ ppm: 0.92 (t, J = 7.6 Hz, 3 H), 1.30-1.44 (m, 5 H), 1.54-1.63 (m, 5 H), 2.55-2.64 (m, 2 H), 3.97-4.10 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H), 7.15-7.29 (m, 4 H) Intermediate 32 (600 MHz, CDCl₃), δ ppm: 1.42 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.9 Hz, 3 H), 4.00-4.15 (m, 2 H), 4.18 (q, J = 6.9 Hz, 1 H), 7.19-7.28 (m, 2 H), 7.39-7.47 (m, 2 H) Intermediate 33 (600 MHz, , CDCl₃) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6 .4 Hz, 3 H), 3.12-3.19 (m, 4 H), 3.79- 3.86 (m, 4 H), 3.95-4.09 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.71 (dd, J = 8.0, 2.1 Hz, 1 H), 6.79 (dd, J = 8.3, 2.3 Hz, 1 H) 7.00-7.03 (m, 1 H), 7.21-7.25 (m, 1 H) Intermediate 34 (600 MHz, CDCl₃) δ ppm: 1.39 (t, J = 7.1 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H), 2.33 (s, 6 H), 2.67-2.76 (m, 2 H), 3.95-4.08 (m, 4 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.84- 6.93 (m, 2 H), 7.19-7.31 (m, 2 H) Intermediate 35 (600 MHz, CDCl₃) δ ppm: 1.40 (t, J = 7.1 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H), 2.54-2.59 (m, 4 H), 2.78 (t, J = 5.7 Hz, 2 H), 3.71-3.75 (m, 4 H), 3.98-4.06 (m, 2 H), 4.08 (t, J = 5.7 Hz, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.86-6.90 (m, 2 H), 7.24-7.28 (m, 2 H) Intermediate 36 (600 MHz, CDCl₃), δ ppm: 1.41 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.27 (d, J = 1.8 Hz, 3 H), 3.98-4.11 (m, 2 H), 4.17 (q, J = 6.9 Hz, 1 H), 6.95- 7.03 (m, 1 H), 7.11-7.16 (m, 1 H), 7.21-7.24 (m, 1 H) Intermediate 37 (200 MHz, CDCl₃) δ ppm: 1.00-1.20 (m, 4H), 1.58 (d, J = 6.6 Hz, 3H), 2.90-3.06 (m, 1H), 3.80 (s, 3H), 4.05- 4.32 (m, 1H), 6.38-6.95 (m, 2H), 7.20-7.30 (m, 2H) Intermediate 38 (600 MHz, , CDCl₃) δ ppm: 1.23 (d, J = 7.3 Hz, 6 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.86- 2.93 (m, 1 H), 3.97-4.09 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 7.19-7.23 (m, 2 H) 7.24-7.27 (m, 2 H) Intermediate 39 (600 MHz, CDCl₃), δ ppm: 1.25 (d, J = 6.9 Hz, 6 H), 1.41 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.4 Hz, 3 H), 2.85-2.97 (m, 1 H), 3.99-4.10 (m, 2 H), 4.16 (q, J = 6.7 Hz, 1 H), 7.06-7.10 (m, 1 H), 7.13-7.18 (m, H), 7.20-7.24 (m, 1 H), 7.26-7.32 (m, 1 H) Intermediate 40 (600 MHz, CDCl₃) δ ppm: 1.48 (t, J = 7.3 Hz, 3 H), 1.61 (d, J = 6.9 Hz, 3 H), 4.09-4.24 (m, 3 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.51-7.56 (m, 2 H), 7.61 (d, J = 6.9 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.85-7.90 (m, 1 H), 8.11- 8.16 (m,1 H) Intermediate 41 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.4 Hz, 3 H), 4.02-4.13 (m, 2 H), 4.18 (q, J = 6.6 Hz, 1 H), 7.41-7.51 (m, 3 H), 7.76-7.92 (m, 4 H) Intermediate 42 (600 MHz, CDCl₃), δ ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.93 (s, 6 H), 3.96-4.09 (m, 2 H), 4.15 (q, J = 6.9 Hz, 1 H), 6.66-6.76 (m, 2 H), 7.17-7.25 (m, 2 H) Intermediate 43 (600 MHz, CDCl₃) δ ppm 1.38-1.61 (m, 6 H), 4.00-4.19 (m, 3 H), 6.69-7.37 (m, 3 H) Intermediate 44 (600 MHz, CDCl₃) δ ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.71-6.80 (m, 2H), 6.99- 7.03 (m, 1H) , 7.20-7.25 (m, 1H) Intermediate 45 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.82 (s, 3 H), 4.02-4.14 (m, 2 H), 4.18 (q, J = 6.7 Hz, 1 H), 7.42 (dd, J = 8.7, 2.8 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 2.3 Hz, 1 H) Intermediate 46 (200 MHz, CDCl₃), δ ppm: 1.33-1.47 (m, 3 H), 1.57 (d, J = 7.0 Hz, 3 H), 3.03-3.19 (m, 4 H), 3.78-3.92 (m, 4 H), 3.95-4.25 (m, 3 H), 6.81-7.00 (m, 2 H), 7.18-7.33 (m, 2 H) Intermediate 47 (200 MHz, CDCl₃), δ ppm: 1.34-1.46 (m, 3 H), 1.48-1.82 (m, 9 H), 3.02-3.18 (m, 4 H), 3.89-4.27 (m, 3 H), 6.88-7.00 (m, 2 H), 7.16-7.29 (m, 2 H) Intermediate 48 (600 MHz, CDCl₃), δ ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 1.96-2.03 (m, 4 H), 3.23- 3.30 (m, 4 H), 3.96-4.09 (m, 2 H), 4.16 (q, J = 6.6 Hz, 1 H), 6.47-6.56 (m, 2 H), 7.15-7.22 (m, 2 H) Intermediate 49 (600 MHz, CDCl₃), δ ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 1.96-2.03 (m, 4 H), 3.23- 3.30 (m, 4 H), 3.96-4.09 (m, 2 H), 4.16 (q, J = 6.6 Hz, 1 H), 6.47-6.56 (m, 2 H), 7.15-7.22 (m, 2 H) Intermediate 50 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.56 (s, 3 H), 4.03-4.14 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H), 7.19 (d, J = 8.7 Hz, 1 H), 7.81 (dd, J = 8.7, 2.8 Hz, 1 H), 8.52 (d, J = 3.2 Hz, 1 H) Intermediate 51 (600 MHz, CDCl₃) δ ppm: 1.40(t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.71-6.80 (m, 2H), 6.09-7.03 (m, 1H), 7.20- 7.25 (m, 1H) Intermediate 52 (600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.63 (d, J = 6.9 Hz, 3 H), 3.96-4.09 (m, 2 H), 4.20 (q, J = 6.9 Hz, 1 H), 7.13-7.17 (m, 1 H), 7.30-7.34 (m, 1 H), 7.77-7.81 (m, 1 H), 8.22-8.25 (m, 1 H) Intermediate 53 (600 MHz, CDCl3) δ ppm 1.46 (t, J = 7.3 Hz, 3 H), 1.62 (d, J = 6.4 Hz, 3 H), 4.06-4.17 (m, 2 H), 4.20 (q, J = 6.6 Hz, 1 H), 7.64-7.68 (m, 1 H), 7.70-7.73 (m, 1 H), 7.85-7.90 (m, 1 H), 8.10-8.13 (m, 1 H), 8.52-8.54 (m, 1 H), 9.19-9.25 (m, 1 H) Intermediate 54 (600 MHz, CDCl₃) δ ppm.: 1.57 (d, J = 6.9 Hz, 3H), 2.34 (s, 3H), 3.59 (s, 3H), 4.16-4.22(m, 1H), 7.15- 7.18 (m, 2H), 7.21-7.25 (m, 2H) Intermediate 55 (600 MHz, CDCl₃) δ ppm: 0.99 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H). 1.77-1.85 (m, 2H), 2.34 (s, 3H), 3.85-3.99 (m, 2H), 4.12 (q, J = 6.9 Hz, 1H), 7.15-7.18 (m, 2H), 7.21-7.24 (m, 2H) Intermediate 56 (600 MHz, CDCl₃) δ ppm: 1.53-1.58 (m, 9H), 2.34 (s, 3H), 4.20 (q, J = 6.9 Hz, 1H), 4.66-4.72 (m, 1H), 7.15- 7.19 (m, 2H), 7.21-7.24 (m, 2H) Intermediate 57 (200 MHz, CDCl₃) δ ppm: 1.31 (t, J = 7.3Hz, 3H), 1.60 (d, J = 6.6 Hz, 3H), 2.28 (s, 3H), 3.60-4.30 (m, 3H), 6.96-7.02 (m, 4H) Intermediate 58 (600 MHz, CDC1₃) δ ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.4 Hz, 3H), 2.34 (s, 3H), 3.99-4.09 (m, 2H). 4.16 (q, J = 6.4 Hz, 1H), 7.15-7.19 (m, 2H), 7.22-7.25 (m, 2H) Intermediate 59 (600 MHz, CDCl₃), δ ppm: 1.44 (t, J = 7.1 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 4.02-4.13 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H), 6.44-6.47 (m, 1 H), 7.04-7.08 (m, 1 H), 7.15-7.25 (m, 2 H), 7.50-7.57 (m, 1 H), 8.72 (s, 1 H) Intermediate 60 (600 MHz, CDCl₃), δ ppm: 1.42 (t, J = 7.1 Hz, 3 H), 1.58 (d, J = 6.4 Hz, 3 H), 3.98-4.10 (m, 2 H), 4.15 (q, J = 6.7 Hz, 1 H), 6.30-6.39 (m, 1 H), 6.87-7.00 (m, 2 H), 7.39-7.52 (m, 2 H), 9.55 (s, 1 H) Intermediate 61 (600 MHz, CDCl₃), δ ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.34 (s, 3 H), 3.99-4.12 (m, 2 H), 4.16 (q, J = 6.9 Hz, 1 H), 6.03-6.13 (m, 1 H), 6.86-7.07 (m, 2 H), 7.28-7.37 (m, 1 H), 8.76 (s, 1 H) Intermediate 62 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.1 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.40 (s, 3H), 3.96-4.07 (m, 2H), 4.23 (q, J = 6.9 Hz, 1H), 6.95-6.97 (m, 1H), 7.13-7.1.5 (m, 1H), 8.07-8.09 (m, 1H) Intermediate 63 (600 MHz, CDCl₃) δ ppm: 1.36-1.45 (m, 3H), 1.60- 1.70 (m, 3H), 2.32 (s, 3H), 3.96-4.10 (m, 2H), 4.16- 4.27 (m, 1H), 7.22-7.27 (m, 1H), 7.56-7.66 (m, 1H). 8.02-8.10 (m, 1H) Intermediate 64 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.59-2.63 (m, 2H). 2.92-2.99 (m, 2H), 4.00-4.11 (m, 2H), 4.18 (q, J = 6.4 Hz, 1H), 6.80-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.21-7.25 (m, 1H), 8.28-8.72 (m, 1H) Intermediate 65 (600 MHz, CDCl₃) δ ppm: 1.35 (t, J = 7.3 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3 H), 3.76 (s, 3 H), 3.93-4.05 (m, 2 H), 4.11 (q, J = 6.4 Hz, 1 H), 6.69 (dd, J = 8.3, 2.3 Hz, 1 H), 6.87 (dd, J = 8.3, 2.3 Hz, 1 H), 6.92 (t, J = 2.3 Hz, 1 H), 7.18-7.24 (m, 1 H) Intermediate 66 (600 MHz, , CDCl₃) δ ppm: 1.14 (t, J = 7.1 Hz, 6 H), 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 3.32 (q, J = 6.9 Hz, 4 H), 3.95-4.07 (m, 2 H), 4.11-4.17 (m, 1 H), 6.46 (dd, J = 8.7, 2.3 Hz, 1 H), 6.50 (dd, J = 8.0, 2.5 Hz, 1 H), 6.67 (t, J = 2.5 Hz, 1 H), 7.14 (t, J = 8.3 Hz, 1 H) Intermediate 67 (600 MHz, CDCl₃) δ ppm: 1.39 (t, J = 7.3 Hz, 3H), 1.62 (d, J = 6.4 Hz, 3H), 2.45 (s, 3H), 3.97-4.09 (m, 2H), 4.19 (q, J = 6.4 Hz, 1H), 6.98-7.01 (m, 1H), 7.13-7.16 (m, 1H), 7.64-7.67 (m, 1H) Intermediate 68 (600 MHz, CDCl₃) δ ppm: 1.45 (t, J = 7.3 Hz, 3H), 1.62 (d, J = 6.9 Hz, 3H), 4.05-4.15 (m, 2H), 4.20 (q, J = 6.9 Hz, 1H), 7.37-7.41 (m, 1H), 7.65-7.68 (m, 1H), 7.84-7.88 (m, 1H), 7.94-7.96 (m, 1H), 8.14-8.19 (m, 1H), 8.90-8.93 (m, 1H) Intermediate 69 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.53-1.60 (m, 5 H), 1.64-1.71 (m, 4 H), 3.95-4.07 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.69-6.74 (m, 2 H), 6.95 (t, J = 2.5 Hz, 1 H), 7.19 (t, J = 8.3 Hz, 1 H) Intermediate 70 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.1 Hz, 3H). 1.58 (d, J = 6.9 Hz, 3H), 2.57-2.61 (m, 2H), 2.89-2.93 (m, 2H), 3.99-4.11 (m, 2H), 4.17 (q, J= 6.9 Hz, 1H), 6.90-6.97 (m, 2H), 7.11-7.15 (m, 1H), 8.66 (s, 1H) Intermediate 71 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.30-2.39 (m, 2 H), 3.85- 3.89 (m, 4 H), 3.94-4.06 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.22-6.25 (m, 1 H), 6.43 (t, J = 2.3 Hz, 1 H), 6.59- 6.63 (m, 1 H), 7.15 (t, J = 8.0 Hz, 1 H) Intermediate 72 (600 MHz, CDCl₃) δ ppm: 1.24 (d, J = 6.4 Hz, 6 H), 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.39- 2.46 (m, 2 H), 3.42-3.46 (m, 2 H), 3.73-3.81 (m, 2 H), 3.97-4.09 (m, 2 H), 4.15 (q, J = 6.9 Hz, 1 H), 6.71 (dd, J = 8.0, 2.1 Hz, 1 H), 6.76 (dd, J = 8.5, 2.1 Hz, 1 H), 6.98 (t, J = 2.3 Hz, 1 H), 7.22 (t, J = 8.3 Hz, 1 H) Intermediate 73 (600 MHz, CDCl₃) δ ppm: 1.42 (d, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 3.92 (s, 3H), 4.02-4.13 (m, 2H), 4.16 (q, J = 6.9 Hz, 1H); 6.90 (s, 1H) Intermediate 74 (600 MHz, CDCl3) δ ppm: 1.45 (t, J = 7.3 Hz, 3 H), 1.63 (d, J= 6.4 Hz, 3 H), 4.06-4.17 (m, 2 H), 4.18- 4.23 (m, 1 H), 7.39-7.44 (m, 1 H), 7.65-7.71 (m, 1 H), 8.02-8.05 (m, 1 H), 8.11-8.16 (m, 2 H), 8.88- 8.91 (m, 1 H) Intermediate 75 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.67 (d, J = 6.4 Hz, 3 H), 1.94-2.02 (m, 4 H), 3.22- 3.29 (m, 4 H), 3.95-4.07 (m, 2 H), 4.10-4.19 (m, 1 H), 6.36 (dd, J = 8.2, 2.3 Hz, 1 H), 6.50-6.56 (m, 2 H), 7.16 (t, J = 8.3 Hz, 1 H) Intermediate 76 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.53 (s, 6H), 3.98-4.11 (m, 2H), 4.18 (q, J = 6.9 Hz, 1H), 7.05 (s, 2H) Intermediate 77 (600 MHz, CDCl₃) δ ppm: 1.46 (t, J = 7.1 Hz, 3H), 1.63 (d, J = 6.9 Hz, 3H), 4.07-4.24 (m, 3H), 7.63-7.65 (m, 1H), 8.00-8.03(m, 1H), 8.11-8.13 (m, 1H) Intermediate 78 (600 MHz, CDCl₃) δ ppm: 1.37 (t, J = 7.1 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 3.96-4.05 (m, 2 H), 4.15 (q, J = 6.7 Hz, 1 H), 6.45-6.50 (m, 1 H), 6.62-6.67 (m, 1 H), 6.71-6.75 (m, 1 H), 7.11 (t, J = 8.0 Hz, 1 H) Intermediate 79 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.27 (s, 6 H), 2.45-2.56 (m, 4 H), 2.58-2.63 (m, 4 H), 3.20-3.24 (m, 4 H), 3.95- 4.07 (m, 2 H), 4.11-4.17 (m, 1 H), 6.68-6.78 (m, 2 H), 6.95-6.98 (m, 1 H), 7.21 (t, J = 8.3 Hz, 1 H) Intermediate 80 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.60 (d, J = 6.9 Hz, 3 H), 4.02-4.15 (m, 2 H), 4.15- 4.22 (m, 1 H), 7.18-7.20 (m, 1 H), 7.22-7.25 (m, 1 H), 7.28-7.30 (m, 1 H), 7.38-7.41 (m, 1 H), 7.46- 7.51 (m, 1 H), 7.54-7.57 (m, 1 H), 7.85-7.89 (m, 1 H) Intermediate 81 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 1.77-1.83 (m, 4 H), 3.27- 3.36 (m, 4 H), 3.95-4.06 (m, 6 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.70-6.75 (m, 2 H), 6.97 (t, J = 2.3 Hz, 1 H), 7.20 (t, J = 8.3 Hz, 1 H) Intermediate 82 (600 MHz, CDCl3) δ ppm: 1.42-1.47 (m, 3 H) 1.62 (dd, J = 6.65, 2.06 Hz, 3 H) 4.05-4.17 (m, 2 H) 4.17-4.22 (m, 1 H) 7.24-7.28 (m, 1 H) 7.48-7.61 (m, 2 H) 7.66 (s, 1 H) 8.52 (s, 2 H) Intermediate 83 (600 MHz, CDCl₃) δ ppm: 1.07 (d, J = 6.9 Hz, 6 H), 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 2.62- 2.67 (m, 4 H), 2.67-2.74 (m, 1 H), 3.19-3.24 (m, 4 H), 3.96-4.08 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.71 (dd, J = 8.3, 2.3 Hz, 1 H), 6.75 (dd, J =8.3, 2.3 Hz, 1 H), 6.97 (t, J = 2.3 Hz, 1 H), 7.21 (t, J = 8.3 Hz, 1 H) Intermediate 84 (600 MHz, CDCl₃) δ ppm: 1.38 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.33 (s, 3H) , 2.40 (s, 3H), 3.97- 4.09 (m, 2H), 4.18 (q, J = 6.9 Hz. 1H), 6.82-6.83 (m, 1H), 6.97-6.98 (m, 1H) Intermediate 85 (600 MHz, CDCl₃) δ ppm: 1.30-1.76 (m, 6H), 2.56 (s, 3H), 2.68 (s, 3H), 4.08-4.19 (m, 3H), 6.59 (s, 1H), 6.73 (s, 1H) Intermediate 86 (600 MHz, CDCl₃) δ ppm: 1.26 (d, J = 6.9 Hz, 6H), 1.40 (t, J = 7.3 Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H), 2.87-2.94 (m, 1H), 3.72 (s, 3H), 3.99-4.11 (m, 2H), 4.14 (q, J = 6.9 Hz, 1H), 6.25 (s, 1H) Intermediate 87 (600 MHz, CDCl₃) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 3.34 (s, 6 H), 3.50-3.57 (m, 8 H), 3.96-4.07 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.51 (dd, J = 8.5, 2.5 Hz, 1 H), 6.56 (dd, J = 7.8, 2.3 Hz, 1 H), 6.69 (t, J = 2.3 Hz, 1 H), 7.15 (t, J = 8.3 Hz, 1 H) Intermediate 88 (600 MHz, CDCl₃) δ ppm: 1.36-1.41 (m, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.28 (s, 6 H), 2.45-2.50 (m, 2 H), 2.94 (s, 3 H), 3.39-3.48 (m, 2 H), 3.94-4.08 (m, 2 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.50 (dd, J = 8.3, 2.3 Hz, 1 H), 6.58 (dd, J = 8.3, 2.3 Hz, 1 H), 6.67 (t, J = 2.5 Hz, 1 H), 7.16 (t, J = 8.3 Hz, 1 H) Intermediate 89 (600 MHz, CDCl₃) δ ppm: 1.39 (t, J = 7.1 Hz; 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.34 (s, 6H), 2.73 (t, J = 5.7 Hz, 2H), 3.98-4.09 (m, 1H), 4.16 (q, J = 6.4 Hz, 1H), 6.75- 6.77 (m, 1H), 6.91-6.93 (m, 1H) , 6.98-7.00 (m, 1H), 7.24-7.27 (m, 1H) Intermediate 90 (600 MHz, CDCl₃) δ ppm: 1.25 (d, J = 6.9Hz, 12H), 1.40 (t, J = 7.1 Hz, 3H), 1.58 (d, J= 6.9 Hz, 3H), 3.76- 3.85 (m, 2H), 3.96-1.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.57-6.70 (m, 2H), 6.88-6.93 (m, 1H), 7.10-7.17 (m, 1H) (Intermediate 91 (600 MHz, CDCl₃) δ ppm: 1.06 (d, J = 6.42 Hz, 6 H) 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 1.68- 1.89 (m, 4 H), 2.17-2.25 (m, 2 H), 2.44-2.53 (m, 1 H), 2.70-2.77 (m, 1 H), 2.94-3.03 (m, 2 H) 3.96-4.08 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 7.03-7.07 (m, 1 H), 7.15-7.22 (m, 2 H), 7.28 (t, J = 8.0 Hz, 1 H) Intermediate 92 (600 MHz, CDCl₃), δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.58-1.62 (m, 12 H), 4.01-4.13 (m, 2 H), 4.18 (q, J = 6.6 Hz, 1 H), 7.42-7.46 (m, 1 H), 7.61-7.65 (m, 1 H), 7.82-7.85 (m, 1 H), 7.87-7.91 (m, 1 H) Intermediate 93 (600 MHz, DMSO-d6) δ ppm: 1.23 (t, J = 7.3 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3 H), 3.82-4.09 (m, 2 H), 4.60 (q, J = 6.0 Hz, 1 H), 6.61-6.69 (m, 2 H), 6.70- 6.77 (m, 1 H), 7.14-7.21 (m, 1 H), 8.28-9.11 (m, 2 H), 9.43-10.55 (m, 1 H) Intermediate 94 (600 MHz, CDCl₃), δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.4 Hz, 3 H), 3.96-4.09 (m, 2 H), 4.17 (q, J = 6.9 Hz, 1 H), 5.06 (s, 2 H), 6.79-6.84 (m, 1 H), 6.91-6.96 (m, 1 H), 7.04-7.08 (m, 1 H), 7.22- 7.46 (m, 6 H) Intermediate 95 (200 MHz, CDCl₃) δ ppm: 1.34 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.8 Hz. 3H). 3.80-4.23 (m, 3H), 5.96 (br s, 1H), 6.88-7.05 (m, 2H), 7.08-7.25 (m, 2H) Intermediate 96 (600 MHz, CDCl₃) δ ppm: 1.42-1.66 (m, 9H), 4.06- 4.20 (m, 5H), 7.01-7.05 (m, 1H), 7.24-7.26 (m, 1H), 7.62-7.69 (m, 2H) Intermediate 97 (600 MHz, CDCl3) δ ppm: 1.02-1.16 (m, 4 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.35 (s, 3 H), 2.52-2.61 (m, 4 H), 2.92-3.01 (m, 1 H), 3.21-3.25 (m, 4 H), 4.24 (q, J = 6.6 Hz, 1 H), 6.68-6.75 (m, 2 H), 6.94-6.98 (m, 1 H), 7.19-7.25 (m, 1 H) Intermediate 98 (600 MHz, CDCL3) δ ppm: 1.03-1.18 (m, 4 H), 1.59 (d, J = 6.9 Hz, 2 H), 2.98-3.04 (m, 1 H), 4.25 (q, J = 6.6 Hz, 1 H), 7.04-7.10 (m, 2 H), 7.30-7.35 (m, 2 H) Intermediate 99 (600 MHz, CDCl3) δ ppm: 0.98-1.20 (m, 4 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.93-3.05 (m, 1 H), 4.22- 4.31 (m, 1 H), 6.33-6.44 (m, 1 H), 6.90-7.05 (m, 2 H), 7.31-7.43 (m, 1 H), 7.46-7.55 (m, 1 H), 9.08- 9.32 (m, 1 H) Intermediate 100 (CDCl₃, 200 MHz) δ 1.02 (t, J = 7.5 Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.68 (bs, 2H), 1.91-2.14 (m, 2H), 2.34 (s, 3H), 3.90 (t, J = 6.4 Hz, 1H), 4.03(q, J = 7.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H) Intermediate 101 (CDCl₃, 200 MHz) δ 0.96 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.8 Hz, 3H), 1.71 (bs, 2H), 2.06-2.24 (m, 1H), 2.34 (s, 3H), 3.69 (d, J = 7.5 Hz, 1H), 4.01 (q, J = 7.3 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H) Intermediate 102 (200 MHz, CDCl₃) δ ppm: 1.01 (t, J = 7.3 Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.70-2.11 (m, 2H), 2.35 (s, 3H), 2.56 (t, J = 5.0 Hz, 4H), 3.24 (t, J = 5.0 Hz, 4H), 3.89 (t, J = 7.3 Hz, 1H), 4.02 (q, J = 7.3 Hz, 2H), 6.74 (dt, J = 2.4, 8.4 Hz, 2H), 7.02 (t, J = 2.4 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H) Intermediate 103 (600 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.36 (s, 3H), 2.55-2.65 (m, 4H), 3.11-3.19 (m, 4H), 3.98-4.19 (m, 3H), 6.87- 6.92 (m, 1H), 6.96-7.04 (m, 2H) Intermediate 104 (600 MHz, CDCl₃) δ ppm: 1.42 (t, J = 6.9 Hz, 3H), 1.62 (s, 6H), 4.31 (q, J = 6.9 Hz, 2H), 7.04-7.09 (m, 2H), 7.34-7.40 (m, 2H) Intermediate 105 (600 MHz, CDCl₃) δ ppm: 1.40 (t, J = 7.1 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.98-3.04 (m, 4H), 3.14- 3.19 (m, 4H), 3.97-4.09 (m, 2H), 4.13-4.18 (m, 1H), 6.70-6.80 (m, 2H), 6.97-7.03 (m, 1H), 7.21- 7.26 (m, 1H) Intermediate 106 (600 MHz, CDCl₃) δ ppm: 1.35 (t, J = 7.3 Hz, 3H), 1.72 (d, J = 6.4 Hz, 3H), 2.12 (s, 3H), 3.14-3.23 (m, 4H), 3.57-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.87- 4.10 (m, 2H), 4.57-4.66 (m, 1H), 6.70-6.81 (m, 2H), 6.95-6.99 (m, 1H), 7.21-7.26 (m, 1H) Intermediate 107 (200 MHz, CDCl₃) δ ppm: 0.94-1.08 (m, 2H), 1.22- 1.31 (m, 2H), 1.47 (t, J = 7.1 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H), 6.98-7.15 (m, 2H), 7.29- 7.42 (m, 2H) Intermediate 108 (600 MHz, CDCl₃) δ ppm: 1.43 (t, J = 7.3 Hz, 3H), 3.97-4.11 (m, 2H), 4.47-4.54 (m, 1H), 7.06- 7.12 (m, 2H), 7.35-7.40 (m, 2H) Intermediate 109 (200 MHz, CDCl₃) δ ppm: 1.41 (t, J = 7.5 Hz, 3H), 3.62 (dd, J = 4.8, 11.8 Hz, 1H), 3.88 (dd, J = 4.8, 11.8 Hz, 1H), 4.05 (q, J = 7.5 Hz, 2H), 4.51-4.60 (m, 1H), 7.04-7.13 (m, 2H), 7.23-7.31 (m, 3H), 7.53 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.8, 2.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H)

INDUSTRIAL APPLICABILITY

Since the compounds of the present invention are excellent Edg-1 (S1P₁) ligands, they are useful as agents for treating or preventing autoimmune diseases, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.

Claims

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

A represents: an oxygen atom,

R1 represents: a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of: a hydroxyl group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, an alkenyl group having from 2 to 8 carbon atoms, an alkynyl group having from 2 to 8 carbon atoms, or a phenyl group;

R1A represents: a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;

R1 and R1A optionally form, together with a carbon atom to which said R1 and

R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms;

R2 represents: a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 8 carbon atoms, an alkynyl group having from 2 to 8 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms;

R3 represents: a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms, a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms, an unsubstituted phenyl group, or a substituted phenyl group (A) or (B) below: (A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of: an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group, a halogen atom, a trifluoromethoxy group, a phenoxy group, a phenyl group, a 1-pyrrolyl group, and —NRARB, wherein each of RA and R3 is an alkyl group having from 1 to 6 carbon atoms, or RA and RB optionally form, together with the nitrogen atom to which said RA and RB are attached, a 3- to 5-membered saturated hydrocarbon ring, wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms; and (B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of: a hydroxyl group, an alkyl group having from 1 to 6 carbon atoms, and an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group, wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom;

R4 represents: a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a carboxyl group;

R5 represents: (i) an alkyl group having from 1 to 10 carbon atoms, (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of: a cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group, and a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms, (iii) a cycloalkyl group having from 3 to 8 carbon atoms, (iv) an alkenyl group having from 2 to 8 carbon atoms, (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, (vi) an alkynyl group having from 2 to 8 carbon atoms, (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or (viii) an optionally substituted aryl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, in Formula (I):

R1 represents: a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group, a cycloalkyl group having from 3 to 8 carbon atoms, an alkenyl group having from 2 to 8 carbon atoms, an alkynyl group having from 2 to 8 carbon atoms, or a phenyl group;

R1A represents a hydrogen atom;

R2 represents: an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 8 carbon atoms, an alkynyl group having from 2 to 8 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms;

R4 represents: a hydrogen atom, or an alkyl group having from 1 to 6 carbon atoms;

R5 represents: (i) an alkyl group having from 1 to 10 carbon atoms, (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of: a cycloalkyl group having from 3 to 8 carbon atoms, a phenyl group, a naphthyl group, a pyridyl group, and a phenyl group substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms, (iii) a cycloalkyl group having from 3 to 8 carbon atoms, (iv) an alkenyl group having from 2 to 8 carbon atoms, (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, (vi) an alkynyl group having from 2 to 8 carbon atoms, (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or (viii) an optionally substituted aryl group.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R1 represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of: a hydroxyl group, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group; and a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;

R1A represents: a hydrogen atom; or an alkyl group having from 1 to 6 carbon atoms; and

R1 and R1A optionally form, together with a carbon atom to which said R1 and R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R1 is: an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and

R1A is a hydrogen atom.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a methyl group or an ethyl group, and R1A is a hydrogen atom.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a hydrogen atom.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is an ethyl group or a cyclopropyl group.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:

(i) an alkyl group having from 1 to 10 carbon atoms,

(ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of: a cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group, and a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms;

(iii) an alkenyl group having from 2 to 8 carbon atoms and optionally substituted with a phenyl group, or

(iv) a phenyl group, a naphthyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a furanyl group, a benzothienyl group, an isoquinolinyl, an isoxazolyl group, a thiazolyl group, a benzothiadiazolyl group, a benzoxadiazolyl group, a dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group, an uracil group, a coumaryl group, a chromanyl group, a dihydroindolyl group, a tetrahydronaphthyl group, or a tetrahydroisoquinolinyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of: an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s), an alkenyl group having from 2 to 8 carbon atoms, a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s), a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiadiazolyl group, and a pyrimidinyl group, each optionally substituted with a substituent(s) selected from Group X consisting of a methyl group, a trifluoromethyl group, a halogen atom, and a methylsulfanyl group, an alkylthio group having from 1 to 6 carbon atoms, an alkylsulfonyl group having from 1 to 6 carbon atoms, a benzenesulfonyl group, a morpholinosulfonyl group, a morpholinocarbonylamino group, an aminosulfonyl group, an alkoxycarbonyl group having from 2 to 10 carbon atoms, a morpholino group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms a phenyl group optionally substituted with an alkoxy group(s) having from 1 to 6 carbon atoms, a phenoxy group, a pyridinecarbonyl group, a pyridineoxy group, a cyano group, an alkanoyl group having from 2 to 7 carbon atoms and optionally substituted with a fluorine atom(s), and an alkanoylamino group having from 2 to 7 carbon atoms.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:

an alkyl group having from 1 to 10 carbon atoms and substituted with a cycloalkyl group having from 3 to 8 carbon atoms,

an alkyl group having from 1 to 10 carbon atoms and substituted with a naphthyl group,

an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,

a phenyl group or a naphthyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of: an alkyl group having from 1 to 6 carbon atoms; a halogen atom, an alkoxy group having from 1 to 6 carbon atoms; a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having from 1 to 6 carbon atoms, an alkylsulfonyl group having from 1 to 6 carbon atoms, an alkanoyl group having from 2 to 7 carbon atoms, an alkoxycarbonyl group having from 2 to 7 carbon atoms, and a cyano group,

a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a methoxycarbonyl group;

a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;

a thienyl group optionally substituted with a substituent (s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or

a benzothienyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:

an alkyl group having from 1 to 6 carbon atoms and substituted with a naphthyl group,

an alkenyl group having from 2 to 6 carbon atoms and substituted with a phenyl group;

an unsubstituted phenyl group,

a phenyl group substituted with 1 to 5 substituents selected from the group consisting of a methyl group, a methoxy group, and a halogen atom,

a phenyl group substituted with 1 to 3 substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having from 1 to 6 carbon atoms, a methylsulfonyl group, an acetyl group, a methoxycarbonyl group, and a cyano group, said phenyl group substituted at either 3 or 4 position or both;

a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of: a halogen atom, an alkyl group having from 1 to 6 carbon atoms, a cyano group, and an alkylsulfonyl group having from 1 to 6 carbon atoms, or

a benzothienyl group, a benzoxadiazolyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, an indanyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:

a phenyl group substituted at 3 and 4 positions each with a halogen atom, or

a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano group.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is a 6-indolyl group.

15. A pharmaceutical preparation, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.