Antitumor Agent

Abstract

The present invention provides a method of enhancing an antitumor effect by a compound strongly inhibiting ribonucleotide reductase (RNR) or a salt thereof.

Description

TECHNICAL FIELD

The present invention relates to an antitumor agent and more particularly relates to a combination formulation comprising a sulfonamide compound or a salt thereof and other antitumor agent(s) in combination, and an agent for enhancing an antitumor effect of other antitumor agent(s).

BACKGROUND ART

Ribonucleotide reductase (hereinafter also referred to as RNR) is composed of a hetero-oligomer of a large subunit M1 and a small subunit M2, and expression of both is required for enzyme activity. RNR recognizes ribonucleoside 5′-diphosphate (hereinafter also referred to as NDP) as a substrate and catalyzes a reduction reaction to 2′-deoxyribonucleoside 5′-diphosphate (hereinafter also referred to as dNDP). Since RNR is a rate-limiting enzyme in the de novo dNTP synthesis pathway, RNR plays an essential role in DNA synthesis and repair (Non-Patent Document 1).

The enzymatic activity of RNR is closely related to cell proliferation, and there is a report that the enzymatic activity is particularly high in cancer (Non-Patent Document 2). Indeed, in various types of solid tumors and blood cancers, numerous correlations have been reported with overexpression of M2, a subunit of RNR, and their prognosis (Non-Patent Documents 3 and 4). In addition, cell growth inhibition by inhibiting RNR and antitumor effect in vivo have been reported in cell lines derived from several cancer types and in nonclinical models (Non-Patent Documents 5 and 6), thus it is strongly suggested that RNR is one of important target molecules for cancer treatment.

Conventionally, hydroxyurea (hereinafter also referred to as HU) and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (hereinafter also referred to as 3-AP) are known as compounds having an RNR inhibitory activity. These compounds differ in structure from the sulfonamide compounds of the present invention. Although HU has been used clinically for over 30 years, its RNR inhibitory activity is very weak and its effect is limited (Non-Patent Document 7). In addition, tolerance to the use of HU is also considered a problem (Non-Patent Document 8). Meanwhile, 3-AP has a structure having the capability to chelate to metal ions, and it has been known that 3-AP chelates mainly to iron ions, thereby inhibiting RNR (Non-Patent Document 9). However, 3-AP has been suggested as having an off-target effect to various other iron-ion-requiring proteins, and it has been known that side effects such as hypoxia, dyspnea, methemoglobinemia and the like are caused in clinical cases (Non-Patent Document 10).

Therefore, it has been strongly desired to develop an RNR inhibitor which has a better RNR inhibitory activity and a structure which does not chelate with metal ions and is useful for diseases associated with RNR, such as tumors.

Some combination effects brought about by combinations of RNR inhibitors and additional antitumor agents have been reported. For example, enhancement in cell proliferation inhibitory effect on a non-small cell lung cancer cell line by the combination of an RNR inhibitor 3-AP and an antimetabolite cytarabine or gemcitabine has been reported (Non-Patent Document 11). Also, in vivo enhancement in life extending effect by the combination of 3-AP and a topoisomerase inhibiting drug etoposide or a platinum drug cisplatin, etc. has been reported using mouse leukemia models (Non-Patent Document 12).

CITATION LIST

Non Patent Literature

• Non-Patent Document 1: Annu. Rev. Biochem. 67, 71-98. (1998)
• Non-Patent Document 2: J. Biol. Chem. 245, 5228-5233. (1970)
• Non-Patent Document 3: Nat. Commun. 5, 3128 doi: 10.1038/ncomms 4128 (2014)
• Non-Patent Document 4: Clin. Sci. 124, 567-578. (2013)
• Non-Patent Document 5: Expert. Opin. Ther. Targets 17, 1423-1437 (2013)
• Non-Patent Document 6: Biochem. Pharmacol. 59, 983-991 (2000)
• Non-Patent Document 7: Biochem. Pharmacol. 78, 1178-1185 (2009)
• Non-Patent Document 8: Cancer Res. 54, 3686-3691 (1994)
• Non-Patent Document 9: Pharmacol. Rev. 57, 547-583 (2005)
• Non-Patent Document 10: Future Oncol. 8, 145-150 (2012)
• Non-Patent Document 11: Biochem. Pharmacol. 73, 1548-1557 (2007)
• Non-Patent Document 12: Biochem. Pharmacol. 59, 983-991 (2000)

SUMMARY OF INVENTION

Technical Problem

An object of the present invention is to provide a method of enhancing an antitumor effect by a compound strongly inhibiting RNR.

Solution to Problem

As a result of extensive studies to solve the above-mentioned problems, the inventors of the present invention have found that a group of compounds having a sulfonamide structure represented by the following formula (I) has excellent antitumor effect enhancing activity by combined use with other compound(s) having an antitumor effect (other antitumor agent(s)), and completed the present invention.

The present invention provides the following: [1] to [15].

[1]

A combination formulation for treating and/or preventing tumor, comprising a sulfonamide compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)]

or a salt thereof, and other antitumor agent(s).

[2]

The combination formulation according to [1], wherein in formula (I):

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents —NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom or a C1-C6 alkyl group;

R² represents a C6-C14 aromatic hydrocarbon group, wherein R² may have R²¹ as a substituent;

R²¹ represents a halogen atom or a C1-C6 alkyl group (when two or more of R²¹ are present, R²¹ are the same as or different from each other);

R³ represents a C6-C14 aromatic hydrocarbon group which may have R³ as a substituent or may be fused with a 4-8 membered saturated heterocyclic ring (wherein the saturated heterocyclic ring may have Rc as a substituent);

R³¹ represents a halogen atom or an aminocarbonyl group (when two or more of R³¹ are present, R³¹ are the same as or different from each other);

Rc represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group (when two or more of Rc are present, Rc are the same as or different from each other); and

R⁴ represents a hydrogen atom.

[3]

The combination formulation according to [1] or [2], wherein in formula (I),

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents —NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²)—;

one of R¹¹ and R¹² represents a hydrogen atom, and the other represents a C1-C6 alkyl group;

R² represents a phenyl group, wherein R² may have R²¹ as a substituent;

R²¹ represents a halogen atom or a C1-C6 alkyl group (when two or more of R²¹ are present, R²¹ are the same as or different from each other);

R³ represents a phenyl group which may have R³¹ as a substituent or may be fused with a monocyclic 6 membered saturated heterocyclic ring having one oxygen atom (wherein the saturated heterocyclic ring may have Rc as a substituent);

R³¹ represents a halogen atom or an aminocarbonyl group (when two or more of R³¹ are present, R³¹ are the same as or different from each other);

Rc represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group (when two or more of Rc are present, Rc are the same as or different from each other); and

R⁴ represents a hydrogen atom.

[4]

The combination formulation according to any one of [1]-[3], wherein in formula (I),

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents —NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²)—;

one of R¹¹ and R¹² represents a hydrogen atom, and the other represents a methyl group;

R² represents a phenyl group having R²¹ as a substituent;

R²¹ represents a halogen atom or a C1-C6 alkyl group (when two or more of R²¹ are present, R²¹ are the same as or different from each other);

R³ represents a phenyl group having R³¹ as a substituent or a chromanyl group having Rc as a substituent;

R³¹ represents a halogen atom or an aminocarbonyl group (when two or more of R³¹ are present, R³¹ are the same as or different from each other);

Rc represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group (when two or more of Rc are present, Rc are the same as or different from each other); and

R⁴ represents a hydrogen atom.

[5]

The combination formulation according to any one of [1]-[4], wherein the sulfonamide compound is selected from the following compounds (1)-(5):

• (1) 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (2) 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (3) 5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (4) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchromane-8-sulfonamide; and
• (5) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychromane-8-sulfonamide.[6]

The combination formulation according to any one of [1]-[5], wherein the sulfonamide compound represented by formula (I) or a salt thereof and the other antitumor agent(s) are administered concurrently, sequentially, or in a staggered manner.

[7]

The combination formulation according to any one of [1]-[6], wherein the other antitumor agent(s) is at least one or more selected from an antimetabolite, a platinum drug, a plant alkaloid drug, and a molecular targeting drug.

[8]

The combination formulation according to any one of [1]-[7], wherein the other antitumor agent(s) is at least one or more selected from 5-fluorouracil (5-FU), trifluridine, fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, decitabine, guadecitabine, azacitidine, cisplatin, oxaliplatin, carboplatin, etoposide, AZD6738, prexasertib, SCH900776, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, and midostaurin.

[9]

An agent for enhancing an antitumor effect of other antitumor agent(s), comprising a sulfonamide compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)]

or a salt thereof as an active ingredient.

[10]

An antitumor agent for treating a cancer patient dosed with other antitumor agent(s), comprising a sulfonamide compound or a salt thereof, wherein the sulfonamide compound is a compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)].

[11]

A pharmaceutical composition comprising a sulfonamide compound or a salt thereof and other antitumor agent(s), wherein the sulfonamide compound is a compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)].

[12]

A sulfonamide compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)]

or a salt thereof for use in treating and/or preventing tumor by administering the sulfonamide compound or a salt thereof and other antitumor agent(s) concurrently, sequentially, or in a staggered manner.

[13]

A product comprising a sulfonamide compound represented by the following formula

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)] or a salt thereof for use in treating and/or preventing tumor by administering the sulfonamide compound or a salt thereof and other antitumor agent(s) concurrently, sequentially, or in a staggered manner, and the other antitumor agent(s), as a combination formulation.

[14]

A method of treating and/or preventing tumor comprising administering a sulfonamide compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)] or a salt thereof and other antitumor agent(s) concurrently, sequentially, or in a staggered manner.

[15]

A method of treating and/or preventing tumor comprising administering a sulfonamide compound represented by the following formula (I):

[In the formula,

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom or —NH—;

X³ represents —NH— or an oxygen atom;

X⁴ represents a hydrogen atom or a C1-C6 alkyl group;

R¹ represents —C(R¹¹)(R¹²)— or —C(═CH₂)—;

R¹¹ and R¹² are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively may be taken together with the carbon atoms to which R¹¹ and R¹² are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms;

R² represents a C6-C14 aromatic hydrocarbon group or a 9 or 10 membered fully unsaturated heterocyclic group,

wherein R² may have substituents, and when R² has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents;

R³ represents a C6-C14 aromatic hydrocarbon group or a 5-10 membered fully unsaturated heterocyclic group,

wherein R³ may have substituents, and when R³ has two substituents on the carbon atoms which are adjacent to each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atoms to which the substituents are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring, either of which may have substituents; and

R⁴ represents a hydrogen atom or a C1-C6 alkyl group;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)]

or a salt thereof to a cancer patient dosed with other antitumor agent(s).

The present invention also relates to the following aspects: A pharmaceutical composition for preventing and/or treating tumor, comprising the above-mentioned sulfonamide compound represented by formula (I) or a salt thereof and other antitumor agent(s).

The sulfonamide compound represented by the above formula (I) or a salt thereof for enhancing an antitumor effect of other antitumor agent(s).

Use of the sulfonamide compound represented by the above formula (I) or a salt thereof for enhancing an antitumor effect of other antitumor agent(s).

Use of the sulfonamide compound represented by the above formula (I) or a salt thereof for manufacturing an agent for enhancing an antitumor effect of other antitumor agent(s).

A method of preventing and/or treating tumor comprising the step of administering prophylactically and/or therapeutically effective amounts of the sulfonamide compound represented by the above formula (I) or a salt thereof and other antitumor agent(s) in combination to a patient.

A method of preventing and/or treating tumor comprising the step of administering a prophylactically and/or therapeutically effective amount of the sulfonamide compound represented by the above formula (I) or a salt thereof to a cancer patient dosed with other antitumor agent(s).

A method of enhancing an antitumor effect comprising the step of administering a therapeutically and/or prophylactically effective amount of the sulfonamide compound represented by the above formula (I) or a salt thereof to a cancer patient dosed with other antitumor agent(s).

A product comprising the sulfonamide compound represented by the above formula (I) or a salt thereof and other antitumor agent(s) as a combination formulation used concurrently, sequentially, or in a staggered manner in preventing and/or treating tumor.

The present specification encompasses the contents disclosed in Japanese Patent Application No. 2017-229681 on which the priority of the present application is based.

Advantageous Effects of Invention

According to the present invention, cancer treatment that exerts an excellent antitumor effect can be performed while side effects are prevented.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 It is a diagram illustrating an antitumor effect by the oral administration of Example Compounds 5 and 11 to human-derived blood cancer cell line subcutaneous transplantation mice in terms of daily variation of relative tumor volume (hereinafter also referred to as “RTV”).

FIG. 2 It is a diagram illustrating an antitumor effect by the oral administration of Example Compounds 1 and 14 to human-derived blood cancer cell line subcutaneous transplantation mice in terms of daily variation of RTV.

FIG. 3 It is a diagram illustrating an antitumor effect by the oral administration of Example Compounds 209A, 222A and 235A to human-derived blood cancer cell line subcutaneous transplantation mice in terms of daily variation of RTV.

FIG. 4 It is a diagram illustrating an antitumor effect by the oral administration of Example Compounds 200A and 228A to human-derived blood cancer cell line subcutaneous transplantation mice in terms of daily variation of RTV.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, RNR inhibitors that bring about an excellent synergistic effect with other antitumor agent(s) are sulfonamide compounds represented by the above formula (I) or salts thereof.

“CA-CB” as used herein for description of groups refers to a group having a carbon number of A-B. For example, “C1-C6 alkyl group” represents an alkyl group having 1 to 6 carbon atoms. The term “A-B membered” indicates that the number of atoms constituting the ring (ring members) is A-B. For example, “5-10 membered unsaturated heterocyclic group” means an unsaturated heterocyclic group whose ring member is 5-10.

“Substituent” as used herein refers to a halogen atom, a hydroxy group, an amino group, an oxo group, a cyano group, a nitro group, a carboxyl group, an aminocarbonyl group, a thioamide group, a C1-C6 alkyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy C1-C6 alkoxy group, a halogeno C1-C6 alkyl group, a halogeno C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, an unsaturated heterocyclic group, a saturated heterocyclic group, a nitrogen-containing saturated heterocyclic group, a nitrogen-containing saturated heterocyclic carbonyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C2-C7 alkoxycarbonyl group, a C1-C14 acyloxy group, C7-C13 aralkyloxy group and the like.

“Halogen atom” as used herein refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

“C1-C6 alkyl group” as used herein refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a hexyl group and the like.

“C2-C6 alkynyl group” as used herein refers to an unsaturated straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one triple bond, e.g., ethynyl, 1- or 2-propynyl group, 1-, 2- or 3-butynyl group, 1-methyl-2-propynyl group and the like.

“C3-C6 cycloalkyl group” as used herein refers to a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.

“C1-C6 alkoxy group” as used herein refers to an oxy group to which a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms is bonded, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group and the like.

“C1-C6 alkoxy C1-C6 alkoxy group” as used herein refers to a C1-C6 alkoxy group in which one of the hydrogen atom of the C1-C6 alkoxy group is substituted with a C1-C6 alkoxy group, for example, a methoxymethoxy group, a methoxyethoxy group, a methoxy propoxy group, an ethoxymethoxy group, an ethoxyethoxy group, a propoxy methoxy group and the like.

“halogeno C1-C6 alkyl group” as used herein refers to a C1-C6 alkyl group in which one or more hydrogen atoms are substituted with a halogen atom, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a fluoroethyl group, 1,1,1-trifluoroethyl group, a mono fluoro-n-propyl group, a perfluoro-n-propyl group, a perfluoro isopropyl group and the like.

“C6-C14 aromatic hydrocarbon group” as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a fluorenyl group and the like.

“Unsaturated heterocyclic group” as used herein refers to a monocyclic or polycyclic unsaturated heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom (preferably 1 to 4, more preferably 1 to 3). The unsaturated heterocyclic group includes a fully unsaturated heterocyclic group (a fully unsaturated heterocyclic group) and a partially unsaturated heterocyclic group (a partially unsaturated heterocyclic group).

A fully unsaturated heterocyclic group includes, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl, a furanyl (a furyl group), an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiophenyl group (a thienyl group), a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyridinyl group (a pyridyl group), a pyrimidinyl group (pyrimidyl group), a pyrazinyl group (a pyrazyl group), a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group (a benzpyrazol group), a benzimidazolyl group, a benzotriazolyl group, an azaindolyl group, a pyrrolopyridinyl group, an imidazopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrrolopyrimidinyl group, an imidazopyrimidinyl group, a pyrazolopyrimidinyl group, a benzofuranyl group, a benzoxazolyl group, a benzothiophenyl group (a benzothienyl group), a benzothiazolyl group, a benzothiadiazolyl group, a benzofuranyl group (a benzofuryl group), a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalyl group and the like.

A partially unsaturated heterocyclic group includes, for example, a dihydropyranyl group, a dihydro triazolyl group, a dihydrofuranyl group, a dihydrooxadiazolyl group, a dihydroquinolyl group, a dihydroquinazolinyl group, an indolinyl group, a tetrahydroisoquinolyl group, a methylenedioxyphenyl group, an ethylenedioxy phenyl group, a dihydrobenzofuranyl group, a dihydro-benzoxazolyl group, a dihydropyridooxazinyl group and the like.

“Saturated heterocyclic group” as used herein refers to a single or polycyclic fully saturated heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom (preferably 1 to 4, more preferably 1 to 3), and includes, for example, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperazinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, a thiazolidinyl group, an oxazolidinyl group and the like.

“Nitrogen-containing saturated heterocyclic group” as used herein refers to a saturated heterocyclic group having one or more nitrogen atoms, which optionally includes a hetero atom other than nitrogen atom, and includes, for example, a morpholino group.

“Nitrogen-containing saturated heterocyclic carbonyl group” as used herein refers to a carbonyl group to which a nitrogen-containing saturated heterocyclic group is bonded, and includes, for example, a morpholinocarbonyl group.

“C1-C14 acyl group”, as used herein refers to a carbonyl group to which a hydrogen atom, a C1-C6 alkyl group, a C6-C14 aromatic hydrocarbon group or an unsaturated heterocyclic group is bonded, and includes, for example: a formyl group; a (C1-C6 alkyl) carbonyl group such as an acetyl group, a propanoyl group, a butanoyl group; a (C3-C6 cycloalkyl) carbonyl group such as a cyclopropanoyl group, a cyclobutanoyl group; or a (C6-C13) arylcarbonyl group such as a benzoyl group, a naphthyl carbonyl group, a fluorenylcarbonyl group.

“C1-C14 acylamino group” as used herein refers to an amino group in which one or two hydrogen atoms are substituted with a C1-C14 acyl group, and includes, for example, an acetylamino group, a propanoylamino group, a butanoylamino group, a cyclopropanoyl amino group.

“C2-C7 alkoxycarbonyl group”, as used herein refers to a carbonyl group to which a C1-C6 alkoxy group is bonded, and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, a tert-butoxycarbonyl group and the like.

“C1-C14 acyloxy group” as used herein refers to, for example, a formyloxy group; a (C1-C6 alkyl)carbonyloxy group such as a methyl carbonyloxy group, an ethyl carbonyloxy group, an n-propyl carbonyloxy group, an isopropylcarbonyloxy group, an n-butylcarbonyloxy group, an iso-butylcarbonyloxy group, a tert-butylcarbonyloxy group, an n-pentylcarbonyloxy group, an iso-pentylcarbonyloxy group, a hexylcarbonyloxy group and the like; a (C3-C6 cycloalkyl)carbonyloxy group such as a cyclopropanoyloxy group, a cyclobutanoyloxy group and the like; a (C6-C13 aryl)carbonyloxy group such as a phenylcarbonyloxy group, naphthylcarbonyloxy group, a fluorenylcarbonyloxy group and the like.

“C7-C13 aralkyloxy group” as used herein refers to an alkyloxy group in which one hydrogen atom is substituted with an aryl group, and includes, for example, a benzyloxy group, a phenethyloxy group, a naphthylmethyloxy group, a fluorenylmethyloxy group and the like.

“Saturated or partially unsaturated hydrocarbon ring” as used herein refers to a monocyclic or polycyclic saturated or partially unsaturated hydrocarbon ring, and includes, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a cyclooctadiene ring and the like.

“Saturated or partially unsaturated heterocyclic ring” as used herein refers to a monocyclic or polycyclic saturated or partially unsaturated heterocyclic a ring having a hetero atom selected from a nitrogen atoms a sulfur atom and an oxygen atom, and includes, for example, an oxirane ring, an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a tetrahydrofuran ring, a tetrahydropyran ring, a dioxane ring, a tetrahydrothiophene ring, a dihydropyran ring, a dihydrofuran ring and the like.

“Spiro heterocyclic group” as used herein refers to a saturated or unsaturated spiro heterocyclic group having a spiro carbon atom and a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom, and includes, for example, a 2-oxa-6-azaspiro[3.4]octanyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group and the like.

“Bridged heterocyclic group” as used herein refers to a bridged heterocyclic group having more than one ring, which have two bridgehead carbons and a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom, and includes, for example, a 3-oxa-8-azabicyclo[3.2.1]octanyl group, an 8-oxa-3-azabicyclo[3.2.1]octanyl group and the like.

In the compounds represented by the formula (I) of the present specification, X¹ is an oxygen atom or a sulfur atom. X¹ is preferably an oxygen atom.

In the compounds represented by the formula (I) of the present specification, X² is an oxygen atom or —NH—. X² is preferably an oxygen atom.

In the compounds represented by the formula (I) of the present specification, X³ is —NH— or an oxygen atom. X³ is preferably —NH—.

In the compounds of the formula (I), X⁴ is a hydrogen atom or a C1-C6 alkyl group.

“C1-C6 alkyl group” represented by X⁴ is preferably a C1-C3 alkyl group, more preferably a methyl group.

X⁴ is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom.

In the compounds of the formula (I), R¹ is, —C(R¹¹)(R¹²)— or —C(═CH₂)—.

In —C(R¹¹)(R¹²)—, R and R¹² are the same or different, and are a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively taken together with the carbon atoms to which they attach to form a saturated hydrocarbon ring having 3 to 8 carbon atoms.

“Halogen atom” represented by R¹¹ and R¹² is preferably a fluorine atom, a chlorine atom, a bromine atom, more preferably a fluorine atom.

“C1-C6 alkyl group” indicated in R¹¹ and R¹² is preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group, more preferably a methyl group.

“Saturated hydrocarbon ring having 3 to 8 carbon atoms”, which is formed by combining R¹¹ and R¹² together with the carbon atoms to which they attached, is preferably a monocyclic saturated hydrocarbon ring of 3 to 6 carbon atoms, and more preferably a cyclopropane ring.

Preferably, R¹¹ is a halogen atom, a hydroxy group, or a C1-C6 alkyl group, and R¹² is a hydrogen atom, a halogen atom, a hydroxy group, or a C1-C6 alkyl group, alternatively R¹¹ and R¹² are taken together with the carbon atoms to which they are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms. More preferably, R¹¹ is a C1-C6 alkyl group, and R¹² is a hydrogen atom, and more preferably R¹¹ is a methyl group, and R¹² is a hydrogen atom.

R¹ is preferably —C(R¹¹) (R¹²)—, R¹¹ is a halogen atom, a hydroxy group, or a C1-C6 alkyl group, and R¹² is a hydrogen atom, a halogen atom, hydroxy group, or a C1-C6 alkyl group, alternatively R¹¹ and R¹² are taken together with the carbon atoms to which they are attached to form a saturated hydrocarbon ring having 3 to 8 carbon atoms. More preferably, —C(R¹¹) (R¹²)—, and, R¹¹ is a C1-C6 alkyl group, R¹² is a hydrogen atom. Even more preferably, it is —CH(CH₃)—.

In the compounds of the formula (I), R² is a C6-C14 aromatic hydrocarbon group or a 9-10 membered fully unsaturated heterocyclic group.

“C6-C14 aromatic hydrocarbon group” represented by R² is preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group or a naphthyl group, even more preferably a phenyl group.

Furthermore, “fully unsaturated heterocyclic group having 9-10 membered” represented by R² is preferably a bicyclic 9-10 membered fully unsaturated heterocyclic group having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a bicyclic 9-10 membered fully unsaturated heterocyclic group having 1-2 hetero atoms selected from a nitrogen atom and a sulfur atom, even more preferably a benzothiophenyl group, a benzothiazolyl group, a quinolyl group.

In the compounds of the formula (I), R² may be unsubstituted or may have a substituent. Further, when R² has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, R² may form a 4 to 8-membered saturated or partially unsaturated hydrocarbon ring or a heterocyclic ring having substituent(s), wherein the substitutes are fused to form a ring together with the carbon atom to which they are attached.

When R² has a substituent, the substituted position of the substituent is not particularly limited, but, for example, preferably 2, 3, 5, or 6-position when R² is a phenyl group. Furthermore, the number of substituent is not particularly limited, but preferably zero, i.e. it is unsubstituted or 1-4, and more preferably 1-4 or 1-3. When the number of substituents is two or more, the types of the substituent may be the same or different.

In the compounds of formula (I), preferably, R² may be substituted with the “substituent”, more preferably, R² may be substituted with R²¹. Also, preferably, when R² has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with the carbon atom to which they are attached to form a saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring optionally substituted with Rz.

R²¹, which can be substituted at R², is a halogen atom, an aminocarbonyl group, a cyano group, a C1-C6 alkyl group which may be substituted with Rx, a C3-C6 cycloalkyl group which may be substituted with Rx, a C2-C6 alkynyl group which may be substituted with Rx, a C6-C14 aromatic hydrocarbon group which may be substituted with Ry, or an unsaturated 5-10 membered heterocyclic ring which may be substituted with Rz.

The position at which R²¹ is a substituted is not particularly limited, but, for example, preferably 2, 3, 5, or 6-position when R is a phenyl group. Furthermore, the number of the substituent R is not particularly limited, but preferably zero, i.e. it is unsubstituted, or 1-4, more preferably 1-4 or 1-3. When the number of the substituent R²¹ is two or more, the types of the substituent may be the same or different.

“Halogen atom” indicated in R²¹ is preferably a fluorine atom, a chlorine atom, or a bromine atom.

“C1-C6 alkyl group” in the “C1-C6 alkyl group which may be substituted with Rx” indicated in R²¹ is preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group.

The substituent Rx in the “C1-C6 alkyl group which may be substituted with Rx” indicated in R²¹ is a halogen atom or a C6-C14 aromatic hydrocarbon group. The substituent Rx is preferably a halogen atom, more preferably a fluorine atom. The number of Rx which is substituted at C1-C6 alkyl group is not particularly limited, but preferably zero, i.e., unsubstituted, or 1-3. When the number of substituent Rx is 2 or more, the types of the substituent may be the same or different.

“C3-C6 cycloalkyl group” in the “C3-C6 cycloalkyl group which may be substituted with Rx” indicated in R²¹ is preferably a cyclopropyl group.

Rx in the “C3-C6 cycloalkyl group which may be substituted with Rx” indicated in R²¹ is a halogen atom as mentioned above, or a C6-C14 aromatic hydrocarbon group, preferably a halogen atom, more preferably a fluorine atom. The number of Rx substituted at the C3-C6 cycloalkyl group is not particularly limited, but preferably zero, i.e. it is unsubstituted, or 1, more preferably 0. When the number of substituents Rx is 2 or more, the types of the substituent may be the same or different.

“C2-C6 alkynyl group” in the “C2-C6 alkynyl group which may be substituted with Rx” indicated in R²¹ is preferably a C2-C4 alkynyl group, more preferably an ethynyl group.

The substituent Rx in the “C2-C6 alkynyl group may be substituted with Rx” indicated in R²¹ is a halogen atom as mentioned above, or a C6-C14 aromatic hydrocarbon group, preferably a C6-C14 aromatic hydrocarbon group, more preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group.

The number of Rx substituted at the C2-C6 alkynyl group is not particularly limited, but preferably zero, i.e. it is unsubstituted, or 1, more preferably 1. When the number of the substituents Rx is 2 or more, the types of the substituent may be the same or different.

“C6-C14 aromatic hydrocarbon group” in the “C6-C14 aromatic hydrocarbon group which may be substituted with Ry” indicated in R²¹ is preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group.

The substituent Ry in the “C6-C14 aromatic hydrocarbon group which may be substituted with Ry” indicated in R²¹ is a halogen atom or a C1-C6 alkoxy group.

A halogen atom indicated in Ry is preferably a fluorine atom or chlorine atom. Also, a C1-C6 alkoxy group indicated in Ry is preferably a C1-C3 alkoxy group, more preferably a methoxy group. The substituent Ry in the “C6-C14 aromatic hydrocarbon group which may be substituted with Ry” indicated in R²¹ is preferably a fluorine atom, a chlorine atom, or a C1-C3 alkoxy group, more preferably a fluorine atom, a chlorine atom or a methoxy group. The number of Ry substituted in the C6-C14 aromatic hydrocarbon group is not particularly limited, but preferably zero, i.e. unsubstituted, or it is 1 or 2. When the number of the substituents Ry is 2 or more, the types of substituent may be the same or different.

“5 to 10-membered unsaturated heterocyclic group” in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rz” indicated in R²¹ is preferably a fully or partially unsaturated monocyclic or bicyclic 5-10 membered heterocyclic group having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom, more preferably a monocyclic 5-6 membered unsaturated heterocyclic group having 1-3 nitrogen atoms or an oxygen atom. Preferably, it is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidyl group, an oxazolyl group, a dihydropyridooxazinyl group, more preferably, a pyrazolyl group, a pyridyl group, a pyrimidyl group, an oxazolyl group, a dihydropyridooxazinyl group, more preferably a pyrazolyl group.

The substituent Rz in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rz” indicated in R²¹ is a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, or a nitrogen-containing saturated heterocyclic carbonyl group.

“Halogen atom” indicated in Rz is preferably a fluorine atom or a chlorine atom.

“C1-C6 alkyl group” indicated in Rz is preferably a C1-C3 alkyl group, more preferably a methyl group, or an ethyl group.

“Halogeno C1-C6 alkyl group” indicated in Rz is preferably a halogeno C1-C3 alkyl group, more preferably a difluoromethyl group or a trifluoromethyl group. “C3-C6 cycloalkyl group” indicated in Rz is preferably a cyclopropyl group or a cyclobutyl group.

“C1-C6 alkoxy group” indicated in Rz is preferably a C1-C3 alkoxy group, more preferably a methoxy group.

“C6-C14 aromatic hydrocarbon group” indicated in Rz is preferably a phenyl group.

“Nitrogen-containing saturated heterocyclic group” represented by Rz is preferably a morpholino group or a piperidinyl group.

“Nitrogen-containing saturated heterocyclic carbonyl group” indicated in Rz is preferably a morpholinocarbonyl group.

The substituent Rz in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rz” is preferably a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a phenyl group, a morpholino group, a piperidinyl group, or a morpholinocarbonyl group, more preferably a C1-C6 alkyl group, more preferably a methyl group. The number of Rz which is substituted at the 5 to 10-membered unsaturated heterocyclic group is not particularly limited, but preferably zero, i.e. unsubstituted, or preferably 1 or 2. When the number of the substituent Rz is 2 or more, the type of the substituent may be the same or different.

R²¹, which can be substituted at R², is preferably, a halogen atom, an aminocarbonyl group, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a C2-C6 alkynyl group (optionally substituted with a C6-C14 aromatic hydrocarbon group) a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from a halogen atom and a C1-C6 alkoxy group), or a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, and a nitrogen-containing saturated heterocyclic carbonyl group).

More preferably, a halogen atom, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (optionally substituted with a group selected from the group consisting of a halogen atom or a C1-C6 alkoxy group), or monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group).

More preferably, a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6-membered unsaturated heterocyclic group having 1 to 3 of a nitrogen atom(s) (optionally substituted with a C1-C6 alkyl group).

More preferably, a halogen atom or a C1-C6 alkyl group.

In the compounds of the formula (I), when the number of the substituents at R is 2 or more, and there are two substituents at the carbons which are adjacent each other on the aromatic hydrocarbon ring, “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which may have substituent(s)”, which is formed by combining the substituents and the carbon atom to which they are attached, is a ring, for example a ring fused to a benzene ring.” Saturated or partially unsaturated 4 to 8-membered hydrocarbon ring or heterocyclic ring” in the “4-8 membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring, which may have substituent(s)” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring, or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms, more preferably, a saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms, more preferably, a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 6 carbon atoms, or a monocyclic 4-6 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen atom, a sulfur atom, and an oxygen atom, and even more preferably, a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbon atoms, more preferably a saturated hydrocarbon ring having 5 carbon atoms.

The substituent Rz in the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring optionally substituted with Rz” is, as mentioned above, a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, or a nitrogen-containing saturated heterocyclic carbonyl group, preferably a C1-C6 alkyl group, and more preferably, a C1-C3 alkyl group, and even more preferably, a methyl group. The number of Rz which substitutes at a saturated or partially unsaturated hydrocarbon ring or heterocyclic ring is not particularly limited, but preferably zero, i.e., unsubstituted, or it is one, more preferably it is zero, i.e., unsubstituted. When the number of the substituents Rz is 2 or more, the type of substituent may be the same or different.

“Saturated or partially unsaturated 4-8 membered hydrocarbon ring or heterocyclic ring optionally substituted with Rz” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms, which is optionally substituted with Rz, or a monocyclic 4-8 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, more preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which may be substituted with a C1-C6 alkyl group) or a monocyclic saturated or partially unsaturated 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a C1-C6 alkyl group), more preferably a saturated or partially unsaturated monocyclic hydrocarbon ring having 4 to 8 carbon atoms (optionally substituted with a C1-C6 alkyl group), more preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group).

In the compounds represented by formula (I), a fused ring, which is formed when the compound has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring of R², is for example, a dihydro-indene ring, a tetrahydronaphthalene ring, a dihydrobenzofuran ring.

In the compounds represented by formula (I), R² is preferably a C6-C14 aromatic hydrocarbon group or a bicyclic fully unsaturated 9-10 membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms, and R² may be substituted with R²¹, and when R² has two substituents on the carbon atom adjacent each other on the aromatic hydrocarbon ring, R² may be a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (optionally substituted with a C1-C6 alkyl group) wherein the substituents are fused together with the carbon atom to which each of the substituent is bonded, or a monocyclic 4-8 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms (optionally substituted with a C1-C6 alkyl group); and

R²¹ is a halogen atom, an aminocarbonyl group, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a C2-C6 alkynyl group (optionally substituted with a C6-C14 aromatic hydrocarbon group), a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkoxy group), or a monocyclic or bicyclic 5-10 membered unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C6-C14 aromatic hydrocarbon group, a nitrogen-containing saturated heterocyclic group, and a nitrogen-containing saturated heterocyclic carbonyl group).

In the compounds represented by formula (I), R² is more preferably a C6-C14 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atom adjacent each other on the aromatic hydrocarbon ring, R² may form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (optionally substituted with a C1-C6 alkyl group) wherein the substituents are fused together with the carbon atom to which each of the substituent is bonded;

R²¹ is a halogen atom, a cyano group, a C1-C6 alkyl group (optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (optionally substituted with a group selected from the group consisting of a halogen atom a C1-C6 alkoxy group), or a monocyclic or bicyclic 5-10 membered unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group).

Also, in the compounds represented by formula (I), R² is more preferably a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atom adjacent each other on the aromatic hydrocarbon ring, R² may form a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbon atoms (optionally substituted with a C1-C6 alkyl group) wherein the substituents are fused together with the carbon atom to which each of the substituents is bonded; and

R²¹ is a halogen atom, a C1-C6 alkyl group, or a monocyclic 5 or 6-membered unsaturated heterocyclic ring having 1-3 nitrogen atom(s) (optionally substituted with a C1-C6 alkyl group).

Also, in the compounds represented by formula (I), R² is especially preferably a phenyl group or a naphthyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkyl group); an indanyl group (2,3-dihydro-1H-indenyl group); or a tetrahydronaphthyl group.

In the compounds represented by formula (I), R³ is a C6-C14 aromatic hydrocarbon group or a 5 to 10-membered fully unsaturated heterocyclic group.

“C6-C14 aromatic hydrocarbon group” indicated in R³ is preferably a C6-C10 aromatic hydrocarbon group, more preferably a phenyl group, or a naphthyl group, particularly preferably a phenyl group.

“5 to 10-membered fully unsaturated heterocyclic group” indicated in R³ is a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1-3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably, a monocyclic or bicyclic 5 to 7-membered fully unsaturated heterocyclic group having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, particularly preferably a monocyclic 5 to 6-membered fully unsaturated heterocyclic ring having 1-3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atoms. Preferably, an imidazolyl group, a pyridyl group, a thiophenyl group, an indolyl group, an indazolyl group, a benzopyranyl group, a benzotriazolyl group, a benzothiadiazolyl group, an isoxazolyl group, a quinolyl group, more preferably an imidazolyl group, a pyridyl group, a thiophenyl group, an indolyl group, an indazolyl group, a benzopyranyl group, a benzotriazolyl group, a benzothiadiazolyl group, a quinolyl group, more preferably a pyridyl group, a thiophenyl group, an indolyl group, an indazolyl group, a benzopyranyl group, a benzotriazolyl group, a quinolyl group, more preferably a pyridyl group.

In the compounds represented by formula (I), R³ may be unsubstituted or may have a substituent. Also, when R³ has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, R³ may form a 4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring, which may be substituted, wherein the substituents are fused together with the carbon atom to which each of the substituents is bonded; and

When R³ has a substituent, the position of the substituent is not particularly limited. Although the number of the substituent is not limited, it is particularly preferably 0, i.e. unsubstituted. Alternatively, the number of the substituent is 1 to 4, more preferably 1 to 3. When the number of substituent is two or more, the types of the substituent may be the same or different.

In the compounds represented by formula (I), preferably R³ may be substituted with the “substituent”, more preferably R³ may be substituted with R³¹. Also, preferably, when R³ has two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring, R³ may form a 4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring, which may be substituted with Rc, wherein the substituents are fused together with the carbon atom to which each of the substituents is bonded.

R³¹, which can be substituted at R³, is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group which may be substituted with Ra, an amino group which may be substituted with Ra, a C3-C6 cycloalkyl group which may be substituted with Rb, a C1-C6 alkoxy group which may be substituted with Rb, a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group which may be substituted with Rb, a C6-C14 aromatic hydrocarbon ring which may be substituted with Rb, an 5 to 10-membered unsaturated heterocyclic ring which may be substituted with Rc, an aminocarbonyl group which may be substituted with Rd and Re, or —S(═O)₂Rf.

Although the number of the substituent is not limited, it is particularly preferably 0, i.e. unsubstituted. Alternatively, the number of the substituent is 1 to 4, more preferably 1 to 3. When the number of substituent is two or more, the types of the substituent may be the same or different.

“Halogen atom” indicated in R³¹ is preferably a fluorine atom, a chlorine atom, or a bromine atom, more preferably a chlorine atom, or a bromine atom.

“C1-C6 alkyl group” of “a C1-C6 alkyl group which may be substituted with Ra” indicated in R³¹ is preferably a C1-C3 alkyl group, more preferably a methyl group.

The substituent Ra of “a C1-C6 alkyl group which may be substituted with Ra” indicated in R³¹ is a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group.

“Halogen atom” indicated in Ra is preferably a fluorine atom.

“C1-C14 acyl group” indicated in Ra is preferably an acetyl group.

“C1-C14 acyloxy group” indicated in Ra is preferably an acetyloxy group.

“C2-C6 alkynyl group” indicated in Ra is preferably an ethynyl group, 1-propynyl group.

“C1-C6 alkoxy C1-C6 alkoxy group” indicated in Ra is preferably a methoxymethoxy group.

The substituent Ra of “a C1-C6 alkyl group may be substituted with Ra” indicated in R³ is preferably a halogen atom, a hydroxy group, a C1-C6 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group, more preferably a halogen atom, or a hydroxy group. Although the number of Ra which is substituted at the C1-C6 alkyl is not particularly limited, preferably zero, i.e. unsubstituted, or one or more. When the number of the substituents Ra is 2 or more, the types of the substituent may be the same or different.

Ra of “an amino group optionally substituted with Ra” indicated in R³ is a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group, or a C1-C6 alkoxy C1-C6 alkoxy group, preferably a C1-C14 acyl group, more preferably an acetyl group.

The number of Ra substituted at the amino group is not particularly limited, preferably zero, i.e. unsubstituted, or is 1, more preferably 0.

“C3-C6 cycloalkyl group” in the “C3-C6 cycloalkyl group optionally substituted with Rb” indicated in R³¹ is preferably a cyclopropyl group.

Rb in the “C3-C6 cycloalkyl group optionally substituted with Rb” indicated in R³ is a halogen atom, an amino group, or a C1-C6 alkoxy group.

“Halogen atom” indicated in Rb is preferably a fluorine atom.

“C1-C6 alkoxy group” indicated in Rb is preferably a C1-C3 alkoxy group, more preferably a methoxy group.

Rb in the “C3-C6 cycloalkyl group optionally substituted with Rb” indicated in R³ is preferably an amino group. The number of Rb substituting at the C3-C6 cycloalkyl group is not particularly limited, preferably zero, i.e. unsubstituted, or is 1, more preferably 0. When the number of substituents Rb is two or more, the types of the substituent may be the same or different.

“C1-C6 alkoxy group” in the “C1-C6 alkoxy group optionally substituted with Rb” indicated in R³¹ is preferably a C1-C3 alkoxy group, more preferably a methoxy group.

Rb in the “C1-C6 alkoxy group optionally substituted with Rb” indicated in R³¹ is, as mentioned above, a halogen atom, an amino group, or a C1-C6 alkoxy group, preferably a halogen atom, more preferably a fluorine atom. Although number of Rb substituent to a C1-C6 alkoxy group is not limited, it is zero, i.e. unsubstituted, or one or two. When the number of substituent Rb is two or more, the types of the substituent may be the same or different.

“C2-C7 alkoxycarbonyl group” indicated in R³¹ is preferably a C2-C4 alkoxycarbonyl group, more preferably a methoxycarbonyl group.

“C1-C14 acyl group” in the “C1-C14 acyl group optionally substituted with Rb” indicated in R³¹ is preferably an acetyl group.

Rb in the “C1-C14 acyl group optionally substituted with Rb” indicated in R³¹ is, as mentioned above, a halogen atom, an amino group, or a C1-C6 alkoxy group, preferably a halogen atom, more preferably a fluorine atom. Although number of Rb substituent at a C1-C14 acyl group is not limited, it may be zero, i.e. unsubstituted, or one to three. When the number of substituents Rb is two or more, the types of the substituent may be the same or different.

“Thioamide group” indicated in R³¹ is preferably —C(═S)—NH₂.

“C6-C14 aromatic hydrocarbon group” in the “C6-C14 aromatic hydrocarbon group optionally substituted with Rb” indicated in R³¹ is preferably a C6-C10 aromatic hydrocarbon group, and more preferably a phenyl group.

The substituent Rb in the “C6-C14 aromatic hydrocarbon group optionally substituted with Rb” indicated in R³¹ is, as mentioned above, a halogen atom, an amino group, or a C1-C6 alkoxy group, and preferably a halogen atom or a C1-C3 alkoxy group, and more preferably a halogen atom, and more preferably a fluorine atom. Although the number of Rb substituting at a C6-C14 aromatic hydrocarbon group is not particularly limited, it is preferably zero, i.e. unsubstituted, or it is one. When the number of the substituents Rb is 2 or more, the type of groups may be the same or different.

“5 to 10-membered unsaturated heterocyclic group” in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rc” indicated in R³¹ is preferably a monocyclic or bicyclic 5-10 membered fully or partially unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferably it is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a tetrazolyl group, an isoxazolyl group, an oxadiazolyl group, a dihydro oxadiazolyl group, preferably a pyrazolyl group, a 1,3,4-oxadiazolyl group, a 2,3-dihydro-1,3,4-oxazolyl group.

The substituent Rc in the “5-10 membered unsaturated heterocyclic group optionally substituted with one or more of Rc” indicated in R³¹ is a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl, or a C1-C14 acylamino group, a C1-C14 acyloxy group, or a C7-C13 aralkyloxy group.

“Halogen atom” indicated in Re is preferably a fluorine atom.

“C1-C6 alkyl groups optionally substituted with a hydroxy group” indicated in Re is preferably a C1-C3 alkyl group optionally substituted with a hydroxy group, and more preferably a methyl group or a hydroxyethyl group.

“Halogeno C1-C6 alkyl group” represented by Re is preferably a halogeno C1-C3 alkyl group, more preferably a trifluoromethyl group, a difluoroethyl group.

“C1-C14 acyl group” indicated in Re is preferably an acetyl group or a cyclopropanoyl group.

“C1-C14 acylamino group” indicated in Re is preferably an acetylamino group.

“C1-C14 acyloxy group” indicated in Re is preferably an acetyloxy group.

“C7-C13 aralkyloxy group” indicated in Re is preferably a benzyloxy group.

Rc in the “5 to 10-membered unsaturated heterocyclic group optionally substituted with Rc” indicated in R³¹ is preferably a halogen atom, a C1-C6 alkyl group, or an oxo group, more preferably a C1-C6 alkyl group or an oxo group, more preferably a C1-C6 alkyl group. Although the number of Re substituting at 5 to 10-membered unsaturated heterocyclic group is not particularly limited, it is preferably zero, i.e. unsubstituted, or preferably it is one or more than 2, more preferably it is zero. When the number of the substituents Re is 2 or more, the type of groups may be the same or different.

“An amino carbonyl group optionally substituted with Rd and Re” indicated in R³ is specifically represented by the following group (II).

Rd and Re are the same or different and represent: a hydrogen atom; a hydroxy group; a C7-C13 aralkyloxy group; or C1-C6 alkyl group optionally substituted with hydroxyl groups; alternatively taken together with a nitrogen atom which is adjacent to Rd and Re to form a saturated or unsaturated 4 to 10-membered heterocyclic ring group optionally substituted with an amino group, a spiro heterocyclic ring group, or a bridged heterocyclic ring group.

“C7-C13 aralkyloxy group” indicated in Rd or Re is preferably a benzyloxy group.

“C1-C6 alkyl group optionally substituted with hydroxy groups” indicated in Rd or Re is preferably a C1-C3 alkyl group optionally substituted with a hydroxy group, more preferably a methyl group, or a hydroxyethyl group.

“A saturated heterocyclic group” in the “4 to 10-membered saturated heterocyclic group optionally substituted with an amino group” in Rd or Re is preferably a monocyclic or bicyclic 4 to 10-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, preferably a 5 to 6-membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, more preferably an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a morpholino group.

“An unsaturated heterocyclic group” in the “4 to 10-membered saturated or unsaturated heterocyclic group optionally substituted with an amino group”, which is formed together with Rd or Re and the adjacent nitrogen atoms, is preferably a monocyclic or bicyclic or 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, more preferably a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, particularly preferably a pyrrolyl group.

“Spiroheterocyclic group” formed together with Rd or Re and the adjacent nitrogen atom is preferably a monosupiro heterocyclic group, more preferably an oxoazaspirononanylcarbamoyl group, or an azasupirooctanylcarbamoyl group.

“Bridged heterocyclic group” formed together with Rd or Re and the adjacent nitrogen atom indicated is preferably a bicyclic bridged heterocyclic group, more preferably an oxoazabicyclooctanylcarbamoyl group.

The substituents Rd and Re in the “aminocarbonyl group optionally substituted with Rd and Re” indicated in R³¹ are preferably the same or different, and present a hydroxy group or a C1-C6 alkyl group, alternatively taken together with the adjacent nitrogen atom to form a monocyclic 5 to 6-membered saturated heterocyclic group, which may be substituted with an amino group, having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a monosupiro heterocyclic group or a bicyclic bridged heterocyclic group.

“An amino carbonyl group optionally substituted with Rd and Re” indicated in R³ is preferably a —CONH₂ group, (a mono or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyamino group, a (C7-C13 aralkyl)oxyaminocarbonyl group, or a cyclicaminocarbonyl group, more preferably a —CONH₂ group, (a mono or di-C1-C3 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group, a benzyloxycarbonylgroup, a pyrrolidin-1-ylcarbonyl group, a piperidin-1-ylcarbonyl group, a piperazin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, an azetidin-1-ylcarbonyl group, an oxo azabicyclooctanylcarbonyl group, an oxo azaspiro nonanylcarbonyl group, an azaspirooctanylcarbonyl group, more preferably a —CONH₂ group, a dimethylaminocarbonyl group, or a pyrrolidin-1-ylcarbonyl group.

Rf of “—S(═O)₂Rf” indicated in R³¹ is an amino group, a C1-C6 alkyl group, or a 4 to 10-membered saturated heterocyclic group.

C1-C6 alkyl group indicated in Rf is preferably a C1-C3 alkyl group, more preferably a methyl group.

A 4 to 10-membered saturated heterocyclic group indicated in Rf is preferably a monocyclic or bicyclic 4 to 10-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic 5 to 6-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, more preferably a pyrrolidinyl group, a piperidino group, or a piperazinyl group.

“—S(═O)₂Rf” indicated in R³¹ is preferably an aminosulfonyl group, a methylsulfonyl group, or a piperidinosulfonyl group.

R³¹ which may be substituted with R³ is preferably a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group (which may be substituted with a C1-C14 acyl group), a C3-C6 cycloalkyl group (which may be substituted with an amino group), a C1-C6 alkoxy group (which may be substituted with halogen atoms), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (which may be substituted with halogen atoms), a C6-C14 aromatic hydrocarbon group (which may be substituted with a group selected from the group consisting of a halogen atom, an amino group and a C1-C6 alkoxy group), monocyclic or bicyclic 5 to 10 membered unsaturated heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which may be substituted with a group consisting of a halogen atom, an oxo group, and a C1-C6 alkyl group), an aminocarbonyl group optionally substituted with Rd and Re (wherein, Rd and Re are the same or different, and present a hydrogen atom, a hydroxy group, a C7-C13 aralkyloxy group, or a C1-C6 alkyl group which may be substituted with a hydroxyl group, alternatively they are taken together with the adjacent nitrogen atom to form a monocyclic or bicyclic 4-10 membered saturated or unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a spiro heterocyclic group, or a bridged heterocyclic group), or —S(═O)₂Rf (wherein Rf is an amino group, a C1-C6 alkyl group, or a 4-10 membered saturated heterocyclic group).

More preferably, it is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (which may be substituted with an amino group), a C1-C6 alkoxy group (which may be substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (which may be substituted with a halogen atom), C6-C10 aromatic hydrocarbon group (which may be substituted with a halogen atom), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which may be substituted with a group selected from the group consisting of a C1-C6 alkyl group and an oxo group), a —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group, a (C7-C13 aralkyl)oxyaminocarbonyl group, a cyclic aminocarbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl a group.

More preferably, it is a halogen atom, an amino group, a C1-C6 alkyl group (which may be substituted with a group selected from the group consisting of a halogen atom and a hydroxy group) a C1-C6 alkoxy group (which may be substituted with halogen atoms), a monocyclic 5 or 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono or di C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino group.

More preferably, it is a halogen atom, an amino group, a C1-C6 alkoxy group, or a —CONH₂ group.

When the compound of the formula (I) has two or more substituents on R³ and two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring of R³, the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which may be substituted”, which is formed with the carbon atoms to which they are attached, is the ring, such as a ring fused to a benzene ring. “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring” in the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which may be substituted” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms, or 4 to 8-membered saturated or partially unsaturated hetero ring having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, more preferably, a monocyclic 4 to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, more preferably a monocyclic 6-membered saturated or partially unsaturated heterocyclic ring having one or two oxygen atom(s).

Substituent Rc in the “4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which is optionally substituted with Rc” is a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group which is optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group, or a C7-C13 aralkyloxy group, preferably a hydroxy group, an amino group, an oxo group, or a C1-C6 alkyl group which is optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acyloxy group, more preferably a hydroxy group, or a C1-C6 alkyl group. The number of Rc which substitutes at a saturated or partially unsaturated hydrocarbon ring or heterocyclic ring is not particularly limited, but is preferably 1 to 3. When the number of substituent Rc is 2 or more, the type of groups may be the same or different.

“4 to 8-membered saturated or partially unsaturated hydrocarbon ring or heterocyclic ring which is optionally substituted with Rc” is preferably a monocyclic saturated or partially unsaturated hydrocarbon ring (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group and a C7-C13 aralkyloxy group), a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom from sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group and a C7-C13 aralkyloxy group).

More preferably, a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, and a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group).

More preferably, a monocyclic 4 to 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (which is optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acylamino group and a C1-C14 acyloxy group).

More preferably, a monocyclic 6-membered saturated or partially unsaturated heterocyclic ring having 1 or two oxygen atom(s) (which is optionally substituted with a group selected from the group consisting of a hydroxyl group and a C1-C6 alkyl group).

In the compounds represented by the formula (I), a fused ring which is formed when there are two substituents on the carbon atoms adjacent each other on the aromatic hydrocarbon ring of R³, is for example, a chroman ring, a dihydrobenzoxazine ring, a dihydroindene ring, an indoline ring, a tetrahydroquinoxaline ring, a dihydrobenzodioxane ring, a tetrahydronaphthalene ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a dihydrobenzothiophene ring, an isoindoline ring, a dihydroisobenzofuran ring, a dihydrobenzoimidazole ring, and the like.

In the compounds represented by the formula (I), R³ is preferably a C6-C14 aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1 to 3 heteroatom(s) selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ may be substituted with R³¹, or when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group consisting of the group selected from a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group, and a C7-C13 aralkyloxy group), or, a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl groups, a C1-C14 acyl group, a C1-C14 acylamino group, a C1-C14 acyloxy group, a C7-C13 aralkyloxy group);

R³¹ is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyl group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group (optionally substituted with a C1-C14 acyl group), a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with halogen atoms), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), a C6-C14 aromatic hydrocarbon group (optionally substituted with a group selected from the group consisting of a halogen atom, an amino group and a C1-C6 alkoxy group), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, an oxo group, and a C1-C6 alkyl group), an amino carbonyl group optionally substituted with Rd and Re (wherein Rd and Re are the same or different, and are a hydrogen atom, hydroxy group, a C7-C13 aralkyloxy group, a C1-C6 alkyl group which is optionally substituted with a hydroxyl group, alternatively taken together with the adjacent nitrogen atom to form a monocyclic or bicyclic 4 to 10-membered saturated or unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen, a sulfur and an oxygen atom, which may be substituted with an amino group, a spiro heterocyclic group, or a bridged heterocyclic group), or —S(═O)₂Rf (wherein Rf is an amino group, a C1-C6 alkyl group, or a 4 to 10-membered saturated heterocyclic group).

In the compounds represented by the formula (I), R³ is more preferably a C6-C10 aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ is optionally substituted with R³¹, and when it has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group consisting of the group selected from a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl groups; a C1-C14 acyl group; a C1-C14 acylamino group; a C1-C14 acyloxy group);

R³¹ is a halogen atom, a cyano group, a nitro group, a carboxyl group, thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), C6-C10 aromatic hydrocarbon group (which may be substituted with a halogen atom), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a C1-C6 alkyl group or an oxo group), —CONH₂ group, (mono- or di-C1-C6 alkyl) aminocarbonyl group, a hydroxyamino group, (C7-C13 aralkyl) oxy aminocarbonyl group, a cyclic amino carbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl group.

In the compounds represented by the formula (I), R³ is more preferably a C6-C10 aromatic hydrocarbon group (wherein the C6-C10 aromatic hydrocarbon group is optionally substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 4 to 6-membered saturated or partially unsaturated hetero ring having 1 to 3 hetero atoms (which is optionally substituted with a group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 5 to 6-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group (mono- or di-C1-C6 alkyl) aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group, and an 8-oxa-3-azabicyclo[3.2.1]octanyl group);

R³¹ is a halogen atom, an amino group, a C1-C6 alkyl group (which is optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group), a C1-C6 alkoxy group (which is optionally substituted with a halogen atom), a 5 or 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a —CONH₂ group, a (mono or di-C1-C6 alkyl) aminocarbonyl group, or a hydroxyamino group.

Also, in the compounds represented by formula (I), R³ is particularly preferably a phenyl group (wherein the phenyl group may be substituted with R³¹, and when a phenyl group has two substituents on the carbon atoms which are adjacent each other on a benzene ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 6-membered saturated or partially unsaturated hetero ring having one or two oxygen atoms (which is optionally substituted with a group selected from the group consisting of a hydroxy group and a C1-C6 alkyl group)), or a pyridyl group (optionally substituted with a —CONH₂ group, a (mono or di C1-C6 alkyl) aminocarbonyl group, or a pyrrolidin-1-yl carbonyl group);

R³¹ is a halogen atom, an amino group, a C1-C6 alkoxy group, or a —CONH₂ group.

In the compounds represented by the formula (I), R⁴ is a hydrogen atom, or a C1-C6 alkyl group.

“C1-C6 alkyl group” indicated in R⁴ is preferably a C1-C3 alkyl group, more preferably a methyl group.

R⁴ is preferably a hydrogen atom, or a methyl group, more preferably a hydrogen atom.

In the sulfonamide compounds of formula (I), preferred compounds include the following.

In formula (I),

X¹ represents an oxygen atom or a sulfur atom;

X² represents an oxygen atom;

X³ represents —NH—;

X⁴ represents a hydrogen atom or a methyl group;

R¹ represents —C(R¹¹)(R¹²) (wherein R¹¹ and R¹² are the same or different, and a hydrogen atom or C1-C6 alkyl group);

R² represents a C6-C14 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbons (which is optionally substituted with a C1-C6 alkyl group);

R²¹ is a halogen atom, a cyano group, C1-C6 alkyl group (which is optionally substituted with a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (which is optionally substituted with a group selected from the group consisting of a halogen atom and a C1-C6 alkoxy group), or a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a morpholino group, a piperidinyl group and a morpholinocarbonyl group);

R³ is a C6-C10 aromatic hydrocarbon group, or a monocyclic or bicyclic 5 to 10-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, wherein R³ is optionally substituted with R³¹, and when R³ has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 8 carbon atoms (which is optionally substituted with a group consisting of the group selected from a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and a C1-C14 acyloxy group), or a monocyclic 4 to 8-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group optionally substituted with a hydroxy group; a halogeno C1-C6 alkyl group; a C1-C14 acyl group; a C1-C14 acylamino group; and C1-C14 acyloxy group);

R³¹ is a halogen atom, a cyano group, a nitro group, a carboxyl group, a thioamide group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, a C1-C14 acyloxy group, a C2-C6 alkynyl group and a C1-C6 alkoxy C1-C6 alkoxy group), an amino group, a C3-C6 cycloalkyl group (optionally substituted with an amino group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a C2-C7 alkoxycarbonyl group, a C1-C14 acyl group (optionally substituted with a halogen atom), a C6-C10 aromatic hydrocarbon ring (optionally substituted with a halogen atom), a monocyclic or bicyclic 5 to 10-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom (optionally substituted with a group selected from the group consisting of a C1-C6 alkyl group and an oxo group), —CONH₂ group, a (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group, a (C7-C13 aralkyloxy)oxyaminocarbonyl group, a cyclic aminocarbonyl group, an aminosulfonyl group, a C1-C6 alkylsulfonyl group, or a piperidinosulfonyl group; and

R⁴ represents a hydrogen atom;

(with the proviso that X¹ is an oxygen atom when X² represents an oxygen atom, X³ represents —NH—, X⁴ represents a hydrogen atom, R¹ represents —CH₂—, R₂ represents a phenyl group, R³ represents 4-methylphenyl group, and R⁴ represents a hydrogen atom)

or a salt thereof.

Furthermore, in the sulfonamide compounds of formula (I) of the present invention, more preferable compounds include the following.

In formula (I),

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents —NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²) (wherein R¹¹ represents a C1-C6 alkyl group, and R¹² represents a hydrogen atom);

R² represents a C6-C10 aromatic hydrocarbon group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbons (which is optionally substituted with a C1-C6 alkyl group);

R²¹ is a halogen atom, a C1-C6 alkyl group or a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 3 nitrogen atom(s) (which is optionally substituted with a C1-C6 alkyl group);

R³ is a C6-C10 aromatic hydrocarbon group (wherein the C6-C10 aromatic hydrocarbon group is optionally substituted with R³¹, and when a C6-C10 aromatic hydrocarbon group has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 4 to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (optionally substituted with a group selected from the group consisting of a hydroxy group, an amino group, an oxo group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C14 acyl group, a C1-C14 acylamino group, and C1-C14 acyloxy group) or a monocyclic 5 to 6-membered fully unsaturated heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (which is optionally substituted with a group selected from the group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group, a C2-C7 alkoxycarbonyl group, a —CONH₂ group, (mono- or di-C1-C6 alkyl) aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group, a morpholin-4-ylcarbonyl group, a 2-oxa-7-azaspiro[3.5]nonanyl group, a 3-oxa-8-azabicyclo[3.2.1]octanyl group, and an 8-oxa-3-azabicyclo[3.2.1]octanyl group);

R³¹ is a halogen atom, an amino group, a C1-C6 alkyl group (optionally substituted with a group selected from the group consisting of a halogen atom and a hydroxy group), a C1-C6 alkoxy group (optionally substituted with a halogen atom), a monocyclic 5 to 6-membered unsaturated heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, a —CONH₂ group, (mono- or di-C1-C6 alkyl)aminocarbonyl group, a hydroxyaminocarbonyl group; and

R⁴ represents a hydrogen atom;

or a salt thereof.

In the sulfonamide compounds of formula (I), more preferable compounds include the following.

In formula (I),

X¹ represents an oxygen atom;

X² represents an oxygen atom;

X³ represents —NH—;

X⁴ represents a hydrogen atom;

R¹ represents —C(R¹¹)(R¹²) (wherein R¹¹ represents a methyl group, and R¹² represents a hydrogen atom);

R² represents a phenyl group or a naphthyl group, wherein R² may be substituted with R²¹, and when R² has two substituents on the carbon atoms which are adjacent each other on the aromatic hydrocarbon ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic saturated or partially unsaturated hydrocarbon ring having 5 or 6 carbons (which is optionally substituted with a C1-C6 alkyl group);

R²¹ is a halogen atom or a C1-C6 alkyl group;

R³ is a phenyl group (wherein the phenyl group is optionally substituted with R³¹, and when a phenyl group has two substituents on the carbon atoms which are adjacent each other on a benzene ring, the substituents may be fused together with carbon atoms to which the substituents are attached to form a monocyclic 6-membered saturated or partially unsaturated heterocyclic ring having 1 or 2 oxygen atom(s) (optionally substituted with a group selected from the group consisting of a hydroxyl group and a C1-C6 alkyl group), or a pyridyl group (optionally substituted with a —CONH₂ group, a (mono- or di-C1-C6 alkyl) aminocarbonyl group, a pyrrolidin-1-ylcarbonyl group)

R³¹ is a halogen atom, an amino group, a C1-C6 alkoxy group, a —CONH₂ group; and

R⁴ represents a hydrogen atom;

or a salt thereof.

Particularly preferable sulfonamide compounds include the following.

• (1) 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (2) 5-chloro-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (3) 5-bromo-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (4) 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (5) 5-chloro-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (6) 5-chloro-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (7) 5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (8) 5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;
• (9) 2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chloro-benzamide;
• (10) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(pyrrolidine-1-carbonyl)pyridine-2-sulfonamide;
• (11) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide;
• (12) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-chroman-8-sulfonamide;
• (13)N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methyl-chroman-8-sulfonamide;
• (14) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide;
• (15) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide;
• (16) 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N,N-dimethylpicolinamide;
• (17) 4-amino-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide;
• (18) 4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide; and
• (19) 5-chloro-2-[[(1S,2R)-3,3,3-trideuterio-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl]sulfamoyl]benzamide.

A method of preparing the sulfonamide compound according to the present invention is described by giving examples. The compounds of the formula (I) of the present invention, for example, can be prepared by the following production method. However, the present invention is not limited to this method.

[wherein, L¹ represents a leaving group. The symbols have the same meanings as defined above.]

[A-1]

In this process, a compound represented by general formula (4) can be prepared by reacting a compound represented by general formula (1) with an organometallic reagent (3) such as Grignard reagent represented by R¹¹MgHal.

Hal represents a halogen atom.

The amount of Grignard reagent (3) 0.8 to 20 equivalents relative to compound (1), preferably 1.0 to 10 equivalents. The reaction temperature is −80° C. to 100° C., preferably −78° C. to 50° C. The reaction time is 0.1 to 24 hours, preferably 0.1 to 3 hours.

In this step, a compound represented by general formula (4), wherein R¹¹ is H, can be prepared by reacting the compound represented by formula (1) with a well-known reducing agent instead of Grignard reagent (3).

The reducing agents to be used include, for example, sodium borohydride, lithium borohydride, lithium aluminum hydride, diethoxy aluminum lithium hydride, triethoxy lithium aluminum hydride, tri-t-butoxy aluminum lithium hydride, aluminum magnesium hydride, aluminum hydride magnesium chloride, sodium aluminum hydride, sodium triethoxyaluminum hydride, bis(2-methoxyethoxy) aluminum sodium hydride, diisobutylaluminum hydride (hereinafter DIBAL-H) and the like, and preferably sodium borohydride.

The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like), alcohols (methanol, ethanol, and the like), and water, and preferably methanol.

The amount of reducing agent used is 0.8 to 10 equivalents relative to the compound (1), preferably 1 to 5 equivalents.

The reaction temperature is from 0° C. to the boiling point temperature of the solvent, preferably 0 to 40° C. The reaction time is from 0.05 to 24 hours, preferably 0.2 to 2 hours. Thus, the compound represented by general formula (4) obtained in the above manner can be subjected to the next step with or without isolation and purification by a well-known separation and purification means described below

[A-2]

In this step, a compound represented by general formula (4) can be prepared by reacting a compound represented by general formula (2) with well-known reducing agents,

The reducing agents to be used include sodium borohydride.

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, and, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), alcohols (methanol, ethanol, 2-propanol, tert-butanol, ethylene glycol, etc.), water and the like, preferably methanol or ethanol.

The amount of reducing agent is 0.8 to 10 equivalents relative to the compound (2), preferably 1 to 5 equivalents.

The reaction temperature is between 0° C. and the boiling point temperature of the solvent, preferably 0 to 40° C. The reaction time is from 0.05 to 24 hours, preferably 0.2 to 2 hours. Thus, the obtained compound represented by general formula (4) can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

[A-3]

In this process, a compound represented by general formula (5) can be prepared by reacting a compound represented by general formula (4) with a halogenating agent or sulfonyl halide hydrocarbons.

Leaving groups represented by L¹ are, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group, an organic sulfonyloxy group such as a p-tolylsulfonyloxy group.

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.), aromatic hydrocarbons (benzene, toluene, xylene, pyridine, etc.), and preferably ethers.

The halogenating agents to be used are, for example, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl bromide, phosphorus tribromide and the like. Preferably, it is thionyl chloride or phosphorus tribromide. The sulfonyl halide hydrocarbons are, for example, methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride or phenylsulfonyl chloride and the like.

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, and, for example, ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), and preferably dichloromethane.

The amount of the halogenating agent or sulfonyl halide hydrocarbons is 0.3 equivalents to 20 equivalents relative to the compound (4), preferably 0.3 to 4 equivalents.

The reaction temperature is −20° C. to 100° C., preferably from 0° C. to 100° C. The reaction time is generally 0.01 to 200 hours, preferably 0.5 hour to 24 hours. Thus, the obtained compound represented by general formula (5) can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

[Symbols in the formula are as defined above.]

[B-1]

In this process, a nickel complex represented by general formula (7) is prepared by reacting a compound represented by general formula (1) or (5) with a readily available compound represented by formula (6).

The reaction solvents to be used are not particularly limited as long as they do not affect the reaction, and for example, organic solvents or mixtures thereof such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (N,N-dimethylformamide (hereinafter, also referred to as DMF), N,N-dimethylacetamide, N-methylpyrrolidinone, and preferably DMF.

The bases to be used are, for example: organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, or collidine; alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; a strong base lithium amide such as lithium diisopropylamide; a strong base hexamethyldisilazane such as lithium hexamethyl disilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane; and preferably sodium hydroxide, potassium hydroxide, potassium tert-butoxide and the like.

The amount of the base to be used is usually 0.1 to 100 equivalents relative to compound (6), preferably 1 to 20 equivalents.

The amount of compound (1) or (5) is 0.5 to 10 equivalents relative to compound (6), preferably 1 to 5 equivalents.

The reaction temperature is −80 to 50° C., preferably −60 to 40° C. The reaction time is 0.2 to 24 hours, preferably 0.5 to 6 hours. The pressure used in the above preparing method may not be particularly limited, and examples thereof include, about 0.1 to 10 atm. A nickel complex represented by general formula (7) which is obtained in this method can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

[B-2]

In this step, an amino acid represented by general formula (8) can be prepared by reacting the nickel complex or a salt thereof with an acid represented by general formula (7).

The acids to be used are not particularly limited but include publicly known acids. The acids may be an inorganic acid or an organic acid. The inorganic acids include such as hydrochloric acid, nitric acid, sulfuric acid, and perchloric acid. The organic acids include such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, propionic acid, butyric acid, valeric acid, and the like. Preferably, the acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, or methanesulfonic acid, more preferably, it is hydrochloric acid, or methanesulfonic acid.

The amount of the acid is not particularly limited, and usually 0.1 to 50 equivalents relative to the nickel complex represented by general formula (7), and preferably 0.3 to 10 equivalents.

The solvent to be used is preferably alcohol, more preferable to methanol or ethanol.

The reaction temperature is usually 0° C. to 100° C., and preferably 40 to 80° C. The reaction time is usually 0.1 to 72 hours, and preferably 0.1 to 10 hours. The pressure used in the above preparing method is not particularly limited, and examples thereof include, 0.1 to 10 atm. The amino acid represented by general formula (8) obtained in the present method can be subjected to the next process with or without a separation and purification means by well-known separation and purification means described below or transformation between protection and deprotection.

[Symbols in the formula are as defined above.]

[C-1]

In this step, a compound represented by general formula (10) can be prepared by reacting a compound represented by general formula (9) with a well-known reducing agent.

The reducing agent is tri(ethoxy) aluminum lithium hydride, tri(sec-butyl)boron lithium hydride, or DIBAL-H, and the like, and preferably DIBAL-H. The amount of the reducing agent to be used is usually 1 to 10 equivalents relative to the compound represented by general formula (9), preferably 2.0 to 10 equivalents.

The solvent to be used is ether type solvents (tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.), halogen solvents (dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents (toluene, xylene, etc.) or a mixed solvent thereof and the like, and preferably dichloromethane.

The reaction temperature is −100° C. to 50° C., preferably −100 to 10° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 5 hours.

The pressure used in the above preparing method may not be particularly limited, and examples thereof include, from about 0.1 to 10 atm.

The compound represented by general formula (10) which is the obtained in this method can be subjected to the next step with or without isolation and purification by well-known separation and purification means described below.

The compound represented by general formula (9) can be prepared by the methods described in the reference (international publication No. WO2011/071,565), or, if necessary, combining the methods described in the reference examples and examples.

[C-2]

In this step, a compound represented by general formula (11) is prepared by reacting with a compound represented by general formula (10) with a cyanide agent and ammonia.

The cyanide agent to be used is, for example, hydrogen cyanide, metal cyanides, cyanohydrin compounds, acyl cyanides, halogenated cyanides and the like. The metal cyanides are, for example, alkali metal cyanides such as sodium cyanides, potassium cyanides; alkaline earth metal cyanides such as calcium cyanide; transition metal cyanides such as copper cyanide. Preferably, it is potassium cyanide.

The ammonia used in the present step can be ammonia gas, liquid ammonia or an aqueous ammonia solution, and an aqueous ammonia solution is desirable in terms of that it does not require complicated reaction apparatus.

The solvent to be used is not particularly limited as long as it does not affect the reaction, and it includes ethers (tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxides, acetonitrile, etc.), halogen solvents (dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents such as toluene, alcohol solvents (methanol, ethanol, etc.), water, and a mixed solvent thereof, and preferably water and a mixed solvent of methanol.

The amount of cyanide agent to be used is generally 1 to 10 equivalents relative to compound (10), preferably 2.0 to 5.0 equivalents. The amount of ammonia used in the reaction is preferably 1.5 to 10 equivalents relative to the compound (10), and more preferably 1.8 to 2.5 equivalents. Ammonium chloride is added as needed. Its amount is usually 0.2 to 2.0 equivalents relative to the compound of (10), preferably 0.1 to 0.5 equivalent.

The reaction temperature is −100° C. to 100° C., preferably 0 to 60° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 5 hours. The pressure used in the above preparing method may not be particularly limited, and examples thereof include, from about 0.1 to 10 atm. The compound represented by general formula (11) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[C-3]

In this process, the compound represented by general formula (12) is prepared in the same manner as [B-2] described above using the compound represented by general formula (11). The compound represented by general formula (12) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below. Hereinafter, post process for the compounds represented by general formulae (8) and (12) are described as an example.

Furthermore, in the present process, R and R′ can be converted to the structures corresponding to protection/deprotection groups or the present invention.

[In the formula, L² represents a leaving group. The symbols have the same meanings as defined above.]

[D-1]

In this step, a carboxylic acid represented by general formula (14) can be prepared by reacting an amino acid represented by general formula (12) with a sulfonic acid halide represented by general formula (13) in the presence of a base.

The base to be used is alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, or organic amines such as trimethylamine or potassium hydroxide, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, and collidine are exemplified, and preferably triethylamine.

The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and it is organic solvents or water, etc. such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. These solvents may be used in a mixture at an appropriate ratio.

The number of equivalents of base and an amine is from 0.5 to 10 equivalents, respectively, preferably 1.0 to 5.0 equivalents.

The amount of the sulfonic acid halide is appropriately set by the compounds represented by general formula (12), but is not limited to, and usually, is 1.0 to 5.0 equivalents relative to the compound represented by general formula (12), more preferably 1.0 to 2.5 equivalents.

The reaction temperature is appropriately by the compounds represented by general formula (12), but is not limited to, and, for example, a −20 to 70° C., preferably 0 to 40° C. The reaction time is generally 0.1 to 24 hours, preferably 0.2 to 6.0 hours. The compound represented by general formula (14) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The compound represented by general formula (13) can be prepared by the methods described in the reference (Tetrahedoron Lett. 51, 418-421 (2010)), or, if necessary, combining the methods described in the reference examples and examples.

[D-2]

In this step, a compound represented by general formula (15) can be prepared by reacting a carboxylic acid represented by general formula (14) with a condensing agent and hydrazine. Alternatively, it can be prepared by reacting hydrazine derivative having an appropriate protecting group with the carboxylic acid represented by general formula (14) in the same manner, and then carrying out the reaction for eliminating the protecting group.

The condensing agent is, for example 1,1′-carbonyldiimidazole (hereinafter, CDI), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, preferably CDI.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), and amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, and they can be used alone or in combination.

The amount of the condensing agent with respect to the compound represented by Formula (14) is generally 1 to 50 equivalents, preferably about 1 to 5. The amount of hydrazine relative to the compound represented by general formula (14) is generally 1 to 100 equivalents, preferably 1-5 equivalents. The base is organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The reaction temperature is −20 to 80° C., preferably 0 to 40° C. The reaction time is usually from 0.05 to 24 hours, more preferably 0.05 to 6 hours. The compound represented by general formula (15) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[D-3]

In this step, a compound represented by general formula (16) of the present invention can be prepared by cyclization of the compound represented by general formula (15) with the acylating agent.

The acylating agent is, for example isobutyl chloroformate, CDI, phosgene, triphosgene and the like, preferably CDI. The base is, organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and like diazabicycloundecene and the like.

The amount of the acylating agent with respect to the compound represented by Formula (15) is typically preferably 1 to 50 equivalents, and more preferably 1 to 5 equivalents.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, etc.) and the like, and they may be used singly or as a mixture.

The reaction temperature is −20 to 80° C., preferably 0 to 50° C. The reaction time is generally 0.5 to 24 hours, preferably 0.5 to 8 hours. The compound represented by general formula (16) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The compound represented by general formula (16) of the present invention can be synthesized by 1) protecting the amino group of the amino acid of the compound represented by above general formula (12) with a well-known suitable protecting group, 2) converting the carboxylic acid moiety to the oxadiazolone ring in the same method as [D-2], 3) deprotecting the protective group in a well-known method, 4) sulfonamidation in the same manner as [D-1].

[In the formula, the symbols have the same meanings as defined above.]

[E-1]

In this step, a compound represented by general formula (17) of the present invention can be prepared by reacting the compound represented by general formula (15) with carbon disulfide.

The base used in this reaction is, for example, alkali metal salts such as sodium hydroxide, potassium hydroxide, organic amines such as triethylamine, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal amides such as lithium diisopropylamide, and preferably potassium hydroxide.

The amount of the base to be used is, with respect to the compound represented by Formula (15), generally 1 to 20 equivalents, preferably 1 to 5 equivalents. The amount of carbon disulfide is, with respect to the compound represented by Formula (15), generally 1 to 20 equivalents, preferably 1 to 5 equivalents.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents, water such as alcohols (methanol, ethanol, propanol), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, and the like, and they can be used singly or as a mixture.

The reaction temperature is 0 to 150° C., preferably between 20 to 100° C. The reaction time is generally from 0.5 to 24 hours, preferably 1.0 to 12 hours. The compound represented by general formula (17) of the present invention can be isolated and purified by well-known separation and purification means.

[In the formula, the symbols have the same meanings as defined above.]

[F-1]

In this step, a compound of general formula (18) can be prepared by condensation and simultaneously cyclization of the compound represented by general formula (14) and thiosemicarbazide.

The condensing agent is, for example CDI, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. They may be used singly or as a mixture.

The amount of the condensing agent is, with respect to the compound represented by general formula (14), 1.0 to 50 equivalents, preferably 1 to 5 equivalents. The amount of thiosemicarbazide is, with respect to the compound represented by general formula (14), generally 1 to 100 equivalents, preferably 1.0 to 5.0 equivalents. The base is organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The reaction temperature is −20 to 180° C., preferably 0 to 100° C. The reaction time is usually 0.05 to 24 hours, preferably 0.05 to 6 hours. The compound represented by formula (18) of the present invention can be isolated and purified by well-known separation and purification means as described below.

[In the formula, the symbols have the same meanings as defined above.]

[G-1]

In this step, a compound represented by general formula (19) can be prepared by reacting the carboxylic acid represented by general formula (14) with a condensation agent and ammonia.

The condensing agent is, for example, 1,1′-carbonyldiimidazole (hereinafter, CDI), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, preferably CDI.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. They may be used singly or as a mixture.

The amount of the condensing agent with respect to the compound represented by general formula (14) is generally 1 to 50 equivalents, preferably 1 to 5 equivalents. Ammonia is used as an aqueous solution or hydrochloric acid salt, and its amount relative to the compound represented by general formula (14) is generally 1 to 100 equivalents, preferably 1.0 to 5.0 equivalents. The bases include, for example, organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The reaction temperature is −20 to 80° C., preferably 0 to 40° C. The reaction time is usually from 0.05 to 24 hours, preferably 0.05 to 6 hours. The compound represented by general formula (19) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[G-2]

In this step, a nitrile represented by general formula (20) can be prepared from the amide compound represented by general formula (19).

Dehydrating agents include, for example, oxalyl chloride, thionyl chloride, cyanuric chloride and the like, preferably cyanuric chloride.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like. They may be used singly or as a mixture.

The amount of dehydrating agent with respect to the compound represented by general formula (19) is usually 1 to 50 equivalents.

The reaction temperature is −20 to 80° C., preferably between 0 to 40° C. The reaction time is usually from 0.05 to 24 hours, preferably from 0.05 to 3 hours. The compound represented by general formula (20) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

[G-3]

In this step, an amidoxime compound is obtained from the nitrile compound represented by general formula (20) by adding hydroxylamine, and then it reacts with an acylating agent followed by cyclization reaction with application of heat to produce a compound represented by general formula (21).

The amount of the hydroxylamine to be used for preparing amidoxime is generally 1 to 50 equivalents in reaction to the compound represented by general formula (20).

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvent such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone and the like). They may be used singly or as a mixture.

The reaction temperature is −20 to 100° C., preferably 0 to 60° C. The reaction time is generally from 0.05 to 3 days, preferably 0.05 to 12 hours. The obtained amidoxime compound represented by general formula (20) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The acylating agent used for amide oxime is, for example, chloroformate, 2-ethylhexyl, CDI, phosgene, triphosgene and the like, preferably chloroformate 2-ethylhexyl. The base to be used includes organic bases such triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, diazabicycloundecene and the like.

The amount of the acylating agent is usually 1 to 50 equivalents relative to the amide oxime compound, and more preferably about 1 to 3 equivalents.

The solvent to be used is not particularly limited as long as it does not affect the reaction, for example, organic solvents such as ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile etc.), amides (DMF, N,N-dimethylacetamide, N-methylpyrrolidinone, etc.) and the like), and they can be used singly or as a mixture, and they can be switched to other solvents during the reaction.

The reaction temperature with the acylating agent is to −20, 80° C., preferably 0 to 40° C. The reaction time is generally 0.5 to 24 hours, preferably 0.5 to 3 hours. The reaction temperature used for cyclization reaction of the obtained acylated compound is 0 to 150° C., preferably 0 to 120° C. The reaction time is generally from 0.5 to 24 hours, preferably 0.5 to 12 hours. The obtained compound represented by general formula (21) can be subjected to the next step with or without isolation and purification by well-known separation and purification means as described below.

The compound represented by formula (I) of the present invention and intermediates thereof can be isolated and purified by well-known separation and purification means such as recrystallization, crystallization, distillation, or column chromatography. The sulfonamide compound of formula (I) and synthetic intermediates are usually possible to form a pharmacologically acceptable salt thereof in a well-known manner, and also can be converted to each other.

When optical isomers, stereoisomers, tautomers, or rotary isomers are present in the sulfonamide compound represented by formula (I), the sulfonamide compound represented by formula (I) encompasses these isomers or the mixture thereof. For example, when an optical isomer in the sulfonamide compound represented by formula (I) is present, unless otherwise stated, racemate and an optical isomer resolved from a racemate are also encompassed in the sulfonamide compound represented by formula (I). These isomers can be obtained by a well-known synthetic method, separation means (concentration, solvent extraction, column chromatography, recrystallization and the like) with a single compound, respectively. In the sulfonamide compound represented by formula (I), for example, when X¹=oxygen atom, X²=oxygen atom, X³═NH, there are tautomers as shown below, any of the isomers are also included in the present invention.

The sulfonamide compound represented by formula (I) or a salt thereof may be amorphous (amorphous) or a crystalline form, and the crystalline form may be a single crystalline form or polymorphic mixture, which are encompassed in the sulfonamide compound represented by formula (I) or a salt thereof. The crystals can be prepared by applying a well-known crystallization method.

Furthermore, the sulfonamide compound represented by formula (I) or a salt thereof can be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the sulfonamide compound represented by formula (I) or a salt thereof. The compounds labeled with isotopes (e.g., deuterium, ³H, ¹⁴C ³⁵S ¹²⁵I, etc.) and the like are also encompassed in the sulfonamide compound represented by formula (I) or a salt thereof.

Although the prodrugs of the sulfonamide compound represented by formula (I) or a salt thereof are also included in the present invention, the prodrugs refer to the compounds which convert into the sulfonamide compound represented by formula (I) or a salt thereof by a reaction with an enzyme or gastric acid under the physiological condition in the living body, i.e., the compounds which convert into the sulfonamide compound represented by formula (I) or a salt thereof by enzymatic oxidation, reduced, or hydrolysis and the like or the compounds which convert into the sulfonamide compound represented by formula (I) or a salt thereof by gastric acid. Furthermore, a prodrug of the sulfonamide compound represented by formula (I) or a salt thereof may be the compounds which convert into the sulfonamide compound represented by formula (I) or a salt thereof under physiological conditions as described in Hirokawa Shoten 1990 annual “Development of Pharmaceuticals” Volume 7 Molecular Design pages 163-198.

A salt of the sulfonamide compound represented by formula (I) means a salt that is pharmaceutically acceptable.

The sulfonamide compound represented by formula (I) or a salt thereof has an inhibitory activity against RNR. The sulfonamide compound represented by formula (I) or a salt thereof is useful as a medicament for prevention or treatment of RNR-related diseases without causing side effects based on the off-target effects of the iron ions requiring protein due to its excellent RNR inhibitory activity and its structure that does not chelate to metal ions.

Use of the sulfonamide compound represented by formula (I) or a salt thereof and other antitumor agent(s) in combination enhances the antitumor effect. A combination formulation of the sulfonamide compound represented by formula (I) or a salt thereof and other antitumor agent(s) may be one formulation form (i.e., a blending agent) or may be combined administrations in two or more separate formulation forms.

In the present invention, the antitumor effect can be evaluated on the basis of, for example, decrease in tumor volume, stagnant tumor growth, or prolongation of survival periods.

In one embodiment, an antitumor agent comprising the sulfonamide compound represented by formula (I) or a salt thereof and other antitumor agent(s) is provided. Furthermore, in another embodiment, an agent for enhancing an antitumor effect of other antitumor agent(s), comprising the sulfonamide compound represented by formula (I) or a salt thereof as an active ingredient is provided.

The other antitumor agent(s) is not particularly limited but includes antimetabolites, platinum drugs, plant alkaloid drugs, and molecular targeting drugs.

The antimetabolites include 5-fluorouracil (5-FU), 5-fluoro-2′-deoxyuridine (FdUrd), tegafur, tegafur-uracil (e.g., UFT), tegafur-gimeracil-oteracil (e.g., TS-1), pemetrexed, trifluridine, trifluridine-tipiracil hydrochloride (e.g., Lonsurf), fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, capecitabine, nelarabine, clofarabine, and DNA methylation inhibitors (decitabine, guadecitabine, azacitidine, etc.). 5-Fluorouracil (5-FU), trifluridine, fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, or a DNA methylation inhibitors (decitabine, guadecitabine, azacitidine, etc.) is preferred, and 5-fluorouracil (5-FU), trifluridine, fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, decitabine, guadecitabine, or azacitidine is preferred.

The platinum drugs include cisplatin, oxaliplatin, carboplatin, and nedaplatin and are preferably cisplatin, oxaliplatin, or carboplatin.

The plant alkaloid drugs include microtube inhibiting drugs such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase inhibiting drugs such as irinotecan (or an active metabolite SN-38), nogitecan, and etoposide. A topoisomerase inhibiting drug such as irinotecan (or an active metabolite SN-38), nogitecan, and etoposide is preferred, a topoisomerase II inhibiting drug such as etoposide is more preferred, and etoposide is even more preferred.

The molecular targeting drugs include ATR (ataxia telangiectasia and Rad3 related protein) inhibitors, Chk1 (checkpoint kinase 1) inhibitors, HSP (heat shock protein) 90 inhibitors, PARP (poly ADP ribose polymerase) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, Her2 inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MET inhibitors, AXL inhibitors, RET inhibitors, FLT3 (fms-related tyrosine kinase 3) inhibitors, KIT inhibitors, CSF1R (colony-stimulating factor 1 receptor) inhibitors, TIE2 (tunica interna endothelial cell kinase 2) inhibitors, and TRKB inhibitors.

The ATR inhibitors include AZD6738, berzosertib, BAY1895344, and VX-803. AZD6738 is preferred.

The Chk1 inhibitors include prexasertib, SCH900776, GDC-0575, and CCT245737. Prexasertib or SCH900776 is preferred.

The HSP90 inhibitors include luminespib, ganetespib, onalespib, and 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide. Luminespib is preferred.

The PARP inhibitors include olaparib, rucaparib, niraparib, veliparib, and talazoparib. Olaparib or talazoparib is preferred.

The EGFR inhibitors include small molecule inhibitors such as lapatinib, gefitinib, erlotinib, afatinib, and vandetanib, and anti-EGFR antibodies such as cetuximab and panitumumab. A small molecule inhibitor such as lapatinib and vandetanib is preferred, and lapatinib is more preferred. Furthermore, multikinase inhibitors are also accepted.

The Her2 inhibitors include small molecule inhibitors such as lapatinib, and anti-Her2 antibodies such as trastuzumab, pertuzumab, and trastuzumab emtansine. A small molecule inhibitor such as lapatinib is preferred, and lapatinib is more preferred. Furthermore, multikinase inhibitors are also accepted.

The VEGFR inhibitors are inhibitors of at least one of VEGFR1, VEGFR2, and VEGFR3 and include small molecule inhibitors such as sunitinib, cabozantinib, midostaurin, sorafenib, vandetanib, pazopanib, lenvatinib, and axitinib, and anti-VEGFR antibodies such as ramucirumab. Sunitinib, cabozantinib, or midostaurin is preferred. Furthermore, multikinase inhibitors are also accepted.

The PDGFR inhibitors are PDGFRα and/or PDGFRβ inhibitors and include sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib. Sunitinib or midostaurin is preferred. Furthermore, multikinase inhibitors are also accepted.

The MET inhibitors include cabozantinib, crizotinib, and tepotinib. Cabozantinib is preferred. Furthermore, multikinase inhibitors are also accepted.

The AXL inhibitors include cabozantinib and gilteritinib. Cabozantinib is preferred. Furthermore, multikinase inhibitors are also accepted.

The RET inhibitors include sunitinib, cabozantinib, sorafenib, lenvatinib, and vandetanib. Sunitinib or cabozantinib is preferred. Furthermore, multikinase inhibitors are also accepted.

The FLT3 inhibitors include sunitinib, cabozantinib, midostaurin, gilteritinib, and sorafenib. Sunitinib, cabozantinib, or midostaurin is preferred. Furthermore, multikinase inhibitors are also accepted.

The KIT inhibitors include sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib. Sunitinib or midostaurin is preferred. Furthermore, multikinase inhibitors are also accepted.

The CSF1R inhibitors include sunitinib, BLZ-945, and ARRY-382. Sunitinib is preferred. Furthermore, multikinase inhibitors are also accepted.

The TIE2 inhibitors include cabozantinib. Cabozantinib is preferred. Furthermore, multikinase inhibitors are also accepted.

The TRKB inhibitors include cabozantinib and entrectinib. Cabozantinib is preferred. Furthermore, multikinase inhibitors are also accepted.

“Multikinase inhibitor” herein is a compound having inhibitory activity against two or more kinases, for example, lapatinib having EGFR inhibitory activity and HER2 inhibitory activity.

The other antitumor agent(s) is preferably an antimetabolite, a platinum drug, a plant alkaloid drug, or a molecular targeting drug, more preferably an antimetabolite, a platinum drug, a topoisomerase II inhibiting drug, or a molecular targeting drug, even more preferably an antimetabolite, a platinum drug, a topoisomerase II inhibiting drug, an ATR inhibitor, a Chk1 inhibitor, a HSP90 inhibitor, a PARP inhibitor, an EGFR inhibitor, a Her2 inhibitor, a VEGFR inhibitor, a PDGFR inhibitor, a MET inhibitor, an AXL inhibitor, a RET inhibitor, a FLT3 inhibitor, or a KIT inhibitors, even more preferably an antimetabolite, a platinum drug, etoposide, an ATR inhibitor, a Chk1 inhibitor, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, or midostaurin, even more preferably an antimetabolite, a platinum drug, etoposide, AZD6738, prexasertib, SCH900776, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, or midostaurin, even more preferably an antimetabolite, cisplatin, oxaliplatin, carboplatin, etoposide, AZD6738, prexasertib, SCH900776, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, or midostaurin, even more preferably 5-fluorouracil (5-FU), trifluridine, fludarabine, cytarabine, gemcitabine, a DNA methylation inhibitor, cisplatin, oxaliplatin, carboplatin, etoposide, AZD6738, prexasertib, SCH900776, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, or midostaurin, even more preferably 5-fluorouracil (5-FU), trifluridine, fludarabine, cytarabine, gemcitabine, decitabine, guadecitabine, azacitidine, cisplatin, oxaliplatin, carboplatin, etoposide, AZD6738, prexasertib, SCH900776, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, or midostaurin.

Tumors of interest in the present invention are not particularly limited as long as an effect of enhancing an antitumor effect is exerted. A tumor on which the sulfonamide compound represented by formula (I) or a salt thereof exerts an antitumor effect is preferred, and an RNR-related malignant tumor is more preferred.

The “RNR-related malignant tumor” includes malignant tumors whose incidence can be decreased or whose symptom is in remission or alleviated and/or completely cured by deleting or suppressing and/or inhibiting functions of RNR. Malignant tumors of interest is not particularly limited, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder⋅bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumor and the like. Gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder⋅bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), or hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), are preferred, large intestine cancer, pancreatic cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), or hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.) are more preferred, and large intestine cancer, pancreatic cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), or leukemia is even more preferred.

“RNR” herein includes a human or non-human RNR, preferably a human RNR.

When using the sulfonamide compound represented by formula (I) or a salt thereof as a medicine, it is optionally formulated with a pharmaceutically acceptable carrier, and various dosage forms can be adopted depending on the prevention or therapeutic purposes, and the dosage forms may be, for example, any of oral agents, injections, suppositories, ointments, and patches. Since the sulfonamide compound represented by formula (I) or a salt thereof has an excellent oral absorbability, oral agents are preferable. These dosage forms can be prepared by preparation methods commonly known by a person with ordinary skill in the art.

With respect to pharmaceutically acceptable carriers, conventional various organic or inorganic carrier substances are used as pharmaceutical materials, and it is formulated as: excipients, binders, disintegrating agents, lubricants, coloring agents for solid formulations; and solvents, solubilizing agents, suspending agents, isotonizing agents, buffers, soothing agent for liquid formulations and the like. Further, if necessary, pharmaceutical additives can also be used, which include such as preservative agents, antioxidants, coloring agents, sweetening agents, flavoring agents, stabilizing agents.

With respect to the pharmaceutically acceptable carriers and the pharmaceutical additives, in general, they include, for example, as the excipient, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like; as arebinders, water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, and the like; as disintegrants, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like; as lubricants, purified talc stearate, borax, polyethylene glycol and the like; as colorant, titanium oxide, iron oxide and the like; as flavoring agents, sucrose, orange peel, citric acid, tartaric acid and the like.

When preparing an oral solid formulation, it can be prepared by adding an excipient to the sulfonamide compound represented by formula (I) or the other antitumor agent(s), and if necessary, further adding binders, disintegrants, lubricants, colorants, or flavoring agents and the like, followed by formulating into tablets, coated tablets, granules, powders, capsules and the like.

When preparing injectable forms, it can be prepared by adding pH control agents, buffers, stabilizers, isotonic agents, local anesthetic agents and the like to the sulfonamide compound represented by formula (I) or the other antitumor agent(s), followed by formulating into subcutaneous, intramuscular and intravenous injections with a conventional manner.

A preparation of the other antitumor agent(s) also includes DDS (drug delivery system) formulations thereof. For example, “paclitaxel” includes albumin-bound paclitaxel (e.g., Abraxane) and paclitaxel micelle (e.g., NK105), and the like, and “cisplatin” includes cisplatin micelle (e.g., NC-6004) and the like.

The amount of the sulfonamide compound represented by formula (I) to be formulated in each dosage unit forms described above can be, in general, per dosage unit form, 0.05 to 1000 mg for the oral dosage, about 0.01 to 500 mg for injection, 1 to 1000 mg for suppositories with the proviso that they may be altered depending on the symptoms of the patients to be applied or its dosage forms.

Further, the daily dose of a drug with the dosage form is, with respect to the sulfonamide compound represented by formula (I), 0.05 to 5000 mg, preferably 0.1 to 2000 mg per day for adult (body weight 50 kg), and preferably the aforementioned amount is administered once or 2 to 3 times a day with the proviso that they may be altered depending on symptoms of the patients, weight, age, or gender and the like.

The schedule of administration of the sulfonamide compound represented by general formula (I) or a salt thereof and the other antitumor agent(s) is appropriately selected within a range in which each active ingredient exerts an antitumor effect, and the active ingredients are administered concurrently or separately in a staggered manner. For separate administration, either of the active ingredients may be administered first.

The sulfonamide compound represented by general formula (I) or a salt thereof and the other antitumor agent(s) may be formulated into two or more of dosage forms of each active ingredient or may be formulated collectively into one dosage form, on the basis of the dosage form or the schedule of administration of each active ingredient. Further, the preparations may be manufactured and distributed in one package suitable for combined use, or may be manufactured and sold in separate packages.

EXAMPLES

The present invention is described below in more detail with examples and test examples, but the present invention is not intended to be limited to these examples.

Various reagents used in the examples were commercially available products, unless otherwise stated. Biotage Ltd. SNAP-ULTRA (registered trademark) Silica prepacked column was used for a silica gel column chromatography, or Biotage made SNAP KP-C18-HS (registered trademark) Silica prepacked column was used for a reverse phase silica gel column chromatography. HPLC purified by preparative reverse phase column chromatography was performed under the following conditions. Injection volume and gradient was carried out appropriately.

Column: YMC-Actus Triart C18, 30×50 mm, 5 μm

UV detection: 254 nm

Column flow rate: 40 mL/min

Mobile phase: water/acetonitrile (0.1% formic acid)

Injection amount: 1.0 mL

Gradient: water/acetonitrile (10% to 90%)

AL400 (400 MHz; JEOL (JEOL)) and Mercury400 (400 MHz; Agilent Technologies) were used for NMR spectra, and tetramethylsilane was used as an internal standard when tetramethylsilane was included in the heavy solvent, otherwise it was measured using NMR solvent as an internal standard, showing all 6 value in ppm. Furthermore, LCMS spectra were measured under the following conditions using a Waters made ACQUITY SQD (quadrupole). Column: Waters made ACQUITY UPLC (registered trademark) BEH C18, 2.1×50 mm, 1.7 μm

MS detection: ESI negativeUV detection: 254 and 280 nmColumn flow rate: 0.5 mL/minMobile phase: water/acetonitrile (0.1% formic acid)Injection amount: 1 μL

TABLE 1
Gradient
Time (min)	Water	Acetonitrile
0	95	5
0.1	95	5
2.1	5	95
3.0	STOP

The meanings of the abbreviations are shown below.s: singletd: doublett: tripletq: quartetdd: double doubletdt: double triplettd: triple doublettt: triple tripletddd: double double doubletddt: double double tripletdtd: double triple doublettdd: triple-double doubletm: multipletbr: broadbrs: broad singletDMSO-d₆: deuterated dimethyl sulfoxideCDCl₃: heavy chloroformCD₃OD: heavy methanolCDI: 1,1-carboxymethyl sulfonyl diimidazoleDAST: N,N-diethylaminosulfur trifluorideDIBAL-H: diisobutylaluminum hydrideDMF: dimethylformamideDMSO: dimethylsulfoxide

THF: Tetrahydrofuran

WSC=EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimideHOBt=1-hydroxybenzotriazole

Reference Example A1 Synthesis of 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene

(Step 1) 1-(6-fluoro-2,3-dimethylphenyl)ethanol

After dropping a diethyl ether solution of methylmagnesium bromide (3.0 M, 70 mL) to a THF solution of 6-fluoro-2,3-dimethyl-benzaldehyde (22.0 g) (300 mL) at 0° C., the reaction mixture was stirred at room temperature for 1 hour. Under ice-bath condition, a saturated aqueous ammonium chloride solution (150 mL) was added dropwise, and ethyl acetate (200 mL) was added, and the resultant was separated into different layers. The organic layer was successively washed with HCl (1M, 200 mL), water (200 mL) and saline (200 mL), and then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1-(6-fluoro-2,3 dimethylphenyl)ethanol (23.7 g).

Step 2

Phosphorus tribromide (26.5 mL) was added dropwise at 0° C. to a chloroform solution (120 mL) of 1-(6-fluoro-2,3-dimethylphenyl)ethanol (23.7 g) obtained in the above Step 1, and the reaction solution was stirred for 30 minutes at 0° C. The reaction mixture was added to an ice-cold saturated aqueous sodium bicarbonate (1 L). After chloroform (500 mL) was added to the mixture, the resultant was separated into different layers, and the organic layer was successively washed with water (200 mL) and saline (200 mL). The organic layer was dried over anhydrous magnesium sulfate to give the title compound (29.5 g) by concentrating under reduced pressure.

Reference Example A2 to A41

Aldehyde and methylmagnesium bromide were reacted together as starting materials in the same manner as in Reference Example A1, Step 1 and Step 2, and then the resultant was reacted with phosphorus tribromide to obtain the compounds of Reference Examples A2 to A41. However, the compounds of Reference Examples A40 and A41 were obtained in the same procedure using ethylmagnesium bromide and methyl iodide-d3-magnesium respectively instead of methylmagnesium bromide.

TABLE 1
Reference		Synthesized
Example	Starting Material	Compound
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30
A31
A32
A33
A34
A35
A36
A37
A38
A39
A40
A41

Reference Example B1 Synthesis of 2-(1-bromoethyl)-4-ethyl-1-fluoro-3-methylbenzene

(Step 1)2-bromo-3-ethyl-6-fluorobenzaldehyde

To a THF solution (150 mL) of 2-bromo-1-ethyl-4-fluorobenzene (14.4 g), a THF solution of lithium diisopropylamide (1.5 M, 54 mL) was added dropwise at −78° C. After stirring the reaction solution for 30 minutes, DMF (6.5 mL) was added and the mixture was further stirred for 20 minutes. Water (50 mL) and hydrochloric acid (6 M, 50 mL) were successively added dropwise to the reaction solution, and the mixture was extracted twice with hexane (100 mL). The combined organic layer was washed with saturated saline (50 mL) twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 2-bromo-3-ethyl-6-fluorobenzaldehyde (14.5 g) was obtained.

(Step 2) 3-ethyl-6-fluoro-2-methylbenzaldehyde

To a 1,4-dioxane solution (200 mL) of 2-bromo-3-ethyl-6-fluorobenzaldehyde obtained from Step 1 above (14.5 g), water (90 mL), tripotassium phosphate (32.0 g), methylboronic acid (6.4 g) and [bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane additive (1.75 g) were added, and the reaction solution was heated under reflux at 110° C. for 2 hours. The reaction solution was allowed to cool to room temperature, and the mixture was further stirred for 2 hours after hexane (90 mL) was added. The reaction solution was filtered through CELITE, and the filtrate was separated after the residue was washed with hexane. The organic layer was washed twice with saturated saline (100 mL), and after being dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate), and 3-ethyl-6-fluoro-2-methylbenzaldehyde (8.4 g) was obtained.

Step 3

According to the methods of Reference Example A1 Steps 1 and 2, using 3-ethyl-6-fluoro-2-methylbenzaldehyde (8.4 g) obtained in the above Step 2, the same operation was carried out to obtain the title compound.

Reference Examples B2 to B6

According to the methods of Reference Example B1 Steps 1 and 2 and Reference Example A1 Steps 1 and 2, the following compounds of Reference Examples B2 to B5 were synthesized. Also, according to the methods of Reference Example B1 Step 1, and Reference Example A1 Steps 1 and 2, the compound of Reference Example B6 was synthesized.

TABLE 2
Reference		Synthesized
Example	Starting Material	Compound
B2
B3
B4
B5
B6

Reference Example C1 Synthesis of 7-(1-chloroethyl)-1-methyl-2,3-dihydro-1H-indene

Sodium borohydride (261 mg) was added to a methanol solution (5.0 mL) of 1-(3-methyl-2,3-dihydro-1H-inden-4-yl)ethanone (1.0 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added to water (10 mL) and then extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5.0 mL), thionyl chloride (2.0 mL) was added at room temperature, and the reaction solution was stirred at 50° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.1 g).

Reference Examples C2 to C4

According to the method of Reference Example C1, the following compounds of Reference Examples C2 to C4 were synthesized.

TABLE 3
Reference		Synthesized
Example	Starting Material	Compound
C2
C3
C4

Reference Example D1 Synthesis of (2S, 3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic Acid

A DMF solution (50 mL) of 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (14.0 g) obtained in Reference Example A1 was added dropwise to a DMF solution (50 mL) of (S)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II) (14.5 g), and potassium hydroxide (16.3 g), and the mixture was stirred at the same temperature for 1 hour. A saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layers were washed successively with water (50 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane). The obtained compound was dissolved in methanol (120 mL), hydrochloric acid (3 M, 90 mL) was added, and the mixture was stirred at 80° C. for 45 minutes. Methanol was distilled off under reduced pressure, and chloroform (50 mL) and water (50 mL) were added to the residue. The aqueous layer was washed with chloroform (50 m L) and concentrated under reduced pressure. The residue was purified by reverse phase silica gel column chromatography (methanol/water) to give the title compound (2.0 g). ¹H NMR (CD₃OD) δ: 7.03 (dd, J=8.2, 5.7 Hz, 1H), 6.79 (dd, J=11.7, 8.4 Hz, 1H), 3.74-3.87 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.40 (dd, J=6.8, 2.4 Hz, 3H)

Reference Examples D2 to D58

After the alkylating agent obtained in Reference Examples A2 to A41, Reference Examples B1 to B6, and Reference Examples C1 to C4 and (S)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II) were reacted, the compounds of Reference Examples D2 to D58 shown below were prepared by acid hydrolysis. However, for the compound of Reference Example D56, 6-fluoro-2,3-dimethylbenzaldehyde was used as a starting material, and the compounds of Reference Examples D57 and 58 were prepared by the same method by using (R)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II) instead of (S)-2-[o-[(N-benzylprolyl)amino]phenyl]-benzylideneamino-acetate (2-)-N,N,N-nickel (II).

TABLE 4
	Starting Material
	(Reference example
Reference	number or structural	Synthesized
Example	formula)	Compound
D2	A1
D3	A2
D4	A3
D5	A4
D6	A5
D7	A6
D8	A7
D9	A8
D10	A9
D11	A10
D12	A11
D13	A12
D14	A13
D15	A14
D16	A15
D17	A16
D18	A16
D19	A17
D20	A18
D21	A19
D22	A20
D23	A21
D24	A22
D25	A23
D26	A24
D27	A25
D28	A26
D29	A27
D30	A28
D31	A29
D32	A30
D33	A31
D34	A32
D35	A33
D36	A33
D37	A34
D38	A35
D39	A36
D40	A37
D41	A38
D42	A39
D43	A40
D44	A41
D45	B1
D46	B2
D47	B3
D48	B4
D49	B5
D50	B6
D51	C1
D52	C1
D53	C2
D54	C3
D55	C4
D56
D57	A1
D58	A1

Reference Example D59 Synthesis of 2-Amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanoic Acid Monohydrochloride

(Step 1)2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanal

2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanenitrile (700 mg) was dissolved in dichloromethane (35 mL) and cooled to −78° C. A toluene solution (1.0 M, 10 mL) of diisobutylaluminum hydride was added, and the reaction solution was stirred for 1 hour at the same temperature. Methanol (5.0 mL) and CELITE (20 g) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through CELITE, washed with hexane/ethyl acetate=1/1 (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hexane/ethyl acetate) to obtain 2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanal (400 mg).

(Step 2) 2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanonitrile

2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanal (400 mg) obtained in the above Step 1 was dissolved in methanol (7.0 mL) and water (10 ml), 28% aqueous ammonia (280 μL), potassium cyanide (130 mg), and ammonium chloride (110 mg) were added, and the reaction solution was stirred for 12 hours at 70° C. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanonitrile (380 mg).

Step 3

2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-methylbutanonitrile (380 mg) obtained from the above Step 2 was dissolved in hydrochloric acid (12M, 5.0 mL), and the reaction solution was stirred for 12 hours at 100° C. The reaction solution was cooled to room temperature and was concentrated under reduced pressure to obtain the title compound (300 mg).

Reference Example D60 Synthesis of 2-Amino-2-(1-(6-fluoro-2,3-dimethylphenyl)cyclopropyl)acetic Acid Monohydrochloride

The title compound was synthesized according to the method of Reference Example D59, using 1-(6-fluoro-2,3-dimethylphenyl)cyclopropanecarbonitrile instead of 2-(6-fluoro-2,3-dimethylphenyl)-2-methylpropanenitrile.

Reference Example D61 Synthesis of 2-Amino-3-(6-fluoro-2,3-dimethylphenyl)-3-butenoic Acid Monohydrochloride

(Step 1)2-(6-fluoro-2,3-dimethyl)-2-hydroxy-propanenitrile

In dichloromethane (20 mL) solution of 1-(6-fluoro-2,3-dimethylphenyl)ethanone (1.3 g), zinc iodide (480 mg) and trimethylsilyl cyanide (2.0 mL) were added, and the reaction mixture was stirred for 12 hours at room temperature. An aqueous solution of sodium hydroxide (2 M, 10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (20 mL). The organic layer was washed with hydrochloric acid (2 M, 20 mL) and saturated saline (20 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-(6-fluoro-2,3-dimethyl)-2-hydroxy-propanenitrile (1.4 g).

(Step 2) 2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)propanenitrile

To dichloromethane solution (5.0 mL) of 2-(6-fluoro-2,3-dimethyl)-2-hydroxy-propanenitrile (170 mg) obtained from the above Step 1, DAST (150 μL) was added, and the reaction solution was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)propanenitrile (100 mg).

(Step 3) 2-amino-3-fluoro-3-(6-fluoro-2,3-dimethylphenyl)-butanenitrile

From 2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)propanenitrile obtained in the above Step 2, according to the method of Reference Example D59 Steps 1-2, 2-amino-3-fluoro-3-(6-fluoro-2,3-dimethylphenyl)-butanenitrile was obtained.

(Step 4)2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-butenoic Acid Monohydrochloride

2-Amino-3-fluoro-3-(6-fluoro-2,3-dimethylphenyl)-butanenitrile (460 mg) obtained in the above Step 3 was dissolved in hydrochloric acid (12 M, 3.0 mL), and the mixture was stirred for 12 hours at 100° C. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound.

Reference Example E1 Synthesis of 5-chloro-8-(chlorosulfonyl)-4-methyl-d 3-chroman-4-yl Acetate

(Step 1) 8-bromo-5-chloro-4-methylchroman-4-ol

THF (50 mL) was added to a diethyl ethyl ether solution (1.0 M, 63 mL) of methyl iodide-d3-magnesium, and a THF solution (50 mL) of 8-bromo-5-chlorochroman-4-one (7.5 g) was added dropwise at room temperature. The reaction solution was stirred for 10 minutes at the same temperature, in an ice bath, hydrochloric acid (1M, 50 mL) was slowly added dropwise, and ethyl acetate (50 mL) was added to separate layers. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layer was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-methylchroman-4-ol (7.7 g).

(Step 2) 8-bromo-5-chloro-4-methyl-d3-chroman-4-yl Acetate

To an anhydrous acetic acid solution (100 mL) of 8-bromo-5-chloro-4-methylchroman-4-ol (7.7 g) obtained in the above Step 1, an acetonitrile solution (12 mL) of scandium trifluoromethanesulfonate (III) (340 mg) was added dropwise at −40° C., and the reaction solution was stirred for 30 minutes at the same temperature. A saturated aqueous sodium hydrogen carbonate solution (100 mL) and ethyl acetate (100 mL) were sequentially added to the reaction solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layers were washed twice with a saturated aqueous sodium hydrogen carbonate solution (100 mL) and once with saturated saline (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-methyl-d3-chroman-4-yl acetate (8.9 g).

(Step 3) 8-(benzylthio)-5-chloro-4-methyl-d3-chroman-4-yl Acetate

To a 1,4-dioxane solution (70 mL) of 8-bromo-5-chloro-4-methyl-d3-chroman-4-yl acetate (6.7 g) obtained in the above Step 2, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (600 mg), tris(dibenzylideneacetone) dipalladium (0) (480 mg), N,N-diisopropylethylamine (7.2 mL) and benzylmercaptan (2.8 ml) were added, and the reaction solution was stirred for 2 hours at 90° C. The reaction solution was allowed to cool to room temperature and filtered through CELITE. After washing the residue with hexane (50 mL), water (50 mL) was added to the filtrate for layering. The organic layer was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-(Benzylthio)-5-chloro-4-methyl-d3-chroman-4-yl acetate (6.3 g).

Step 4

To an acetonitrile solution (100 mL) of 8-(benzylthio)-5-chloro-4-methyl-d3-chroman-4-yl acetate (6.3 g) obtained in the above Step 3, water (3 mL), acetic acid (4.3 mL) and 1,3-dichloro-5,5-dimethylhydantoin (7.2 g) were each added, and the reaction solution was stirred for 30 minutes at the same temperature. A saturated aqueous sodium hydrogen carbonate solution (70 mL) and ethyl acetate (70 mL) were added to the reaction solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (70 mL). The combined organic layer was washed with saturated saline (70 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (5.3 g).

Reference Example E5 Synthesis of 5-chloro-8-(chlorosulfonyl)-4-(trifluoromethyl)chroman-4-yl Acetate

(Step 1) 8-bromo-5-chloro-4-(trifluoromethyl)chroman-4-ol

To a THF solution (4 mL) of 8-bromo-5-chloro-chromanon-4-one (398.2 mg), cesium fluoride (340.2 mg) and trifluoromethyltrimethylsilane (0.68 mL) were added at room temperature, and the reaction solution was stirred for 4 hours. An ammonium chloride aqueous solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-(trifluoromethyl)chromanone-4-ol (139.2 mg).

Step 2

From 8-bromo-5-chloro-4-(trifluoromethyl)chroman-4-ol obtained from the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 2-4.

Reference Example E6 Synthesis of 8-(chlorosulfonyl)-4-(trifluoromethyl)chroman-4-yl Acetate

The compound of Reference Example E6 was synthesized according to the method of Reference Example E5 steps 1 and 2 using 8-bromo-chromanon-4-one as a starting material.

Reference Examples E2 to E4 and E7 to E34

According to the method of Reference Example E1 Steps 1-4, the compounds of Reference Examples E2 to E4 were synthesized. According to the method of Reference Examples E1 Step 3 and 4, the compounds of Reference Examples E7 to E32 were synthesized. According to the method of Reference Example E1 Step 2-4, the compounds of Reference Example E33 and E34 were synthesized. The compounds of Reference Examples E2 to E4 and E7 to E34, and the starting materials are listed in the following table.

TABLE 5
Reference		Synthesized
Example	Starting Material	Compound
E2
E3
E4
E7
E8
E9
E10
E11
E12
E13
E14
E15
E16
E17
E18
E19
E20
E21
E22
E23
E24
E25
E26
E27
E28
E29
E30
E31
E32
E33
E34

Reference Example E35 Synthesis of 5-Chloro-6-(pyrrolidine-1-carbonyl)pyridine-2-sulfonyl Chloride

(Step 1) methyl 6-(benzylthio)-3-chloropicolinate

According to the method of Reference Example E1 Step 3, methyl 6-(benzylthio)-3-chloropicolinate was obtained from methyl 6-bromo-3-chloropicolinate.

(Step 2) 6-(benzylthio)-3-chloropicolinic Acid

Methyl 6-(benzylthio)-3-chloropicolinate (1.0 g) obtained in the above Step 1 was dissolved in THF (5.0 mL) and water (1.0 ml), lithium hydroxide (165 mg) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-(benzylthio)-3-chloropicolinic acid (920 mg).

(Step 3) (6-(benzylthio)-3-chloropyridin-2-yl)(pyrrolidin-1-yl)methanone

6-(benzylthio)-3-chloro-picolinic acid (100 mg) obtained in the above Step 2 was dissolved in DMF (2.5 mL), CDI (the 116 mg) was added, the reaction solution was stirred at room temperature for 10 minutes, and then triethylamine (150 μL) and pyrrolidine (60 μL) were added, and the reaction solution was stirred for 12 hours at 50° C. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain (6-(benzylthio)-3-chloropyridin-2-yl)(pyrrolidin-1-yl)methanone (105 mg).

Step 4

The title compound was obtained from (6-(benzylthio)-3-chloropyridin-2-yl)(pyrrolidin-1-yl)methanone obtained in the above Step 3 according to the method of Reference Example E1 Step 4.

Reference Examples E36 to E43

According to the method of Reference Examples E35 Step 3 and E1 Step 4, the compounds of Reference Examples E36 to E43 shown below were synthesized from 6-(benzylthio)-3-chloropicolinic acid obtained from Reference Example E35 Step 2

TABLE 6
Reference Synthesized
Example   Compound
E36
E37
E38
E39
E40
E41
E42
E43

Reference Example E44 Synthesis of 1-(6-chloro-3-(chlorosulfonyl)-2-methoxyphenyl)ethyl Acetate

(Step 1) 3-bromo-6-chloro-2-methoxybenzaldehyde

According to the method of Reference Example B1 Step 1, 3-bromo-6-chloro-2-methoxybenzaldehyde was obtained from 1-bromo-4-chloro-2-methoxybenzene.

(Step 2) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol

From 3-bromo-6-chloro-2-methoxybenzaldehyde obtained in the above Step 1, 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol was obtained according to the method of Reference Example A1 Step 1.

(Step 3) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl Acetate

1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol (1.9 g) obtained in the above Step 2 was dissolved in dichloromethane (20 mL), triethylamine (2.0 mL), N,N-dimethyl-4-aminopyridine (100 mg), and acetic acid anhydride (1.2 mL) were successively added, and the reaction solution was stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(3-bromo-6-chloro-2-methoxyphenyl)ethylacetate)(2.2 g).

Step 4

From the 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl acetate obtained in the above Step 3, the title compound was obtained according to the method of Reference Examples E1 Steps 3 and 4.

Reference Example E45 Synthesis of 1-(5-Chloro-2-(chlorosulfonyl)-3-methoxypyridin-4-yl)ethyl Acetate

According to each of the methods of Reference Example B1 Step 1, Reference Example A1 Step 1, Reference Example E44 Step 3 and Reference Example E1 Steps 3 and 4, the title compound was obtained using 2-bromo-5-chloro-3-methoxypyridine instead of 1-bromo-4-chloro-2-methoxybenzene.

Reference Example E46 Synthesis of 2-(6-chloro-3-(chlorosulfonyl)-2-methoxyphenyl)propan-2-yl Acetate

(Step 1) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanone

To a dichloromethane solution (30 mL) of 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanol (2.8 g) obtained by Reference Example E44 Step 2, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (5.4 g) was added, and the reaction solution was stirred for 20 minutes at room temperature. The reaction solution was added dropwise to a mixed solution of a saturated sodium hydrogen carbonate aqueous solution/a sodium hydrogen sulfite solution=1/1 (50 mL) in an ice bath, and the layers were separated. The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanone (2.7 g).

(Step 2) 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl Acetate

From 1-(3-bromo-6-chloro-2-methoxyphenyl)ethanone obtained in the above Step 1, 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl acetate was obtained according to the method of Reference Example E1 Steps 1 and 2.

Step 3

From the 1-(3-bromo-6-chloro-2-methoxyphenyl)ethyl acetate (500 mg) obtained in the above Step 2, the title compound was obtained according to the method of Reference Examples E1 steps 3 and 4.

Reference Example E47 Synthesis of 4-Chloro-2-(2,2-difluoroethoxy)benzene-1-sulfonyl Chloride

(Step 1) 1-bromo-4-chloro-2-(2,2-difluoroethoxy)benzene

To a DMF solution (5 mL) of 2-bromo-5-chlorophenol (244 mg), potassium carbonate (325 mg) and 2,2-difluoroethyl 4-methylbenzenesulfonate (320 mg) were added, and the reaction solution was stirred for 3 hours at 95° C. The reaction solution was added to an aqueous sodium hydroxide solution (1 M, 20 mL) and extracted with toluene/ethyl acetate=1/1 (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-bromo-4-chloro-2-(2,2-difluoroethoxy)benzene (315 mg).

Step 2

The title compound was synthesized from 1-bromo-4-chloro-2-(2,2-difluoroethoxy)benzene obtained in the above Step 1 according to the method of Reference Examples E1 Steps 3 and 4.

Reference Examples E48 and E49

According to the methods of Reference Example E47 Step 1 and Reference Example E1 Steps 3 and 4, the compounds of Reference Examples E48 and 49 shown below were synthesized. However, regarding Reference Example 48, sodium chlorodifluoroacetate was used instead of 2,2-difluoroethyl 4-methylbenzenesulfonate.

TABLE 7
Reference		Synthesized
Example	Starting Material	Compound
E48
E49

Reference Example E50 Synthesis of 4-chloro-2-(isoxazol-5-yl)benzene-1-sulfonyl Chloride

(Step 1) 5-(2-bromo-5-chlorophenyl)isoxazole

An N,N-dimethylformamide dimethyl acetal solution (6.0 mL) of 1-(2-bromo-5-chlorophenyl)ethanone (400 mg) was stirred for 16 hours at 140° C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate). The obtained compound was dissolved in methanol (4.0 mL), hydroxylamine hydrochloride (175 mg) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was added to an aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to purify (eluent: hexane/ethyl acetate) to obtain 5-(2-bromo-5-chlorophenyl)isoxazole (430 mg).

Step 2

From 5-(2-bromo-5-chlorophenyl)isoxazole obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Steps 3,4.

Reference Example E51 Synthesis of Tert-Butyl Benzyloxy(5-chloro-2-(chlorosulfonyl)benzoyl)carbamate

(Step 1)N-(benzyloxy)-2-(benzylthio)-5-chlorobenzamide

According to the method of Reference Example E1 Step 3, N-(benzyloxy)-2-(benzylthio)-5-chlorobenzamide was synthesized from N-(benzyloxy)-2-bromo-5-chlorobenzamide.

(Step 2) Tert-Butyl Benzyloxy (2-(benzylthio)-5-chloro-benzoyl)carbamate

To a dichloromethane (10 mL) solution of N-(benzyloxy)-2-(benzylthio)-5-chlorobenzamide (433 mg) obtained from Reference Example 1, N,N-dimethyl-4-aminopyridine (280 mg) and di-tert-butyl dicarbonate (740 mg) were added, and the reaction solution was stirred for 16 hours at 55° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butylbenzyloxy (2-(benzylthio)-5-chlorobenzoyl)carbamate (549 mg).

Step 3

From the tert-butylbenzyloxy (2-(benzylthio)-5-chlorobenzoyl)carbamate obtained in the above Step 2, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E52 Synthesis of Tert-Butyl (5-chloro-2-(chlorosulfonyl)benzoyl)(methyl)carbamate

(Step 1) 2-bromo-5-chloro-N-methylbenzamide

From 2-bromo-5-chlorobenzoic acid and methylamine, 2-bromo-5-chloro-N-methylbenzamide was obtained according to the method of Reference Example E35 Step 3.

(Step 2) tert-butyl (2-bromo-5-chlorobenzoyl)(methyl)carbamate

(2-bromo-5-chlorobenzoyl)(methyl)carbamate was obtained from 2-bromo-5-chloro-N-methylbenzamide obtained in the above step 1 according to the method of Reference Example E51 Step 2.

Step 3

From the tert-butyl (2-bromo-5-chlorobenzoyl)(methyl)carbamate obtained in the above Step 2, the title compound was obtained according to the method of Reference Examples E1 steps 3 and 4.

Reference Example E53 Synthesis of Methyl 5-chloro-2-(chlorosulfonyl)-4-nitrobenzoate

(Step 1) methyl 2-bromo-5-chloro-4-nitrobenzoate

To a 2-methyl-2-propanol solution (5 mL) of 1-bromo-4-chloro-2-methyl-5-nitrobenzene (1.0 g), water (5 mL), anisole (2.5 mL), and potassium permanganate (1.6 g) were added, and the reaction solution was stirred at 100° C. for 20 hours. The reaction solution was cooled to room temperature, filtered through CELITE, and washed with water (10 mL) and ethyl acetate (10 mL). The combined filtrates were added to hydrochloric acid (1 M, 20 mL), and the layers were separated. The aqueous layer was extracted three times with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.0 mL), dichloromethane (10 mL) and a hexane solution of trimethylsilyldiazomethane (0.6 M, 6.0 mL) were added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 2-bromo-5-chloro-4-nitrobenzoate (529 mg).

Step 2

From the methyl 2-bromo-5-chloro-4-nitrobenzoate obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Steps 3 and 4.

Reference Example E54 Synthesis of 4-chloro-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzene-1-sulfonyl Chloride

(Step 1) 5-(2-bromo-5-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one

CDI (310 mg) was added to a THF (6.0 mL) suspension of 2-bromo-5-chlorobenzoic acid (300 mg), and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was ice-cooled, hydrazine⋅monohydrate (160 μL) was added, and the reaction solution was stirred at the same temperature for 20 minutes. The reaction solution was added to water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (6.0 mL), CDI (310 mg) was added, and the reaction solution was stirred at 45° C. for 2 hours. The reaction solution was added to water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(2-bromo-5-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one (300 mg).

Step 2

From the 5-(2-bromo-5-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one obtained in the above Step 1, the title compound is obtained in accordance with the method of Steps 3 and 4 of Reference Example E1.

Reference Example E55 Synthesis of Tert-Butyl N-tert-butoxycarbonyl-N-(1-(5-chloro-2-chlorosulfonyl-phenyl)cyclopropyl]carbamate

(Step 1) 1-(2-benzylsulfanyl-5-chlorophenyl)cyclopropanamine

To a THF (10 mL) suspension of 2-(benzylthio)-5-chlorobenzonitrile (1.0 g) and titanium tetraisopropoxide (1.3 mL), a diethyl ether solution (3.0 M, 3.0 mL) of methylmagnesium bromide was added dropwise at −78° C., and the reaction solution was stirred at the same temperature for 10 minutes. To the reaction solution, boron trifluoride diethyl ether complex (1.1 mL) was added, and the mixture was further stirred at room temperature for 1 hour, and then water (5 mL) and an aqueous sodium hydroxide solution (1 M, 5 mL) were added to separate layers, the aqueous layer was extracted with diethyl ether (20 mL). The combined organic layers were washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropanamine (490 mg).

(Step 2) tert-butyl N-[1-(2-benzylsulfanyl-5-chloro-phenyl)-cyclopropyl]-N-tert-butoxycarbonyl-carbamate

To a 1,2-dichloroethane solution (10 mL) of 1-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropanamine (490 mg) obtained in the above Step 1, N,N-dimethyl-4-aminopyridine (210 mg) and di-tert-butyl dicarbonate (1.8 g) were added, and the reaction solution was stirred at 50° C. for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane) to obtain tert-butyl N-[1-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropyl]-N-tert-butoxycarbonyl-carbamate (502 mg).

Step 3

From tert-butyl N-[1-(2-benzylsulfanyl-5-chloro-phenyl)cyclopropyl]-N-tert-butoxycarbonyl-carbamate obtained in the above Step 2, the title compound is obtained in accordance with the method of Reference Example E1 step 4.

Reference Example E56 Synthesis of Methyl 6-(bis(tert-butoxycarbonyl)amino)-3-chlorosulfonyl-2-methoxy-benzoate

(Step 1) methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromo-2-methoxybenzoate

From methyl 6-amino-3-bromo-2-methoxybenzoate, methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromo-2-methoxybenzoate was obtained according to the method of Reference Example E55 Step 2.

Step 2

The title compound was obtained from methyl 6-(bis(tert-butoxycarbonyl)amino)-3-bromo-2-methoxybenzoate obtained in the above step 1 according to the method of Reference Examples E1 Steps 3 and 4.

Reference Example E57 Synthesis of 5-Chloro-4,4-difluorochroman-8-sulfonyl Chloride

(Step 1) 8-(benzylthio)-5-chlorochroman-4-one

From 8-bromo-5-chlorochroman-4-one, 8-(benzylthio)-5-chlorochroman-4-one was obtained according to the method of Reference Example E1 Step 3.

(Step 2) 8-(benzylthio)-5-chloro-4,4-difluorochroman

From 8-(benzylthio)-5-chlorochroman-4-one (125 mg) obtained in the above Step 1, 8-(benzylthio)-5-chloro-4,4-difluorochroman was obtained according to the method of Reference Example D61 Step 2.

Step 3

From the 8-(benzylthio)-5-chloro-4,4-difluorochroman obtained in the above Step 2, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E58 Synthesis of Tert-Butyl 5-chloro-8-(chlorosulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate

(Step 1) 8-bromo-5-chloro-3,4-dihydro-2H-benzoxazine

1,2-dibromoethane (500 μL) and potassium carbonate (3.0 g) were added to a DMF solution (6 mL) of 2-amino-6-bromo-3-chlorophenol (1.3 g), and the reaction solution was stirred for 12 hours at 100° C. The reaction solution was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, the layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-3, 4-dihydro-2H-benzoxazine (400 mg).

(Step 2) tert-butyl 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate

To dioxane solution (5 mL) of 8-bromo-5-chloro-3,4-dihydro-2H-1,4-benzoxazine (223 mg), 4-dimethylaminopyridine (44 mg), triethylamine (0.25 mL) and di-tert-butyl dicarbamate (458 mg) were added at room temperature, and the reaction solution was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butyl 8-bromo-5-chloro-2H-benzo [b][1,4]oxazin-4(3H)-carboxylate (140 mg).

Step 3

From tert-butyl 8-bromo-5-chloro-2H-benzo [b][1,4]oxazin-4(3H)-carboxylate obtained in the above Step 2, the title compound is obtained according to the method of Steps 3 and 4 of Reference Example E1.

Reference Example E59 Synthesis of Tert-Butyl 8-(chlorosulfonyl)-2H-benzo [b][1,4]oxazin-4(3H)-carboxylate

(Step 1) tert-butyl 8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate

From 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine, tert-butyl 8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate was obtained according to the method of Reference Example E58 Step 2.

Step 2

From tert-butyl 8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate obtained in the above Step 1, the title compound was obtained, in accordance with Reference Example E1 Steps 3 and 4.

Reference Example E60 Synthesis of Tert-Butyl 4-(chlorosulfonyl)-1H-indole-1-carboxylate

From the commercially available tert-butyl 4-bromo-1H-indole-1-carboxylate (Ark Pharm, Inc.), the title compound was obtained according to the method of Reference Example E1 steps 3 and 4.

Reference Example E61 Synthesis of 5-chloro-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-sulfonyl Chloride

(Step 1) 8-bromo-5-chloro-4-ethyl-2,3-dihydro-1,4-benzoxazine

To a DMSO solution (2.0 mL) of 8-bromo-5-chloro-3,4-dihydro-2H-benzoxazine (380 mg) obtained in Reference Example E58 Step 1, potassium hydroxide (120 mg) and ethyl iodide (100 μL) were added, and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was allowed to cool to room temperature, a saturated aqueous solution of ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-bromo-5-chloro-4-ethyl-2,3-dihydro-1,4-benzoxazine (105 mg).

Step 2

From the 8-bromo-5-chloro-4-ethyl-2,3-dihydro-1,4-benzoxazine obtained in the above Step 1, the title compound was obtained according to the method of Reference Examples E1 Steps 3 and 4.

Reference Example E62 Synthesis of 4-(cyclopropanecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-sulfonyl Chloride

(Step 1) (8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)(cyclopropyl)methanone

Sodium hydride (18 mg) was added to a THF solution (2.0 mL) of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (62 mg) at 0° C., and the reaction solution was stirred for 30 minutes. Cyclopropanecarbonyl chloride (170 μL) was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution (10 mL) and ethyl acetate (10 mL) were sequentially added to the reaction solution to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give (8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)(cyclopropyl)methanone (87 mg).

Step 2

From (8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)(cyclopropyl)methanone obtained in the above Step 1 according to the method of Steps 3 and 4 of Reference Example E1, the title compound was obtained.

Reference Example E63 Synthesis of 5-chloro-4-(2,2-difluoroethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-sulfonyl Chloride

(Step 1) 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one

2-amino-6-bromo-3-chlorophenol (140 mg) was dissolved in THF (2.0 mL), chloroacetyl chloride (100 μL) and sodium hydrogencarbonate (240 mg) were added and the reaction solution was stirred at room temperature for 3 hours. Potassium carbonate (440 mg) was added to the reaction solution, and the mixture was further stirred at 80° C. for 5 hours. The reaction solution was allowed to cool to room temperature, and a saturated aqueous solution of ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to separate layers, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (160 mg).

(Step 2) 8-bromo-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

To a DMF (2.5 mL) solution of 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (69 mg) obtained in the above Step 1, potassium carbonate (420 mg) and 2,2-difluoroethyl paratoluene sulfonate (500 mg) were sequentially added, and the reaction solution was stirred at 100° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and a saturated aqueous solution of ammonium chloride (10 mL) and ethyl acetate (10 mL) were added to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 8-bromo-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (85 mg).

(Step 3) 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

From 8-bromo-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one obtained in the above Step 2, 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one was obtained according to the method of Reference Example E1 Step 3.

Step 4

From the 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, the title compound was obtained in the above Step 3, according to the method of Reference Example E1 Step 4.

Reference Example E64 and E65

From 8-bromo-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one obtained from Reference Example E63 Step 1, the following compounds of reference examples E64 and E65 are synthesized according to method of Reference Example E63 Step 2, and Reference Example E1 Steps 3 and 4.

TABLE 8
Reference		Synthesized
Example	Alkylating agent	Compound
E64	MeI
E65

Reference Example E66 Synthesis of 5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonyl Chloride

(Step 1) 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a THF solution (5 mL) of 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (270 mg) obtained from Reference Example 63 Step 3, dimethylsulfide borane (1.0 mL) was added, and the reaction solution was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, methanol (5 mL), ethyl acetate (10 mL), and water (10 mL) were added in order to separate layers, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (154 mg).

Step 2

From the 8-(benzylthio)-5-chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E67 Synthesis of 2-cyano-5-(morpholine-4-carbonyl)benzene-1-sulfonyl Chloride

(Step 1) ethyl 3-(benzylthio)-4-cyanobenzoate

Ethyl 3-(benzylthio)-4-cyanobenzoate was obtained from ethyl 3-bromo-4-cyanobenzoate according to the method of Reference Example E1 Step 3.

(Step 2) 6-(benzylthio)-4-cyano-benzoic Acid

An aqueous sodium hydroxide solution (3 M, 4.0 mL) was added to a THF (4.0 mL) solution of ethyl 3-(benzylthio)-4-cyanobenzoate (344 mg) obtained in the above Step 1, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-(benzylthio)-4-cyanobenzoic acid (210 mg).

(Step 3) 2-(benzylthio)-4-(morpholine-4-carbonyl)benzonitrile

Using 6-(benzylthio)-4-cyano-benzoic acid obtained from the above Step 2 and morpholine, 2-(benzylthio)-4-(morpholine-4-carbonyl)benzonitrile was obtained according to Reference Example E35 Step 3.

Step 4

From the 2-(benzylthio)-4-(morpholine-4-carbonyl)benzonitrile obtained in the above Step 3, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E68 Synthesis of 2-cyano-5-(dimethylcarbamoyl)benzene-1-sulfonyl Chloride

(Step 1)2-(benzylthio)-4-cyano-N,N-dimethylbenzamide

According to the method of Reference Example E35 Step 3, from 6-(benzylthio)-4-cyanobenzoic acid obtained in Reference Example E67 Step 2 and dimethylamine, 2-(benzylthio)-4-cyano-N,N-dimethylbenzamide was obtained.

Step 2

From the 2-(benzylthio)-4-cyano-N,N-dimethylbenzamide obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E69 Synthesis of 4-chloro-2-cyano-5-(dimethylcarbamoyl)benzene-1-sulfonyl Chloride

The title compound was synthesized from methyl 5-bromo-2-chloro-4-cyanobenzoate according to each of the methods of Reference Example E1 Step 3, Reference Example E67 Step 2, Reference Example E35 Step 3 and Reference Example E1 Step 4.

Reference Example E70 Synthesis of Tert-Butyl (5-chloro-8-(chlorosulfonyl)chroman-4-yl)carbamate

(Step 1) 8-benzyl-sulfanyl-5-chlorochroman-4-one

From 8-bromo-5-chlorochroman-4-one, 8-benzylsulfanyl-5-chlorochroman-4-one was obtained according to the method of Reference Example E1 Step 3.

(Step 2) 8-benzyl-sulfanyl-5-chlorochroman-4-amine

8-benzylsulfanyl-5-chlorochroman-4-one (460 mg) obtained in the above Step 1 was dissolved in methanol (3.0 mL), ammonium chloride (1.2 g) was added, and the reaction solution was stirred at room temperature for 2 hours. Sodium cyanoborohydride (670 mg) was added to the reaction solution, and the mixture was further stirred at 80° C. for 14 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL), an aqueous sodium hydroxide solution (5 M, 10 mL) and chloroform (20 mL) were added successively to the reaction solution to separate layers, and the aqueous layer was extracted twice with chloroform (20 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 8-benzylsulfanyl-5-chlorochroman-4-amine (216 mg).

(Step 3) tert-butyl (8-(benzylthio)-5-chlorochroman-4-yl)carbamate

From 8-benzylsulfanyl-5-chloro-chroman-4-amine (216 mg) obtained in the above Step 2, tert-butyl (8-(benzylthio)-5-chlorochroman-4-yl)carbamate was obtained according to Reference Example E58 Step 2.

Step 4

From the tert-butyl (8-(benzylthio)-5-chlorochroman-4-yl)carbamate obtained in the above Step 3, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example E71 Synthesis of 4-acetamido-5-chlorochroman-8-sulfonyl Chloride

(Step 1)N-(8-bromo-5-chlorochromanon-4-yl)acetamide

8-Bromo-5-chlorochromanon-4-amine (250 mg) was dissolved in DMF (2.0 mL) and THF (7.0 mL), N,N-dimethyl-4-aminopyridine (45 mg), triethylamine (400 μL) and acetic anhydride (200 μL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain N-(8-bromo-5-chlorochromanon-4-yl)acetamide (260 mg).

Step 2

From the N-(8-bromo-5-chlorochromanon-4-yl)acetamide obtained in the above Step 1, the title compound was obtained according to the method of Reference Examples E1 steps 3 and 4.

Reference Example E72 Synthesis of 1-(3-chloro-6-(chlorosulfonyl)pyridin-2-yl)-2,2,2-trifluoroethylacetate

(Step 1) 1-(6-bromo-3-chloropyridin-2-yl)-2,2,2-trifluoroethanol

Cesium fluoride (700 mg) and (trifluoromethyl)trimethylsilane (700 μL) were added to a THF (10 mL) solution of 6-bromo-3-chloropicolinaldehyde (770 mg), and the reaction solution was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-(6-bromo-3-chloropyridin-2-yl)-2,2,2-trifluoroethanol (600 mg).

Step 2

From 1-(6-bromo-3-chloropyridin-2-yl)-2,2,2-trifluoroethanol obtained in the above Step 1, according to the method of Reference Examples E44 Step 3 and E1 Steps 3 to 4, the title compound was obtained.

Reference Example E73 Synthesis of Methyl 5-bromo-2-(chlorosulfonyl)nicotinate

(Step 1) methyl 2-(benzylthio)-5-bromo-nicotinate

Sodium hydride (285 mg) was added to a THF (5.0 mL) solution of benzyl mercaptan (700 μL) at 0° C., and the reaction solution was stirred at room temperature for 15 min. A THF (3.0 mL) solution of methyl 2,5-dibromonicotinate (1.59 g) was added dropwise to the reaction solution, and the mixture was stirred at 0° C. for 20 minutes. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 2-(benzylthio)-5-bromonicotinate (1.5 g).

Step 2

From the methyl 2-(benzylthio)-5-bromonicotinate obtained in the above Step 1, the title compound was obtained according to the method of Reference Example E1 Step 4.

Reference Example F1 Synthesis of 5-((1S,2R)-1-Amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2 (3H)-one Monohydrochloride

(Step 1) (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic Acid

Water (9 mL), 1,4-dioxane (9 mL) and triethylamine (955 μL) were sequentially added to (2S, 3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (515 mg) obtained in Reference Example D1, and the mixture was cooled to 0° C. Di-tert-butyl dicarbonate (650 mg) was added to the reaction solution at the same temperature, and the mixture was stirred for 45 minutes. The reaction solution was added to hydrochloric acid (1 M, 20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain (2S, 3R)-2-((tert-butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (745 mg).

(Step 2) Tert-Butyl ((1 S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)carbamate

To a THF solution (14.0 mL) of (2S, 3R)-2-(tert-butoxycarbonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (440 mg) obtained in the above Step 1, CDI (302 mg) was added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0° C., hydrazine⋅monohydrate (200 μL) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. CDI (560 mg) was added to a 1,4-dioxane (14 mL) solution of the obtained residue, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography by purification (eluent: hexane/ethyl acetate) to obtain tert-butyl ((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)carbamate (356 mg).

Step 3

tert-butyl ((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)carbamate (550 mg) obtained in the above Step 2 was dissolved in hydrochloric acid-1,4-dioxane (4 M, 5.0 mL), and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound.

Reference Examples F2 to F10

According to the method of Reference Example F1 Steps 1 to 3, the following compounds of Reference Examples F2 to F10 were synthesized.

TABLE 9
	Starting Material
Re-	(Reference
fer-	example
ence	number or
Exam-	structural	Synthesized
ple	formula)	Compound
F2	Reference Example D6
F3	Reference Example D3
F4	Reference Example D13
F5	Reference Example D10
F6	Reference Example D41
F7	Reference Example D4
F8	Reference Example D5
F9	Reference Example D45
F10	Reference Example D61

Example 1

Synthesis of 5-bromo-2-(N-((1 S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide

Step 1

To a 1,4-dioxane (5.0 mL) solution and water (5.0 mL) of (2S, 3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (300 mg) obtained in Reference Example D1, triethylamine (570 μL) was added and then cooled to 0° C. 4-Bromo-2-cyanobenzene-1-sulfonyl chloride (362 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 45 minutes. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain (2S, 3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (465 mg).

Step 2

To a THF (5.0 mL) solution of (2S, 3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (465 mg) obtained in the above Step 1, CDI (210 mg) was added, and the reaction solution was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0° C., hydrazine⋅monohydrate (200 μL) was added, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

CDI (211 mg) was added to a 1,4-dioxane (4.0 mL) solution of the obtained residue, and the reaction solution was stirred at 45° C. for 1 hour. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (386 mg).

Step 3

To a DMSO (5.0 mL) solution of 4-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (386 mg) obtained in the above Step 2, hydrogen peroxide water (1.0 mL) and potassium carbonate (420 mg) were added sequentially in an ice bath, and the reaction solution was stirred at 60° C. for 2.5 hours. The reaction solution was slowly added to hydrochloric acid (1 M, 15 mL) in an ice bath and then extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 2 to 128

Compounds of Examples 2 to 43 were synthesized according to the method of Example 1 Steps 1 to 3. Compounds of Examples 44 to 128 were synthesized according to the method of Example 1 Step 1 and 2. The necessary raw materials are listed in the following table. “ArSO2Cl” in the subsequent tables refers to an arylsulfonyl chloride compound used in a reaction with starting materials in each Example.

TABLE 10
Example	Starting Material	ArSO2Cl	Name of the Synthesized Compound
2	Reference	E22	6-Chloro-3-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-
	Example D10		4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinamide
3	Reference Example D6		5-chloro-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
4	Reference Example D6		5-bromo-2-(N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
5	Reference Example D1		5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
6	Reference Example D3		5-chloro-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
7	Reference Example D7		15-chloro-2-(N-((1S,2R)-2-(5-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
8	Reference Example D20		5-chloro-2-(N-((1S,2R)-2-(8-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
9	Reference Example D8		5-chloro-2-(N-((1S,2R)-2-(3-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
10	Reference Example D1		2-(N-((1S,2R)-2-(3-6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-methylbenzamide
11	Reference Example D45		5-chloro-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
12	Reference Example D3		2-(N-((1S,2R)-2-(2-Fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-methylbenzamide
13	Reference Example D46		5-chloro-2-(N-((1S,2R)-2-(2,3-difluoro-5,6-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
14	Reference Example D4		5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
15	Reference Example D3		5-bromo-2-(N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
16	Reference	Reference	5-Cyclopropyl-2-(N-((1S,2R)-2-(6-Fluoro-2,3-dimethylphenyl)-1-(5-
	Example D1	Example E20	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
17	Reference Example D15		5-chloro-2-(N-((1S)-2-(2-chloro-6-fluoro-3-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
18	Reference	Reference	5-Ethyl-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E21	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
19	Reference	Reference	6-Chloro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E22	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinamide
20	Reference Example D1		2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
21	Reference Example D16		5-chloro-2-(N-((1S,2R)-2-(2-fluoro-5-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
22	Reference Example D17		5-chloro-2-(N-((1S,2R)-2-(2-fluoro-6-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
23	Reference Example D18		5-chloro-2-(N-((1S,2S)-2-(2-fluoro-6-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzainide
24	Reference Example D37		5-chloro-2-(N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)- 2-(o-tolyl)propyl)sulfamoyl)benzamide
25	Reference Example D4		5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
26	Reference Example D47		5-chloro-2-(N-((1S,2R)-2-(3-cyclopropyl-6-fluoro-2-methylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide
27	Reference Example D48		5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2-methyl-3- (trifluoromethyl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide
28	Reference Example D19		5-chloro-2-(N-((1S,2R)-2-(3,6-difluoro-2-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
29	Reference Example D49		3-((1S,2R)-1-(4-chloro-2-methoxyphenylsulfonamido)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propan-2-yl)-4-fluoro-2- methylbenzamide
30	Reference Example D5		2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chlorobenzamide
31	Reference	Reference	3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E18	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinamide
32	Reference Example D2		5-chloro-2-(N-((1S,2S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
33	Reference Example D57		5-chloro-2-(N-((1R,2S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
34	Reference Example D58		5-chloro-2-(N-((1R,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
35	Reference Example D5		5-bromo-2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
36	Reference	Reference	2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E67	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(morpholine-4-
			carbonyl)benzamide
37	Reference	Reference	3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E68	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N1,N1-
			dimethylterephthalamide
38	Reference	Reference	4-carbamoyl-2-chloro-5-(N-((1S,2R)-2-(6-fluoro-2,3-
	Example D1	Example E16	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
			yl)propyl)sulfamoyl)benzoic acid
39	Reference	Reference	2-chloro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E69	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N1,N1-dimethyl
			terephthalamide
40	Reference	Reference	2-chloro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E32	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)isonicotinamide
41	Reference Example D1		2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5- (trifluoromethyl)benzamide
42	Reference Example D5		2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5- (trifluoromethyl)benzamide
43	Reference Example D44		5-chloro-2-[[(1S,2R)-3,3,3-trideuterio-2-(6-fluoro-2,3- dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5- yl)propyl]sulfamoyl]benzamide
44	Reference Example D11		4-bromo-N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)benzenesulfonamide
45	Reference Example D27		N-((1S,2R)-2-(benzo[b]thiophen-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-bromobenzenesulfonamide
46	Reference Example D11		2,4-dichloro-N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
47	Reference Example D21		2-chloro-4-cyclopropyl-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1- yl)propyl)benzenesulfonamide
48	Reference Example D51		5-bromo-N-((1S)-2-(3-methyl-2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-2-sulfonamide
49	Reference Example D22		N-((1S,2R)-2-(9H-fluoren-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-5-bromopyridine-2-sulfonamide
50	Reference Example D23		N-((1S,2R)-2-(9H-fluoren-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-5-bromopyridine-2-sulfonamide
51	Reference Example D11		N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-nitrobenzenesulfonamide
52	Reference Example D21		5-chloro-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2- 5,6,7,8-tetrahydronaphthalen-1-yl)propyl)pyridine-2-sulfonamide
53	Reference Example D21		4-bromo-3-methoxy-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzene sulfonamide
54	Reference Example D21		4-chloro-2-nitro-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)-2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzenesulfonamide
55	Reference Example D21		2,4-dimethoxy-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)-2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzenesulfonamide
56	Reference Example D24		4-chloro-N-((1S,2R)-2-(6-fluoro-naphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
57	Reference Example D21		2-methoxy-4-nitro-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1- yl)propyl)benzenesulfonamide
58	Reference Example D21		methyl 4-methoxy-5-(N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-(5,6,7,8-tetrahydronaphthalen-1- yl)propyl)sulfamoyl)thiophene-3-carboxylate
59	Reference Example D10		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2yl)propyl)benzo[c][1,2,5]thiadiazole-4-sulfonamide
60	Reference Example D10		4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-fluorobenzenesulfonamide
61	Reference Example D10		3-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-fluorobenzenesulfonamide
62	Reference Example D33		N-((1S,2R)-2-(benzo[b]thiophen-3-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide
63	Reference Example D40		N-((1S,2R)-2-(benzo[d]thiazol-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide
64	Reference Example D30		4-chloro-N-((1S,2R)-2-(2,3-dihydrobenzofuran-7-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
65	Reference Example D31		4-chloro-2-methoxy-N-((1S,2R)-2-(2-methylnaphthalen-1-yl)-1-(5- oxo-4,5-dihydio-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
66	Reference Example D29		4-chloro-N-((1S,2R)-2-(2,3-dihydrobenzofuran-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
67	Reference Example D53		4-chloro-2-methoxy-N-((1S,2R)-2-(2-methyl-2,3-dihydro-1H-inden- 4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide
68	Reference Example D10		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)naphthalene-1-sulfonamide
69	Reference Example D52		4-chloro-2-methoxy-N-((1S,2S)-2-(3-methyl-2,3-dihydro-1H-inden- 4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide
70	Reference Example D28		4-chloro-2-methoxy-N-((1S,2R)-2-(2-methyl-[1,1′-biphenyl]-3-yl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
71	Reference Example D13		4-chloro-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
72	Reference Example D35		4-chloro-2-methoxy-N-((1S,2R)-2-(3-methyl-2,3-dihydrobenzofuran- 4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide
73	Reference Example D36		4-chloro-2-methoxy-N-((1S,2S)-2-(3-methyl-2,3-dihydrobenzofuran- 4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- ylpropyl)benzenesulfonamide
74	Reference Example D34		4-chloro-N-((1S)-2-(2,3-difluorophenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
75	Reference Example D32		4-chloro-N-((1S,2R)-2-(3-fluoro-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
76	Reference Example D3		4-chloro-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
77	Reference Example D9		chloro-N-((1S,2R)-2-(4-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
78	Reference Example D55		(S)-4-chloro-2-methoxy-N-(2-(8-methylnaphthalen-1-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)benzenesulfonamide
79	Reference Example D38		4-chloro-N-((1S)-2-(2,6-difluoro-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
80	Reference Example D39		4-chloro-N-((1S)-2-(2-fluoro-3-methylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
81	Reference	Reference	5-chloro-4,4-difluoro-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1-(5-
	Example D13	Example E57	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-sulfonamide
82	Reference Example D25		4-chloro-N-((1S,2R)-2-(5-fluoronaphthalen-1-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
83	Reference Example D1		4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
84	Reference Example D1		4-chloro-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
85	Reference Example D14		4-chloro-N-((1S,2R)-2-(2-isopropyl-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
86	Reference Example D12		4-chloro-N-((1S,2R)-2-(3-ethyl-2-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
87	Reference Example D42		4-chloro-N-((1S,2R)-2-(2-ethyl-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
88	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E7	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide
89	Reference Example D50		N-((1S)-2-(2-bromo-5,6-difluoro-3-methylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2- methoxybenzenesulfonamide
90	Reference Example D46		4-chloro-N-((1S,2R)-2-(2,3-difluoro-5,6-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
91	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E50	dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(isoxazol-5-
			yl)benzenesulfonamide
92	Reference Example D1		4-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
93	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E64	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3-oxo-3,4-dihydro-
			2H-benzo[b][1,4]oxazine-8-sulfonamide
94	Reference	Reference	5-chloro-4-ethyl-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example D1	Example E61	oxo4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-
			benzo[b][1,4]oxazine-8-sulfonamide
95	Reference	Reference	5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E2	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-
			methylchroman-4-ylacetate
96	Reference Example D45		5-bromo-2-(N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
97	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-
	Example D1	Example E23	1,3,4-oxadiazol-2-yl)propyl)-2,2-dimethyl-4-oxochroman-8-
			sulfonamide
98	Reference Example D1		2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
99	Reference	Reference	4-(cyclopropanecarbonyl)-N-((1S,2R)-2-(6-fluoro-2,3-
	Example D1	Example E62	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-
			3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide
100	Reference	Reference	5-chloro-8-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-
	Example D4	Example E2	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-
			methylchroman-4-yl acetate
101	Reference	Reference	5-chloro-4-(2,2-difluoroethyl)-N-((1S,2R)-2-(6-fluoro-2,3-
	Example D1	Example E63	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-
			3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide
102	Reference	Reference	5-chloro-4-(2,2-difluoroethyl)-N-((1S,2R)-2-(6-fluoro-2,3-
	Example D1	Example E66	dimethylphenyl)-1-(5-oxo-4,5-dihydro-2,3,4-oxadiazol-2-yl)propyl)-
			3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide
103	Reference Example D1		methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate
104	Reference Example D49		4-chloro-N-((1S,2R)-2-(3-cyano-6-fluoro-2-methylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
105	Reference	Reference	5-chloro-6-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example D1	Example E18	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-2-sulfonamide
106	Reference	Reference	8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E6	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-
			(tifluoromethyl)chroman-4-ylacetate
107	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-diinethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E25	dihydro-1,3,4-oxadiazol-2-yl)propyl)-8-oxo-5,6,7,8-
			tetrahydronaphthalene-1-sulfonamide
108	Reference	Reference	2-(6-chloro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E46	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2-
			methoxyphenyl)propan-2-ylacetate
109	Reference	Reference	methyl 3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example D1	Example E10	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinate
110	Reference Example D1		2,6-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
111	Reference Example D1		4-chloro-2,6-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
112	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E27	dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-methoxypyridine-2-
			sulfonamide
113	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E37	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(moipholine4-
			carbonyl)pyridine-2-sulfonamide
114	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E35	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(pyrrolidine-1-
			carbonyl)pyridine-2-sulfonamide
115	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example D1	Example E43	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(6-azaspiro[3.4]octane-6-
			carbonyl)pyridine-2-sulfonamide
116	Reference	Reference	6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-chloro-N-((1S,2R)-
	Example D1	Example E39	2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
			oxadiazol-2-yl)propyl)pyridine-2-sulfonamide
117	Reference	Reference	6-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-5-chloro-N-((1S,2R)-
	Example D1	Example E40	2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
			oxadiazol-2-yl)propyl)pyridine-2-sulfonamide
118	Reference	Reference	methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example D1	Example E11	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate
119	Reference	Reference	methyl 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-
	Example D1	Example E73	(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate
120	Reference	Reference	1-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E45	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-
			methoxypyridin-4-yl)ethylacetate
121	Reference	Reference	methyl 5-chloro-4-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-
	Example D1	Example E28	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
			yl)propyl)sulfamoyl)benzoate
122	Reference	Reference	methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example D1	Example E14	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-
			methoxybenzoate
123	Reference	Reference	5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example D1	Example E5	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-
			(trifluoromethyl)chroman-4-ylacetate
124	Reference	Reference	N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-
	Example D5	Example E7	dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-oxochroman-8-
			sulfonamide
125	Reference Example D59		(S)-4-chloro-N-(2-(6-fluoro-2,3-dimethylphenyl)-2-methyl-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
126	Reference Example D54		(S)-4-chloro-N-(2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide
127	Reference Example D60		(S)-4-chloro-N-((1-(6-fluoro-2,3-dimethylphenyl)cyclopropyl)(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-2- methoxybenzenesulfonamide
128	Reference Example D43		4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)butyl)-2-methoxybenzenesulfonamide

Example 129

Synthesis of 5-Chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methyl-d3-chroman-4-yl Acetate

To a pyridine (1.5 mL) solution of 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (45 mg) obtained from Reference Example F1, 5-chloro-8-(chlorosulfonyl)-4-methyl-d3-chroman-4-ylacetate (80 mg) obtained in Reference Example E1 was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (59 mg) as a 1:1 diastereomer mixture.

Examples 130 to 185

According to the method of Example 129, the following compounds of Examples 130 to 185 and Examples 338 to 343 were synthesized. The necessary raw materials are listed in the following table.

TABLE 11
Example	Starting Material	ArSO2Cl	Name of the Synthesized Compound
130	Reference Example F6		5-bromo-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2- (quinoline-8-yl)propyl)pyridine-2-sulfonamide
131	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-fluoro-3- (methylsulfonyl)benzenesulfonamide
132	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)quinoline-8-sulfonamide
133	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-(isoxazol-4-yl)benzenesulfonamide
134	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
135	Reference Example F5		4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-ethylbenzenesulfonamide
136	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-3-methylquinoline-8-sulfonamide
137	Reference Example F5		4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
138	Reference Example F5		2-(difluoromethoxy)-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
139	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b]thiophene-6- sulfonamide 1,1-dioxide
140	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-5,6,7,8-tetrahydronaphthalene-1- sulfonamide
141	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-methoxypyridine-3-sulfonamide
142	Reference	E34	1-(3-chloro-6-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-
	Example F5		4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)pyridin-2-
			yl)ethylacetate
143	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-5-nitroquinoline-8-sulfonamide
144	Reference	Reference	1-(6-chloro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example F1	Example E44	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2-
			methoxyphenyl)ethyl acetate
145	Reference	Reference	4-chloro-2-(2,2-difluoroethoxy)-N-((1S,2R)-2-(6-fluoro-2,3-
	Example F1	Example E47	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
			yl)propyl)benzenesulfonamide
146	Reference	Reference	4-chloro-2-(difluoromethoxy)-N-((1S,2R)-2-(6-fluoro-2,3-
	Example F1	Example E48	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
			yl)propyl)benzenesulfonamide
147	Reference	Reference	2-acetyl-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example F1	Example E19	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
148	Reference Example F1		6-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxypyridine-3- sulfonamide
149	Reference	E54	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example F1		dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(5-oxo-4,5-dihydro-1,3,4-
			oxadiazol-2-yl)benzenesulfonamide
150	Reference Example F2		N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-methylbenzenesulfonamide
151	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-methylbenzenesulfonamide
152	Reference	E60	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-
	Example F1		1,3,4-oxadiazol-2-yl)propyl)-1H-indole-4-sulfonamide
153	Reference Example F1		5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)quinoline-8-sulfonamide
154	Reference Example F1		6-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methoxypyridine-3- sulfonamide
155	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example F1	Example E38	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-oxa-6-aza-
			spiro[3.4]octane-6-carbonyl)pyridine-2-sulfonamide
156	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example F1	Example E42	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-oxa-7-
			azaspiro[3.5]nonane-7-carbonyl)pyridine-2-sulfonamide
157	Reference	Reference	N-(5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example F1	Example E71	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)chroman-4-
			yl)acetamide
158	Reference Example F1		5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)thiophene-2-sulfonamide
159	Reference	Reference	5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example F1	Example E8	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide
160	Reference Example F1		2-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-1-methyl-1H-imidazole-4- sulfonamide
161	Reference Example F1		4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1H-tetrazol-5- yl)benzenesulfonamide
162	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-oxoindoline-5-sulfonamide
163	Reference Exampel F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1,3-dioxoisoindoline-5-sulfonamide
164	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- sulfonamide
165	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfonamide
166	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b]thiophene-6- sulfonamide 1,1-dioxide
167	Reference	Reference	8-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-
	Example F8	Example E2	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-5-chloro-4-
			methylchroman-4-yl)acetate
168	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-5-sulfonamide
169	Reference Example F1		4-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-3- (methylsulfonyl)benzenesulfonamide
170	Reference Example F1		2,4-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylpheny)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6- methoxybenzenesulfonamide
171	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3-(piperidin-1- ylsulfonyl)benzenesulfonamide
172	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dioxo-1,2,3,4- tetrahydroquinoxaline-6-sulfonamide
173	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxin-6- sulfonamide
174	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-8-oxo-5,6,7,8-tetrahydronaphthalene-2- sulfonamide
175	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1-oxo-1,3-dihydroisobenzofuran-4- sulfonamide
176	Reference Example F1		4-chloro-N1-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)benzene-1,3-disulfonamide
177	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
178	Reference Example F1		methyl 2,6-difluoro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzoate
179	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-6-sulfonamide
180	Reference	Reference	methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example F1	Example E53	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-
			nitrobenzoate
181	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1H-benzo[d][1,2,3]triazole-5- sulfonamide
182	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1H-indazole-5-sulfonamide
183	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)chroman-6-sulfonamide
184	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-1-methyl-1,2,3,4-tetrahydroquinoline-7- sulfonamide
185	Reference Example F10		(S)-4-chloro-N-(2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)allyl)-2-methoxybenzensulfonamide
338	Reference Example F1		4-bromo-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- (trifluoromethoxy)benzenesulfonamide
339	Refernce Example F1		4-bromo-2,5-difluoro-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
340	Reference Example F1		N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)propyl)-4-nitrobenzenesulfonamide
341	Reference Example F1		4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide
342	Reference Example F1		4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
343	Reference Example F1		4-bromo-3-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide

Example 186

Synthesis of 2,4-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)benzenesulfonamide

Step 1

Methyl 3-(chlorosulfonyl)-2,6-difluorobenzoate (33 mg) was added to a pyridine (1.0 mL) solution of 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (20 mg) obtained from Reference Example F1, and the reaction solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 2,6-difluoro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (12.5 mg).

Step 2

To a THF (2.0 mL) solution of methyl 2,6-difluoro-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (12.5 mg) obtained from the above Step 1, a diethyl ether (3.0 M, 84 μL) solution of methylmagnesium bromide was added dropwise at 0° C., and the reaction solution was stirred for 1 hour at room temperature. A saturated ammonium chloride aqueous solution (10 mL) was added dropwise in an ice bath, ethyl acetate (10 mL) was added, and the layers were separated. The organic layer was washed successively with hydrochloric acid (1 M, 10 mL), water (10 mL) and saturated saline (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane ethyl acetate) to obtain the title compound.

Examples 187 to 195

According to the method of Example 186, the following compounds of Examples 187 to 195 were synthesized. The necessary raw materials are listed in the following table.

TABLE 12
	Starting
Example	Material	ArSO2Cl	Name of the Synthesized Compound
187	Reference Example F5		4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(2-hydroxypropan-2- yl)benzenesulfonamide
188	Reference Example F5		4-bromo-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2- yl)benzenesulfonamide
189	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-2,4-difluoro-3-(2-hydroxypropan-2- yl)benzenesulfonamide
190	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-(2-hydroxypropan-2-yl)-3-methoxythiophene-2- sulfonamide
191	Reference Example F5		N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)-2,4- dimethoxybenzenesulfonamide
192	Reference Example F5	Reference Example E10	5-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-hydroxypropan-2-yl)pyridine- 2-sulfonamide
193	Reference Example F1	Reference Example E10	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2-hydroxypropan-2-yl)pyridine- 2-sulfonamide
194	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-8-hydroxy-8-methyl-5,6,7,8- tetrahydronaphthalene-2-sulfonamide
195	Reference Example F1		N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-6-sulfonamide

Example 196

Synthesis of 5-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(2-hydroxypropan-2-yl)benzamide

Step 1

From 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (60 mg) obtained from Reference Example F1 and methyl 2-fluoro-5-(chlorosulfonyl)-4-cyanobenzoate (94 mg) obtained in Reference Example E15, in accordance with the method of Example 129, methyl 4-(cyano-2-fluoro-5 (N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (49 mg) was obtained.

Step 2

From methyl 4-cyano-2-fluoro-5-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (49 mg) obtained from the above Step 1, according to the method of Example 186 Step 2, 2-cyano-4-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-(2-hydroxypropan-2-yl)benzenesulfonamide (27.5 mg) was obtained.

Step 3

From 2-cyano-4-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-(2-hydroxypropan-2-yl)benzenesulfonamide (27.5 mg) obtained from the above Step 2, according to the method of Example 1 Step 3, the title compound was obtained.

Examples 197 to 199

According to the method of Example 129, Example 186 Step 2, Example 1 Step 3, the following compounds of Examples 197 to 199 were synthesized. The necessary raw materials are listed in the following table. However, for Example 199, the synthesis was carried out using 1-propynyl magnesium bromide instead of methyl magnesium bromide.

TABLE 13
	Starting
Example	Material	ArSO2Cl	Name of the Synthesized Compound
197	Reference	Reference	2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-
	Example	Example	1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(2-hydroxypropan-2-
	F1	E13	yl)benzamide
198	Reference	Reference	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(2-hydroxypropan-2-
	F1	E16	yl)benzamide
199	Reference	Reference	2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-
	Example	Example	1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(hydroxyhepta-2,5-diyn-4-
	F1	E13	yl)benzamide

Example 200

Synthesis of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-sulfonamide Isomer A and Isomer B

1:1 diastereomer mixture of 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methyl-d3-chroman-4-yl acetate (59 mg) obtained from Example 129 was dissolved in methanol (2.0 mL) and water (1.0 mL), lithium hydroxide (5 mg) was added, and the reaction solution was stirred at 55° C. for 1 hour. After concentrating the reaction solution, hydrochloric acid (1 M, 10 mL) and ethyl acetate (10 mL) were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL), and the combined organic layers were washed with saturated saline (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile), and the fractions were concentrated to give each of two diastereomeric products. The substance eluted first was designated Compound A, and the substance eluted later was designated as Compound B.

Examples 201 to 229

According to the method of Example 200, the following compounds of Examples 201 to 229 were synthesized. In the case of separating the diastereomers, the previously eluted compound was designated as A and the later eluted compound as B. The ratio of diastereomers is 1:1 mixture unless otherwise specified. The necessary raw materials are listed in the following table.

TABLE 14
	Starting
Example	Material	ArSO2Cl	Name of the Synthesized Compound
201	Reference	Reference	2,4-dichloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-
	Example	Example E33	dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-
	F5		hydroxyethyl)benzenesulfonamide (diastereomer mixture)
202	Reference	Reference	5-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-
	Example	Example E34	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(1-hydroxyethyl)pyridine-2-
	F5		sulfonamide (diastereomer mixture)
203	Reference	Reference	4-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
	Example	Example E44	oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-
	F2		methoxybenzenesulfonamide (diastereomer mixture)
204	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E44	dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-
	F1		methoxybenzenesulfonamide (diastereomer mixture)
205	Reference	Reference	4-chloro-N-((1S,2R)-2-(2-fluoronaphthalene-1-yl)-1-(5-oxo-4,5-dihydro-
	Example	Example E44	1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-
	F3		methoxybenzenesulfonamide (diastereomer mixture)
206A	Reference	Reference	4-chloro-N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-
	Example	Example E44	dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-
	F9		methoxybenzenesulfonamide
207A	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
207B	Example	Example E2	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8-
	F1		sulfonamide
208A	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
208B	Example	Example E44	dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-
	F1		methoxbenzenesulfonamide
209A	Reference	Reference	5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-
209B	Example	Example E2	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8-
	F7		sulfonamide
210	Reference Example F1		5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid
211A	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
	Example	Example E6	oxadiazol-2-yl)propyl)-4-hydroxy-4-(trifluoromethyl)chroman-8-
	F1		sulfonamide
212	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E46	dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)-2-
	F1		methoxybenzenesulfonamide
213	Reference	Refernce	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E11	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid
	F1
214	Reference	Reference	5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E73	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid
	F1
215	Reference	Reference	3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E10	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)picolinic acid
	F1
216	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E45	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-(1-hydroxyethyl)-3-
	F1		methoxypyridine-2-sulfonamide (diastereomer mixture)
217	Reference	Reference	5-chloro-4-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example	Example E28	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid
	F1
218	Reference	Reference	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E12	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-methylbenozic acid
	F1
219	Reference	Reference	5-chloro-3-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example	Example E29	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid
	F1
220A	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
220B	Example	Example E5	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-
	F1		(trifluoromethyl)chroman-8-sulfonamide
221	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example E72	dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2,2,2-trifluoro-1-
	F1		hydroxyethyl)pyridine-2-sulfonamide (diastereomer mixture)
222A	Reference	Reference	N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-
222B	Example	Example E2	1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methylchroman-8-
	F8		sulfonamide
223	Reference	Reference	7-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-
	Example	Example E17	1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2,3-dihydrobenzo[b][1,4]dioxin-
	F1		6-Carboxylic Acid
224A	Reference	Reference	5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
224B	Example	Example E3	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8-
	F1		sulfonamide
225A	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
	Eaxmple	Example E4	oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-5-(trifluoromethyl)chroman-
	F1		8-sulfonamide
226A	Reference	Reference	N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-
226B	Example	Example E1	1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methyl-d3-chroman-
	F8		8-sulfonamide
227A	Reference	Reference	N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-
227B	Example	Example E3	1,3,4-oxadiazol-2-yl)propyl)-5-fluoro-4-hydroxy-4-methyl-d3-chromn-8-
	F8		sulfonamide
228A	Reference	Reference	5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-
228B	Example	Example E1	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methyl-d3-chroman-8-
	F7		sulfonamide
229A	Reference	Reference	N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-
229B	Example	Example E3	1,3,4-oxadiazol-2-yl)propyl)-5-fluoro-4-hydroxy-4-methylchroman-8-
	F7		sulfonamide

Example 230

Synthesis of 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide Isomer A and Isomer B

Step 1

Using 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (40 mg) obtained from Reference Example F1 and 5-fluoro-4-oxochroman-8-sulfonyl chloride (60 mg) obtained from Reference Example E8, 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (44 mg) was obtained in accordance with the method of Example 129.

Step 2

Sodium borohydride (13.5 mg) was added to an ethanol (2.0 mL) solution of 5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (44 mg) obtained from the above Step 1 and the reaction solution was stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added to the residue, separated, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile), and the fractions were concentrated to obtain each of two diastereomeric products. The substance eluted first was designated as Compound A, and the substance eluted later was designated as Compound B.

Examples 231 to 244

According to the method of Example 129 and Example 230 Step 2, the compounds of Examples 231 to 244 shown below were synthesized. In the case of separating the diastereomers, the first eluted compound was designated as A and the later eluted compound as B. The ratio of diastereomers is 1:1 mixture unless otherwise specified. The necessary raw materials are listed in the following table.

TABLE 15
Example	Starting Material	ArSO2Cl	Name of the Synthesized Compound
231	Reference Example F5		4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1- hydroxyethyl)benzensulfonamide (diastereomer mixture)
232	Reference	Reference	5-chloro-4-hydroxy-N-((1S,2R)-2-(8-methylnaphthalene-1-yl)-1-
	Example F4	Eample E7	(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-
			sulfonamide (diastereomer mixture)
233	Reference	Reference	5-chloro-N-((1S,2R)-2-(2-fluoronaphthalene-1-yl)-1-(5-oxo-4,5-
	Example F3	Example E7	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-
			sulfonamide (diastereomer mixture)
234A	Reference	Reference	5-chloro-N-((1S,2R)-2-(2-fluoronaphthalene-1-yl)-1-(5-oxo-4,5-
	Example F3	Example E7	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-
			sulfonamide
235A	Reference	Reference	5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
235B	Example F1	Example E7	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-
			sulfonamide
236	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example F1	Example E19	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(1-
			hydroxyethyl)benzenesulfonamide (diastereomer mixture)
237A	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example F1	Example E23	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-2,2-
			dimethylchroman-8-sulfonamide
238A	Reference	Reference	5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-
	Example F7	Example E7	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-
			hydroxychroman-8-sulfonamide
239A	Reference	Reference	5-chloro-N-((1S,2R)-2-(3-ethyl-6-fluoro-2-methylphenyl)-1-(5-
	Example F9	Example E7	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-
			hydroxychroman-8-sulfonamide
240	Reference	Reference	4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example F1	Example E25	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-8-hydroxy-5,6,7,8-
			tetrahydronaphthalene-1-sulfonamide (diastereomer mixture)
241	Reference	Reference	5-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example F1	Example E8	4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-
			sulfonamide (diastereomer mixture)
242	Reference	Reference	5,7-difluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example F1	Example E30	oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-
			hydroxychroman-8-sulfonamide (diastereomer mixture)
243A	Reference	Reference	N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-
243B	Example F8	Example E7	dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-
			hydroxychroman-8-sulfonamide
244A	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
244B	Example F1	Example E9	dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-5-
			(trifluoromethyl)chroman-8-sulfonamide

Example 245

Synthesis of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinamide

Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (100 mg) obtained from Reference Example D1 and methyl 5-chloro-2-(chlorosulfonyl)nicotinate (140 mg) obtained from Reference Example E11, according to the method of Example 1 Steps 1, 2, methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate (174 mg) was obtained.

Step 2

Methyl 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinate (174 mg) obtained from the above Step 1 was dissolved in THF (2.5 mL) and water (2.5 mL), lithium hydroxide (30 mg) was added, and the reaction solution was stirred at 50° C. for 16 hours. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid (145 mg).

Step 3

To a toluene (1.2 mL) solution of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)nicotinic acid (10 mg) obtained from the above Step 2, DMF (30 μL) and thionyl chloride (60 μL) were sequentially added, and the reaction solution was stirred at 95° C. for 40 minutes. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The THF (2.0 mL) solution of the residue was slowly added dropwise to 28% aqueous ammonia solution (1.0 mL) at −10° C., and the reaction solution was stirred at room temperature for 30 min. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 246 to 264

Compounds of Examples 246 to 264 shown below were synthesized according to the procedures of Example 1 Steps 1 and 2, and Example 245 Step 2 and 3. The necessary raw materials are listed in the following table.

TABLE 16
	Starting
Example	Material	ArSO2Cl	Amine	Name of the Synthesized Compound
246	Reference Example D1			5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N,N-dimethylbenzamide
247	Reference Example D1			2-(azetidine-1-carbonyl)-4-chloro-N-((1S,2R)-2-(6-fluoro- 2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)benzenesulfonamide
248	Reference Example D1			5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N-(2-hydroxyethyl)benzamide
249	Reference	Reference	NH3	5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-
	Example	Example E11		methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D4			yl)propyl)sulfamoyl)nitotinamide
250	Reference	Reference	NH3	5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-
	Example	Example E73		1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)nicotinamide
251	Reference	Reference	MeNH2	5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-
	Example	Example E73		1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)-N-methylnicotinamide
252	Reference	Reference	MeNH2	3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-
	Example	Example E10		1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)-N-methylpicolinamide
253	Reference Example D1	Reference Example E10		3-chloro-6-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)-N,N-dimethylpicolinamide
254	Reference	Reference	NH3	5-bromo-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-
	Example	Example E73		methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D4			yl)propyl)sulfamoyl)nicotinamide
255	Reference	Reference	NH3	5-chloro-4-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-
	Example	Example E28		dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)benzamide
256	Reference Example D1		NH3	3,5-dichloro-2-(N-((1S,2R)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide
257	Reference	Reference	NH3	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-
	Example	Example E12		1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)-4-methylbenzamide
258	Reference	Reference	NH3	5-chloro-3-fluoro-2-(N-((1S,2R)-2-(6-fluoro-2,3-
	Example	Example E29		dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)benzamide
259	Reference	Reference	NH3	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-
	Example	Example E14		1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)-4-methoxybenzamide
260	Reference	Reference	NH3	2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example	Example E31		4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4,5-
	D1			dimethoxybenzamide
261	Reference	Reference	NH3	7-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-
	Example	Example E17		4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2,3-
	D1			dihydrobenzo[b][1,4]dioxin-6-carboxamide
262	Reference	Reference	NH3	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-
	Example	Example E53		1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)-4-nitrobenzamide
263	Reference	Reference	NH3	4-(2,2-difluoroethoxy)-2-(N-((1S,2R)-2-(6-fluoro-2,3-
	Example	Example E47		dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1			yl)propyl)sulfamoyl)benzamide
264	Reference	Reference	NH3	2-(N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-
	Example	Example E11		(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D5			yl)propyl)sulfamoyl)-5-chloronicotinamide

Example 265

Synthesis of 4-amino-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

Step 1

Using (2S,3R)-2-amino-3-(2-fluoronaphthalen-1-yl)butanoic acid (45 mg) obtained in Reference Example D3 and 2-methoxy-4-nitrobenzene-1-sulfonyl chloride (60 mg), according to the method of Example 1, Steps 1 and 2, N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxy-4-nitrobenzenesulfonamide (32 mg) was obtained.

Step 2

N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxy-4-nitrobenzenesulfonamide (32 mg) obtained from the above Step 1 was dissolved in ethanol (2.0 mL) and water (1.0 mL), iron (30 mg) and ammonium chloride (20 mg) were sequentially added, and the reaction solution was stirred at 80° C. for 1 hour. The reaction solution was filtered through CELITE, and the residue was washed with ethyl acetate (10 mL). The combined filtrates were concentrated and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 266 to 272

Compounds of Examples 266 to 272 shown below were synthesized according to the method of Example 1 Steps 1 and 2 and Example 265 Step 2. The necessary raw materials are listed in the following table.

TABLE 17
Example	Starting Material	ArSO2Cl	Name of the Synthesized Compound
266	Reference Example D21		4-amino-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)- 2-(5,6,7,8-tetrahydronaphthalen-1-yl)propyl)benzenesulfonamide
267	Reference Example D10		4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methylbenzenesulfonamide
268	Reference Example D10		5-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)quinoline-8- sulfonamide
269	Reference Example D13		4-amino-2-methoxy-N-((1S,2R)-2-(8-methylnaphthalen-1-yl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide
270	Reference Example D10		4-amino-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
271	Reference Example D1		2-amino-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)benzenesulfonamide
272	Reference	Reference	methyl 4-amino-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-
	Example D1	Example E53	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
			yl)propyl)sulfamoyl)benzoate

Example 273

Synthesis of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (50 mg) obtained in Reference Example D1 and 4-(2-(benzyloxy)ethyl)-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonyl chloride (142 mg) obtained in Reference Example E65, according to the method of Example 1 Steps 1 and 2, 4-(2-(benzyloxy)ethyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (22 mg) was obtained.

Step 2

To a THF (1.5 mL) solution of 4-(2-(benzyloxy)ethyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (20 mg) obtained from the above Step 1, 20 wt % palladium hydroxide (30 mg) was added, and the reaction mixture was stirred at room temperature for 30 minutes under hydrogen atmosphere. The reaction solution was filtered through CELITE, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Example 274

Synthesis of N-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetamide

To a dichloromethane (1.0 mL) solution of 2-Amino-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (5.0 mg) obtained from Example 271, Pyridine (5.0 μL) and acetic anhydride (4.0 μL) were sequentially added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was added to hydrochloric acid (1 M, 5.0 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 275

Synthesis of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

Step 1

From 5-((1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one monohydrochloride (14.3 mg) obtained in Reference Example F1 and tert-butyl 5-chloro-8-(chlorosulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate (25.3 mg) obtained in Reference Example E58, according to the method of Example 129, tert-butyl 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (30.4 mg) was obtained.

Step 2

To tert-butyl 5-chloro-8-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate (30.4 mg) obtained from the above Step 1, hydrochloric acid-1, 4-dioxane (4 M, 5.0 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain the title compound.

Examples 276 to 283

Compounds of Examples 276 to 283 shown below were synthesized according to the method of Example 129 and Example 275 Step 2. The necessary raw materials are listed in the following table.

TABLE 18
	Starting
Example	Material	ArSO2Cl	Name of the Synthesized Compound
276	Reference	Reference	methyl 6-amino-3-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-
	Example	Example	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2-methoxybenzoate
	D10	E56
277	Reference	Reference	5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example	dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N-methylbenzamide
	D1	E52
278	Reference	Reference	4-amino-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-
	Example	Example	dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-sulfonamide
	D1	E70
279	Reference	Reference	2-(1-aminocyclopropyl)-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-
	Example	Example	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
	D1	E55	yl)propyl)benzenesulfonamide
280	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
	Example	Example	oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide
	D1	E59
281	Reference	Reference	N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-
	Example	Example	oxadiazol-2-yl)propyl)-1,2,3,4-tetrahydroisoquinoline-5-sulfonamide
	D1	E24
282	Reference	Reference	N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-
	Example	Example	oxo-4,5-dihydro-1,3-oxadiazol-2-yl)propyl)sulfamoyl)benzamide
	D1	E51
283	Reference	Reference	6-(3-aminopyrrolidine-1-carbonyl)-5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-
	Example	Example	dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-
	D1	E41	2-sulfonamide

Example 284

Synthesis of 4-acetyl-5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3, 4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

To a dichloromethane (1.0 mL) solution of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3, 4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (31.5 mg) obtained in Example 275, triethylamine (40 μL) and acetic anhydride (20μL) were sequentially added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain the title compound.

Example 285

Synthesis of 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N-hydroxybenzamide

Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (125 mg) obtained in Reference Example D1 and tert-butylbenzyloxy (5-chloro-2-(chlorosulfonyl)benzoyl)carbamate (280 mg) obtained in Reference Example E51 as a starting material, according to the method of Example 1 Step 1, (2S,3R)-2-(2-((benzyloxy)(tert-butoxycarbonyl)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (250 mg) was synthesized.

Step 2

(2S,3R)-2-(2-((benzyloxy)(tert-butoxycarbonyl)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (250 mg) obtained in the above Step 1 was dissolved in hydrochloric acid-1,4-dioxane (4 M, 4 mL), and the reaction solution was stirred at 45° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to give (2S,3R)-2-(2-((benzyloxy)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (215 mg).

Step 3

From (2S,3R)-2-(2-((benzyloxy)carbamoyl)-4-chlorophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (215 mg) obtained from the above Step 2, according to the method of Example 1 Step 2, N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (75 mg) was given.

Step 4

To a methanol (4.0 mL) solution of N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (75 mg) obtained from the above Step 3, 10% palladium-carbon (55 mg) was added, and the reaction solution was stirred under a hydrogen atmosphere for 1.5 hours. Insoluble matter was removed by CELITE filtration, and the residue was washed with methanol (10 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 286

Synthesis of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-N-hydroxybenzamide

To dichloromethane (3.0 mL) solution of N-(benzyloxy)-5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (66 mg) obtained from Example 285 Step 3, boron tribromide (1.0 M, 170 μL) was added at −60° C., and the reaction solution was stirred at 0° C. for 1 hour. Methanol (1.0 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to obtain the title compound.

Example 287

Synthesis of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzothioamide

To a toluene (500 μL) solution of 5-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2-oxo-3H-1,3,4-oxadiazol-5-yl)propyl)sulfamoyl)benzamide (15 mg) obtained in Example 5, Lawesson's reagent (20 mg) was added at room temperature, and the reaction solution was stirred at 100° C. for 12 hours. After allowing to cool to room temperature and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Example 288

Synthesis of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

To a methanol (1.0 mL) solution of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (48 mg) obtained in Example 275, acetic acid (20 μL) and aqueous 37% formaldehyde solution (30 μL) were added successively, and the reaction solution was stirred at room temperature for 30 minutes. Sodium borohydride (12 mg) was added to the reaction solution, and the mixture was further stirred for 20 minutes. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Example 289

Synthesis of 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

Step 1

From 5-((1S,2R)-1-amino-2-(3-chloro-6-fluoro-2-methylphenyl)propyl)-1,3,4-oxadiazol-2 (3H)-one monohydrochloride (10.3 mg) obtained in Reference Example F7 and tert-butyl 5-chloro-8-(chlorosulfonyl)-2H-benzo[b][1,4]oxazin-4 (3H)-carboxylate (25.3 mg) obtained from Reference Example E58, according to the method of Example 129, tert-butyl 5-chloro-8-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-carboxylate (25.4 mg) was obtained.

Step 2

To tert-butyl 5-chloro-8-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4 (3H)-carboxylate (25.4 mg) obtained from the above Step 1, hydrochloric acid-1,4-dioxane (4 M, 5.0 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (15.2 mg).

Step 3

From 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide (15.2 mg) obtained from the above Step 2, according to the method of Example 288, the title compound was synthesized.

Example 290

Synthesis of 4-chloro-N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-2-hydroxy-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide

Step 1

Using (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)-3-hydroxypropionic acid (139 mg) obtained from Reference Example D56 and 4-chloro-2-methoxybenzenesulfonyl chloride (175 mg), according to the method of Example 1 Step 1, (2S)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)-3-hydroxypropionic acid (163 mg) was synthesized.

Step 2

To a DMF (10 mL) solution of (2S)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)-3-hydroxypropionic acid (163 mg) obtained from the above Step 1, Imidazole (753 mg) and tert-butyldimethylchlorosilane (563 mg) were sequentially added, and the reaction solution was stirred at 60° C. for 12 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate/hexane=1/1 (30 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and THF (2.0 mL), potassium carbonate (1.0 g) and water (2.0 mL) were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was added to hydrochloric acid (1 M, 20 mL) and extracted with ethyl acetate/hexane=1/1 (30 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain (2S)-3-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)propionic acid (175 mg).

Step 3

From (2S)-3-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-methoxyphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)propionic acid (175 mg) obtained from the above Step 2, according to the method of Example 1 Step 2, N-((1S)-2-((tert-butyldimethylsilyl)oxy)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-4-chloro-2-methoxybenzenesulfonamide (126 mg) was obtained.

Step 4

To a THF (6.0 mL) solution of N-((1S)-2-((tert-butyldimethylsilyl)oxy)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-4-chloro-2-methoxybenzenesulfonamide (126 mg) obtained in the above Step 3, acetic acid (600 μL) and tetra-n-butylammonium fluoride (6.0 mL) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate/hexane=1/1 (30 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound as a diastereomeric mixture.

Example 291

Synthesis of 4-chloro-N-((1R)-2-fluoro-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide

To a dichloromethane (200 μL) solution of 4-chloro-N-((1 S)-2-(6-fluoro-2,3-dimethylphenyl)-2-hydroxy-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-2-methoxybenzenesulfonamide (5.6 mg) obtained from Example 290, DAST (10 μL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate/hexane=1/1 (10 mL). The organic layer was washed with saturated saline (5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water/acetonitrile) to obtain the title compound as a diastereomeric mixture.

Example 292

Synthesis of 5-chloro-4-fluoro-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)chroman-8-sulfonamide

From 5-chloro-N-((1S,2R)-2-(2-fluoronaphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide (13 mg) obtained in Example 233, according to the method of Example 291, the title compound was obtained as a 1:1 diastereomeric mixture.

Example 293

Synthesis of 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2,2,2-trifluoroacetyl)pyridine-2-sulfonamide

From 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-sulfonamide (15.6 mg) obtained in Example 221, according to the method of Reference Example E46 Step 1, the title compound was obtained.

Example 294

Synthesis of 3-acetyl-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

From 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-methoxybenzenesulfonamide obtained in Example 204, the title compound was obtained according to the method of Reference Example E46 Step 1.

Example 295

Synthesis of 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2H-chromene-8-sulfonamide

Step 1

From (2S,3R)-2-amino-3-(2,3-dimethylphenyl)butanoic acid (58 mg) obtained in Reference Example D6 and 5-chloro-4-oxochroman-8-sulfonyl chloride (88 mg) obtained in Reference Example E7, in accordance with the procedures of Example Steps 1 and 2, 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (63.4 mg) was obtained.

Step 2

From 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-oxochroman-8-sulfonamide (63.4 mg) obtained from the Step 1 above, according to the method of Example 230 Step 2, 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide (48 mg) was obtained as a diastereomeric mixture.

Step 3

To a toluene (2.0 mL) solution of 5-chloro-N-((1S,2R)-2-(2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychroman-8-sulfonamide (10 mg) obtained from the above Step 2, p-toluenesulfonic acid monohydrate (2.0 mg) was added, and the reaction solution was stirred at 110° C. for 30 minutes. The reaction solution was added to water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 296

Synthesis of 4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4 oxadiazol-2-yl)propyl)-2-(hydroxymethyl)benzenesulfonamide

Step 1

Using (2S,3R)-2-amino-3-(2,3-dihydro-1H-inden-4-yl)butanoic acid (50 mg) obtained from Reference Example D10 and methyl 5-chloro-2-(chlorosulfonyl)benzoate (71 mg), according to the method of steps 1 and 2 of Example 1, methyl 5-chloro-2-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (43 mg) was obtained.

Step 2

To a THF (2.0 mL) solution of methyl 5-chloro-2-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (15 mg) obtained in the above Step 1, a THF solution of lithium borohydride (2 M, 100 μL) was added, and the reaction solution was stirred at 60° C. for 1 hour. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Example 297

Synthesis of 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxy-3-(1-(methoxymethoxy)ethyl)benzenesulfonamide

To a toluene (1.5 mL) solution of 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-hydroxyethyl)-2-methoxybenzenesulfonamide (10 mg) obtained from Example 204, N, N-diisopropylethylamine (25 μL) and chloromethyl methyl ether (10 μL) were sequentially added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound.

Example 298

Synthesis of 4-chloro-N-((1S,2R)-2-(4-fluoro-4′-methoxy-2-methyl-[1,1′-biphenyl]-3-yl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

Step 1

Using (2S,3R)-2-amino-3-(3-bromo-6-fluoro-2-methylphenyl)butanoic acid (200 mg) obtained in Reference Example D5 and 4-chloro-2-methoxybenzenesulfonyl chloride (280 mg), according to the method of steps 1 and 2 of Example 1,N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (262 mg) was synthesized.

Step 2

To a 1,4-dioxane (1.0 mL) solution of N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (11 mg), 4-methoxyphenylboronic acid (5.0 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (4.0 mg), and a sodium carbonate aqueous solution (2 M, 100 μL) was added sequentially at room temperature, and the reaction solution was stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature, insoluble matter was removed by CELITE filtration, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Examples 299-324

Using N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide obtained from Example 298 Step 1, according to the method of Example 298, Step 2, compounds of Examples 299 to 324 shown below were synthesized. The boronic acids or boronic acid esters used are listed in the following table.

TABLE 19
Example	Reagent	Name of the Synthesized Compound
299		4-chloro-2-methoxy-N-((1S,2R)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2- (3′,4,5′-trifluoro-2-methyl-[1,1′-biphenyl]-3-yl)propyl)benzenesulfonamide
300		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(pyridin-3-yl)phenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
301		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1H-pyrazol-3-yl)phenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
302		4-chloro-N-((1S,2R)-2-(4′-chloro-4-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
303		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1H-pyrazol-4-yl)phenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzensulfonamide
304		4-chloro-N-((1S,2R)-2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
305		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-3-yl)phenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
306		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
307		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1H-methyl-1H-pyrazol-5-yl)phenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
308		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(3-methyl-1H-pyrazol-4-yl)phenyl)- 1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
309		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(2-phenyloxazol-5-yl)phenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
310		4-chloro-N-((1S,2R)-2-(3-(1-ethyl-1H-pyrazol-4-yl)-6-fluoro-2-methylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
311		4-chloro-N-((1S,2R)-2-(3-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
312		4-chloro-N-((1S,2R)-2-(3-(1-cyclobutyl-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
313		4-chloro-N-((1S,2R)-2-(3-(6-chloropyridin-3-yl)-6-fluoro-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
314		4-chloro-N-((1S,2R)-2-(6-fluoro-3-(6-methoxypyridin-3-yl)-2-methylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
315		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(6-morpholinopyridin-3-yl)phenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
316		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(3-(trifluoromethyl)-1H-pyrazol-4- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
317		4-chloro-N-((1S,2R)-2-(3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
318		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(pyrimidin-5-yl)phenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
319		4-chloro-N-((1S,2R)-2-(6-fluoro-3-(2-methoxypyrimidin-5-yl)-2-methylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide
320		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(6-(piperidin-1-yl)pyridin-3- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
321		4-chloro-N-((1S,2R)-2-(3-(5-chloro-6-methoxypyridin-3-yl)-6-fluoro-2- methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
322		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine-7-yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)-2-methoxybenzenesulfonamide
323		4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(5-(morpholine-4-carbonyl)pyridin-3- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2- methoxybenzenesulfonamide
324		5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzamide

Example 325

Synthesis of 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide

Step 1

From (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (200 mg) obtained from Reference Example D1 and 3-bromo-4-chlorobenzenesulfonyl chloride (306 mg), according to the method of Steps 1 and 2 of Example 1,3-bromo-4-chloro-N-((1 S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (274 mg) was synthesized.

Step 2

To a 1,4-dioxane (0.7 ml) solution of 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (5.6 mg) obtained from the above Step 1, (1-methyl-1H-pyrazol-4-yl)boronic acid (6.2 mg), [1,1′-bis(diphenylphosphino)ferrocene] palladium (II) dichloride dichloromethane adduct (5.0 mg), a sodium carbonate aqueous solution (2 M, 100 μL) were added sequentially at room temperature, and the reaction solution was stirred for 4 hours at 100° C. The reaction solution was allowed to cool to room temperature, insoluble matter was removed by CELITE filtration, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Example 326

Synthesis of 6-chloro-2′-fluoro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-[1,1′-biphenyl]-3-sulfonamide

Using 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide obtained from Example 325 Step 1 and (2-fluorophenyl)boronic acid, the title compound was synthesized according to the method of Example 325 Step 2.

Example 327

Synthesis of 4-chloro-N-((1S,2R)-2-(6-fluoro-2-methyl-3-(phenylethynyl)phenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide

To a DMF (1.0 mL) solution of N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (10.9 mg) obtained from Example 298 Step 1, dichlorobis (triphenylphosphine) palladium (II) (1.5 mg), copper (I) iodide (1.5 mg), triethylamine (30 μL) and ethynylbenzene (20 μL) were sequentially added at room temperature, the reaction solution was added at 100° C., and the mixture was stirred for 4 hours. The reaction solution was allowed to cool to room temperature, and insoluble matter was removed by CELITE filtration, and the residue was washed with hexane/ethyl acetate=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound.

Example 328

Synthesis of 4-amino-5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methylchroman-8-sulfonamide

To a benzene (1.5 ml) solution of 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchroman-8-sulfonamide (17 mg) obtained from Example 209A, trimethylsilylazide (50 μL), boron trifluoride-dimethylethercomplex (100 μL) were sequentially added, and the reaction solution was stirred for 1 hour at room temperature. To the reaction solution, a saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate/hexane=1/1 (10 mL). The organic layer was washed with saturated saline (10 mL), dried with anhydride sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in THF (1.5 ml) and water (50 μL). Triphenylphosphine (15 mg) was added to the residue, and the reaction solution was stirred for 2 hours at room temperature. Insoluble matter was removed by CELITE filtration, and the residue was washed with ethyl acetate/hexane=1/1 (10 mL). The combined filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water/acetonitrile) to give the title compound as a 1:1 diastereomeric mixture.

Example 329

Synthesis of 4-amino-N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-methyl-chroman-8-sulfonamide

The title compound was prepared using N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-5-chloro-4-hydroxy-4-methylchroman-8-sulfonamide obtained in Example 222A according to the method of example 328.

Example 330

Synthesis of 4-amino-5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3, 4-oxadiazol-2-yl)propyl)-4-methyl chroman-8-sulfonamide isomer A and isomer B

To a 1,4-dioxane solution (1.0 mL) of a diastereomeric mixture of 4-amino-5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methylchroman-8-sulfonamide (6.4 mg) obtained in Example 328, triethylamine (100 μL) and di-tert-butyl dicarbonate (54 mg) were added at room temperature, and the reaction solution was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was purified by reverse phase HPLC (water/acetonitrile), and the fractions were concentrated to give each of two diastereomeric products. The substance eluted first was designated Compound A, and the substance eluted later was designated as Compound B. The obtained Compounds A and B were each dissolved in hydrochloric acid-dioxane (4 M, 2.0 mL), and the reaction solution was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. The substance obtained from compound A was designated as compound 330A, and the substance obtained from compound B as compound 330B.

Example 331

Synthesis of 2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-4-(1,3,4-oxadiazol-2-yl)benzamide

Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (80 mg) obtained in Reference Example D1 and ethyl 3-(chlorosulfonyl)-4-cyanobenzoate (146 mg) obtained in Reference Example E13, according to the method of steps 1 and 2 of Example 1, ethyl 4-cyano-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (40 mg) was obtained.

Step 2

To a DMSO (1 mL) solution of ethyl 4-cyano-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (40 mg) obtained from the above Step 1, 30% hydrogen peroxide water (0.5 mL) and potassium carbonate (20 mg) were added, and the reaction solution was stirred at 70° C. for 1 hour. 1M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to give 4-carbamoyl-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid (8.9 mg).

Step 3

To a dichloromethane (1.5 mL) solution of 4-carbamoyl-3-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid (16 mg) obtained from the above Step 2, (isocyanoimino) triphenylphosphorane (36 mg) was added thereto, and the reaction solution was stirred at room temperature for 72 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reversed phase HPLC (water/acetonitrile) to obtain the title compound (1.1 mg).

Example 332

Synthesis of 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide

Step 1

(2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (300 mg) obtained from Reference Example D1 was dissolved in water (5.0 mL) and 1,4-dioxane (5.0 mL), triethylamine (570 μL) was added, and it was cooled to 0° C. 4-Bromo-2-cyanobenzene-1-sulfonyl chloride (362 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 45 minutes. The reaction solution was added to hydrochloric acid (1 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with saturated saline (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate/2% acetic acid) to give (2S,3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (465 mg).

Step 2

To a THF (1.5 mL) solution of (2S,3R)-2-(4-bromo-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (22 mg) obtained from the above Step 1, CDI (13 mg) was added, the reaction solution was stirred at room temperature for 30 minutes, then hydrazine⋅monohydrate (12 μL) was added and the mixture was stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (1.2 mL), carbon disulfide (10 μL) and potassium hydroxide (10 mg) were sequentially added, and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was added to hydrochloric acid (1 M, 10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline(10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Examples 333 to 335

According to the method of Example 332 steps 1 and 2, the compounds of Examples 333 to 335 shown below were synthesized. The raw materials are listed in the following table.

TABLE 20
Example	Starting Material	ArSO2Cl	Name of the Synthesized Compound
333	Reference Example D10		methyl 2,6-dichloro-3-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4- yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzoate
334	Reference Example D10		methyl 2-chloro-5-(N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1- (5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzoate
335	Reference Example D26		4-bromo-N-((1S,2R)-2-(5,5-dimethyl-5,6,7,8- tetrahydronaphthalen-1-yl)-1-(5-thioxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)propyl)benzenesulfonamide

Example 336

Synthesis of 4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(2-hydroxypropan-2-yl)benzenesulfonamide

Step 1

Using (2S,3R)-2-amino-3-(2,3-dihydro-1H-inden-4-yl)butanoic acid (20 mg) and 3-acetyl-4-chlorobenzene-1-sulfonyl chloride (20 mg) obtained in Reference Example D10, according to the method of Example 332 steps 1 and 2, 3-acetyl-4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (12 mg) was obtained.

Step 2

From 3-acetyl-4-chloro-N-((1S,2R)-2-(2,3-dihydro-1H-inden-4-yl)-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide (12 mg) obtained from the above Step 1, the title compound was obtained according to the method of Example 186 Step 2.

Example 337

Synthesis of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4 oxadiazol-2-yl)propyl)-N-methylsulfamoyl)benzamide

Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (530 mg) obtained from Reference Example D1 and 4-chloro-2-cyanobenzene-1-sulfonyl chloride (660 mg), according to the method of Example 1 Step 1, (2S,3R)-2-(4-chloro-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (777 mg) was obtained.

Step 2

To a THF (500 μL) solution of (2S,3R)-2-(4-chloro-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (11 mg) obtained from the above Step 1, CDI (15 mg) was added, and the reaction solution was stirred for 1 hour at room temperature. Methanol (1.0 mL) was added to the reaction solution, and the mixture was further stirred for 16 hours. The reaction solution was added to water (10 mL) and extracted with diethyl ether (15 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl (2S,3R)-2-(4-chloro-2-cyanophenyl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (12 mg).

Step 3

To methyl (2S,3R)-2-(4-chloro-2-cyanophenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (100 mg) obtained from the above Step 2, Methanol (2 mL), dichloromethane (2 mL), and a hexane solution of trimethylsilyl diazomethane (0.6 M, 800 μL) were sequentially added, and the reaction solution was stirred at room temperature for 1 hour. By concentrating the reaction solution under reduced pressure, methyl (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (101 mg) was obtained.

Step 4

Methyl (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (101 mg) obtained from the Step 3 above, according to the method of Example 245 Step 2, (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (8.5 mg) was obtained.

Step 5

To (2S,3R)-2-(4-chloro-2-cyano-N-methylphenylsulfonamide)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (8.5 mg) obtained from the above Step 4, according to the method of Example 1 Step 2, 4-chloro-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-N-methylbenzenesulfonamide (6.0 mg) was obtained.

Step 6

From 4-chloro-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-N-methylbenzenesulfonamide (6.0 mg) obtained from the above Step 5, according to the method of Example 1 Step 3, the title compound was obtained.

Example 344

Synthesis of 6-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4′-methoxy-[1,1′-biphenyl]-3-sulfonamide

Using 3-bromo-4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide and (4-methoxyphenyl)boronic acid obtained from Example 325 step 1, the title compound was synthesized according to the method of Example 325 Step 2.

Example 345

Synthesis of 3-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-2′-methoxy-[1,1′-biphenyl]-4-carboxamide

Step 1

From (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid obtained from Reference Example D1 and 5-bromo-2-cyanobenzenesulfonyl chloride, according to the method of steps 1 and 2 of Example 1, 5-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide was synthesized.

Step 2

Using 5-bromo-2-cyano-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide obtained from the above Step 1 and 2-methoxyphenylboronic acid, according to the method of Example 325 Step 2 and Example Step 3, the title compound was obtained.

Example 346

Synthesis of 4-(N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2 yl)propyl)sulfamoyl)-3-methoxybenzamide

From 4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide obtained in Example 342, the title compound was obtained according to the method of Example 1 Step 3.

Example 347

Synthesis of 4-(N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2 yl)propyl)sulfamoyl)benzamide

From 4-cyano-N-((1S,2R)-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzenesulfonamide obtained in Example 341, according to the method of Example 1 Step 3, the title compound was obtained.

Example 348

Synthesis of 4-bromo-N-((1S,2R)-2-(naphthalen-1-yl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)benzenesulfonamide

Step 1

Using (2S,3R)-2-amino-3-(naphthalen-1-yl)butanoic acid obtained in Reference Example D11 and 4-bromobenzenesulfonyl chloride, according to the method of Step 1 of Example 1, (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanoic acid was obtained.

Step 2

To a DMF (2.5 mL) solution of (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanoic acid (283 mg) obtained from the above Step 1, ammonium chloride (41 mg), HOBt (103 mg), triethylamine (0.264 mL) and WSC (146 mg) were added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanamide as a crude product.

Step 3

To a DMF (2 mL) solution of (2S,3R)-2-((4-bromophenyl)sulfonamido)-3-(naphthalen-1-yl)butanamide obtained from the above Step 2, cyanuric chloride (59 mg) was added at 0° C., and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added to water and extracted with a mixed solvent of ethyl acetate/toluene. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 4-bromo-N-((1S,2R)-1-cyano-2-(naphthalen-1-yl)propyl)benzene sulfonamide (137 mg).

Step 4

To an ethanol (2 mL) solution of 4-bromo-N-((1S,2R)-1-cyano-2-(naphthalen-1-yl)propyl)benzenesulfonamide (137 mg) obtained from the above Step 3, water (0.66 mL) and a 50% aqueous solution of hydroxylamine (0.060 mL) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2S,3R)-2-((4-bromophenyl)sulfonamido)-N-hydroxy-(3-naphthalen-1-yl)butanamide (130 mg) as a crude product.

Step 5

To a DMF (1.0 mL) solution of (2S,3R)-2-((4-bromophenyl)sulfonamido)-N-hydroxy-3-(naphthalen-1-yl)butanamide (20 mg) obtained from the above Step 4, Pyridine (0.004 mL) and 2-ethylhexyl chloroformate (0.009 mL) were added, and the reaction solution was stirred at room temperature for 1 hour. Further, xylene was added, and the reaction solution was stirred overnight at 100° C. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate/hexane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound (37 mg).

Example 349

Synthesis of 4-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-2-methoxybenzenesulfonamide

Step 1

Using (2S,3R)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid obtained in Reference Example D1 and 4-chloro-2-methoxybenzenesulfonyl chloride, according to the method of Example 1 Step 1, (2S,3R)-2-((4-chloro-2-methoxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid was obtained.

Step 2

From (2S,3R)-2-((4-chloro-2-methoxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid obtained from the above Step 1, the titled compound was obtained according to the method of Example 348 Step 2 to Step 5.

Example 350

(2S,3R)-2-((4-chloro-2-methoxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (142 mg) obtained from Example 348 Step 1 was dissolved in a DMF (3.3 mL), and WSC (130 mg), HOBt (100 mg), N, N-diisopropylethylamine (200 μL) and thiosemicarbazide (70 mg) were sequentially added, and the reaction solution was stirred at 80° C. for 4 hours. The reaction solution was added to a saturated aqueous solution of ammonium chloride (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated saline (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate). The obtained residue was dissolved in ethanol (1.5 mL), a 20% aqueous sodium hydroxide solution (2.0 mL) was added, and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was added to hydrochloric acid (1 M, 5.0 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated saline (5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound.

Hereinafter, the structural formulas and physical properties of Example Compounds 1 to 350 are shown.

TABLE 21
Ex-
am-
ple	Structural Formula	Physical Property Value
1		1H NMR (CD3OD) δ: 7.74-7.78 (m, 3H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.78-4.81 (m, 1H), 3.51-3.61 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 525, 527
2		1H NMR (CD3OD) δ: 8.20 (1H, d, J = 8.1 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.03-7.00 (1H, m), 6.98-6.96 (2H, m), 4.63-4.61 (1H, m), 3.40-3.36 (1H, m), 2.91-2.82 (4H, m), 2.03-1.99 (2H, m), 1.41 (3H, d, J = 7.0 Hz); LC/MS RT 1.66 min, m/z [M − H]− 476, 478
3		1H NMR (CD3OD) δ: 7.77 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H), 7.03 (dd, J = 7.0, 2.2 Hz, 1H), 6.90-6.99 (m, 2H), 4.53 (d, J = 9.5 Hz, 1H), 3.52-3.61 (m, 1H), 2.20 (s, 3H), 2.18 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.63 min, m/z [M − H]− 463, 465
4		1H NMR (CD3OD) δ: 7.74 (s, 1H), 7.67-7.69 (m, 2H), 7.01-7.07 (m, J = 6.2 Hz, 1H), 6.91-6.99 (m, 2H), 4.54 (d, J = 9.5 Hz, 1H), 3.51-3.65 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 507, 509
5		1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (dd, J = 8.2, 5.7 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.82 (d, J = 11.4 Hz, 1H), 3.50-3.60 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 481, 483
6		1H NMR (CD3OD) δ: 8.11 (d, J = 8.8 Hz, 1H), 7.76-7.89 (m, 3H), 7.62 (d, J = 2.2 Hz, 1H), 7.51-7.59 (m, 2H), 7.40-7.47 (m, 1H), 7.22 (dd, J = 11.5, 9.0 Hz, 1H), 4.90-4.98 (m, 1H), 4.09-4.18 (m, 1H), 1.60 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 503, 505
7		1H NMR (CD3OD) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H), 6.80 (dd, J = 10.4, 2.7 Hz, 1H), 6.69 (dd, J = 9.2, 2.7 Hz, 1H), 4.55 (d, J = 8.8 Hz, 1H), 3.53-3.65 (m, 1H), 2.21 (s, 3H), 2.15 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 481, 483
8		1H NMR (CD3ODδ: 7.62-7.79 (m, 2H), 7.46-7.52 (m, 2H), 7.38-7.45 (m, 2H), 7.29-7.35 (m, 1H), 7.20-7.28 (m, 2H), 4.82-4.86 (m, 1H), 4.44-4.62 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]− 503, 505
9		1H NMR (CD3OD δ: 8.01-8.11 (m, 1H), 7.75-7.85 (m, 1H), 7.43-7.59 (m, 4H), 7.22-7.38 (m, 3H), 4.78 (d, J = 7.3 Hz, 1H), 4.20 (t, J = 7.0 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 503, 505
10		1H-NMR (CDCl3) δ: 7.85 (1H, d, J = 7.7 Hz), 7.67 (1H, s), 7.36-7.33 (1H, m), 6.92-6.88 (2H, m), 6.69 (1H, dd, J = 11.7, 8.4 Hz), 6.00 (1H, s), 5.87 (1H, s), 4.89 (1H, t, J = 10.1 Hz), 3.45 (1H, s), 2.42 (3H, s), 2.17-2.15 (6H, m), 1.44 (3H, d, J = 6.6 Hz); LC/MS RT 1.59 min, m/z [M − H]− 461
11		1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.75 (dd, J = 11.7, 8.8 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 3.50-3.60 (m, 1H), 2.52-2.59 (m, 2H), 2.24 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H),; LC/MS RT 1.73 min, m/z [M − H]− 495, 4.97
12		1H NMR (CD3OD) δ: 8.10 (br d, J = 8.8 Hz, 1H), 7.76-7.84 (m, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.39-7.45 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 11.4, 9.2 Hz, 1H), 4.91 (d, J = 11.7 Hz, 1H), 4.07-4.21 (m, 1H), 2.39 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 483
13		1H NMR (CD3OD) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.57-7.61 (m, 1H), 6.91 (dd, J = 11.0, 8.4 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 3.55-3.66 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]− 499, 501
14		1H NMR (CD3OD) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (dd, J = 8.8, 5.1 Hz, 1H), 6.88 (t, J = 10.0 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.55-3.65 (m, 1H), 2.37 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]− 501, 503
15		1H NMR (CD3OD) δ: 8.11 (d, J = 8.8 Hz, 1H), 7.69-7.92 (m, 5H), 7.54 (br t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.21 (dd, J = 11.4, 9.2 Hz, 1H), 4.89-5.01 (m, 1H), 4.10-4.24 (m, 1H), 1.60 (br d, J = 6.6 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]− 547, 549
16		1H NMR (CD3OD) δ: 7.69 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.2, 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 12.1, 8.4 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 3.46-3.60 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.95-2.04 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.06 (dd, J = 8.4, 1.8 Hz, 2H), 0.72-0.90 (m, 2H); LC/MS RT 1.67 min, m/z [M − H]− 487
17		1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.53-7.66 (m, 2H), 7.12-7.22 (m, 1H), 6.89-7.03 (m, 1H), 4.71-4.82 (m, 1H), 3.86-4.04 (m, 1H), 2.28 (s, 3H), 1.47 (br d, J = 6.2 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 501, 503
18		1H NMR (CD3OD) δ: 7.74 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.37 (dd, J = 8.2, 1.6 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 3.47-3.63 (m, 1H), 2.71 (q, J = 7.7 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.21-1.28 (m, 3H); LC/MS RT 1.66 min, m/z [M − H]− 475
19		1H NMR (CD3OD) δ: 8.32 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 4.84 (d, J = 11.4 Hz, 1H), 3.55-3.68 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 482, 484
20		1H NMR (CD3OD) δ: 7.87 (d, J = 7.6 Hz, 1H), 7.53-7.70 (m, 3H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.50-3.52 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.54 min, m/z [M − H]− 447
21		1H NMR (CD3OD) δ: 7.76 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.52-7.55 (m, 1H), 6.96-7.05 (m, 2H), 6.83 (s, 1H), 4.59 (d, J = 9.5 Hz, 1H), 3.37-3.44 (m, 1H), 2.22 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.60 min, m/z [M − H]− 467, 469
22		LC/MS RT 1.6 min, m/z [M − H]− 467, 469
23		1H NMR (CD3OD) δ: 7.73 (d, J = 8.4 Hz, 1H), 7.52-7.59 (m, 2H), 7.07 (td, J = 7.9, 5.5 Hz, 1H), 6.90-6.97 (m, 1H), 6.66-6.77 (m, 1H), 4.77 (d, J = 11.4 Hz, 1H), 3.43-3.59 (m, 1H), 2.38 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]− 467, 469
24		1H NMR (cdcl3) δ: 7.73 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.0--7.16 (m, 4H), 4.56 (dd, J = 15.8, 7.7 Hz, 1H), 3.37-3.62 (m, 1H), 2.29 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]− 449, 451
25		1H NMR (CD3OD δ: 7.74-7.79 (m, 3H), 7.25 (dd, J = 8.9, 5.0 Hz, 1H), 6.85-6.94 (m, 1H), 4.77-4.83 (m, 1H), 3.55-3.65 (m, 1H), 2.37 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]− 545, 547
26		1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 6.94 (dd, J = 8.5, 5.9 Hz, 1H), 6.73 (dd, J = 11.9, 8.5 Hz, 1H), 4.77 (d, J = 11.4 Hz, 1H), 3.50-3.65 (m, 1H), 2.39 (s, 3H), 1.73-1.83 (m, 1H), 1.46 (d, J = 7.0 Hz, 3H), 0.80-0.98 (m, 2H), 0.37-0.55 (m, 2H); LC/MS RT 1.76 min, m/z [M − H]− 507, 509
27		1H-NMR (CDCl3) δ: 8.26 (1H, br s), 7.94 (1H, d, J = 8.1 Hz), 7.55-7.47 (3H, m), 6.90 (2H, t, J = 9.7 Hz), 6.19-6.14 (1H, m), 4.90 (1H, t, J = 10.1 Hz), 3.56 (1H, br s), 2.39 (3H, s), 1.48 (3H, d, J = 7.0 Hz), 1.24 (1H, s).; LC/MS RT 1.73 min, m/z [M − H]− 535, 537
28		1H NMR (CD3OD) δ: 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.4, 2.2 Hz, 1H), 6.83-6.95 (m, 2H), 4.78 (d, J = 11.0 Hz, 1H), 3.45-3.56 (m, 1H), 2.20 (d, J = 2.2 Hz, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.60 min, m/z [M − H]− 485, 487
29		1H-NMR (CDCl3) δ: 8.88 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.24-7.21 (1H, m),7.03-7.01 (1H, m), 6.94-6.93 (1H, m), 6.84 (1H, dd, J = 11.4, 8.4 Hz), 6.02-5.95 (2H, m), 5.89 (1H, s), 4.80 (1H, t, J = 10.8 Hz), 3.93 (3H, s), 3.46 (1H, s), 2.35 (3H, s), 1.49 (3H, d, J = 5.9 Hz).; LC/MS RT 1.38 min, m/z [M − H]− 497, 499
30		1H NMR (CD3OD) δ: 7.85 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.57-7.61 (m, 1H), 7.44 (dd, J = 8.8, 5.1 Hz, 1H), 6.80-6.86 (m, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.55-3.65 (m, 1H), 2.43 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]− 545, 547
31		1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.6, 5.3 Hz, 1H), 6.65-6.80 (m, 1H), 4.83-4.91 (m, 1H), 3.55-3.65 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.3 Hz, 3H); LC/MS RT 1.52 min, m/z [M − H]− 482, 484
32		1H NMR (CD3OD) δ: 7.67 (1H, d, J = 8.8 Hz), 7.54-7.52 (2H, m), 6.95-6.92 (1H, m), 6.59-6.53 (1H, m), 4.79 (1H, d, J = 11.0 Hz), 3.56-3.54 (1H, m), 2.24 (3H, s), 2.19 (3H, s), 1.15 (3H, d, J = 7.0 Hz); LC/MS RT 1.66 min, m/z [M − H]− 481, 483
33		1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.53-7.70 (m, 2H), 6.98 (dd, J = 8.2, 5.7 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 3.48-3.61 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 481, 483
34		1H NMR (CD3OD) δ: 7.68 (dd, J = 7.9, 0.9 Hz, 1H), 7.51-7.58 (m, 2H), 6.94 (dd, J = 8.2, 6.0 Hz, 1H), 6.52-6.66 (m, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.51-3.68 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.16 (d, J = 6.6 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 481, 483
35		1H NMR (CD3OD) δ: 7.77 (s, 3H), 7.41-7.51 (m, 1H), 6.72-6.91 (m, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.52-3.73 (m, 1H), 2.43 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.73 min, m/z [M − H]− 589, 591
36		1H-NMR (CDCl3) δ: 9.73 (1H, br s), 7.87 (1H, s), 7.64-7.56 (2H, m), 7.06-7.04 (1H, m), 6.91 (1H, dd, J = 8.2, 5.7 Hz), 6.70-6.65 (2H, m), 6.47 (1H, s), 4.87 (1H, t, J = 10.6 Hz), 3.78-3.76 (4H, m), 3.64-3.62 (2H, m), 3.48-3.46 (1H, m), 3.41-3.39 (2H, m), 2.16-2.14 (6H, m), 1.46 (3H, d, J = 6.6 Hz).; LC/MS RT 1.50 min, m/z [M − H]− 560
37		1H-NMR (CDCl3) δ: 7.86 (1H, s), 7.65-7.55 (2H, m), 7.06-7.03 (1H, m), 6.93-6.89 (1H, m), 6.71-6.66 (1H, m), 6.14 (1H, s), 6.03 (1H, s), 4.96 (1H, t, J = 10.3 Hz), 3.43-3.41 (1H, m), 3.11 (3H, s), 2.94 (3H, s), 2.15 (6H, s), 1.51 (3H, d, J = 7.0 Hz); LC/MS RT 1.51 min, m/z [M − H]− 518
38		1H NMR (CD3OD) δ: 8.18 (1H, s), 7.67 (1H, s), 6.96 (1H, dd, J = 8.4, 5.9 Hz), 6.71 (1H, dd, J = 11.7, 8.4 Hz), 4.81 (1H, d, J = 11.0 Hz), 3.56 (1H, s), 3.33 (1H, s), 2.20 (3H, s), 2.16 (3H, s), 1.45 (3H, d, J = 6.6 Hz).; LC/MS RT 1.46 min, m/z [M − H]− 552, 527
39		1H NMR (CD3OD) δ: 7.88 (1H, s), 7.72 (1H, s), 6.99-6.94 (1H, m), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 4.77 (1H, d, J = 11.0 Hz), 3.58 (1H, s), 3.13 (3H, s), 2.90 (3H, s), 2.22 (3H, s), 2.17 (3H, s), 1.44-1.42 (3H, m); LC/MS RT 1.58 min, m/z [M − H]− 552, 5554
40		1H NMR (CD3OD) δ: 8.76 (s, 1H), 7.62 (s, 1H), 6.98 (dd, J = 8.2, 6.0 Hz, 1H), 6.73 (dd, J = 11.9, 8.6 Hz, 1H), 4.83-4.86 (m, 1H), 3.51-3.73 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 482, 484
41		1H NMR (CD3OD) δ: 8.06 (d, J = 9.2 Hz, 1H), 7.87-7.91 (m, 2H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.72 (dd, J = 11.7, 8.3 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 3.49-3.66 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 515
42		1H NMR (CD3OD) δ: 8.08 (d, J = 8.1 Hz, 1H), 7.88-7.94 (m, 2H), 7.44 (dd, J = 8.8, 5.1 Hz, 1H), 6.82 (dd, J = 11.4, 8.8 Hz, 1H), 4.79-4.85 (m, 1H), 3.56-3.71 (m, 1H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]− 579, 581
43		1H NMR (CD3OD) δ: 7.84 (d, J = 8.4 Hz, 1H), 7.55-7.65 (m, 2H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.54 (br d, J = 11.4 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H); LC/MS RT 1.64 min, m/z [M − H]− 484, 486
44		1H NMR (CD3OD) δ: 8.01 (d, J = 8.4 Hz, 1H), 7.78-7.86 (m, 1H), 7.71 (dd, J = 8.6, 2.0 Hz, 1H), 7.50 (s, 4H), 7.37-7.47 (m, 3H), 7.09-7.25 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.05-4.23 (m, 1H), 1.54 (d, J = 6.6 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 486, 488
45		1H NMR (CD3OD) δ: 7.76-7.85 (m, 1H), 7.65-7.74 (m, 2H), 7.54 (s, 2H), 7.51 (d, J = 5.5 Hz, 1H), 7.34 (d, J = 5.5 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.14-7.23 (m, 1H), 4.67 (d, J = 9.5 Hz, 1H), 3.44-3.58 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]− 492, 494
46		LC/MS RT 1.89 min, m/z [M − H]− 476, 478
47		1H NMR (CD3OD) δ: 7.83 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 6.90-7.00 (m, 2H), 6.83 (d, J = 7.0 Hz, 1H), 4.29 (d, J = 10.6 Hz, 1H), 3.54-3.63 (m, 1H), 2.59-2.83 (m, 4H), 1.90-1.98 (m, 1H), 1.61-1.82 (m, 4H), 1.37 (d, J = 7.0 Hz, 3H), 1.03-1.12 (m, 2H), 0.76-0.87 (m, 2H); LC/MS RT 1.97 min, m/z [M − H]− 486
48		1H NMR (CD3OD) δ: 8.58-8.67 (m, 1H), 8.08-8.34 (m, 1H), 7.78-7.96 (m, 1H), 6.89-7.18 (m, 3H), 4.72 (d, J = 10.3 Hz, 0.5H), 4.41 (d, J = 11.0 Hz, 0.5H), 3.36-3.50 (m, 2H), 2.93-3.10 (m, 1H), 2.70 (dt, J = 15.9, 8.2 Hz, 1H), 1.98-2.27 (m, 1H), 1.67-1.85 (m, 1H), 1.46 (d, J = 6.6 Hz, 1.5H), 1.35 (d, J = 6.6 Hz, 1.5H), 1.15 (d, J = 7.0 Hz, 1.5H), 1.10 (d, J = 7.0 Hz, 1.5H); LC/MS RT 1.79 min, m/z [M − H]− 491, 493
49		1H NMR (CD3OD) δ: 8.53 (dd, J = 2.2, 0.7 Hz, 1H), 8.11 (dd, J = 8.2, 2.4 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.26-7.41 (m, 4H), 7.16 (d, J = 7.7 Hz, 1H), 4.68 (d, J = 9.9 Hz, 1H), 3.87 (s, 2H), 3.49-3.61 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.83 min, m/z [M − H]− 525, 527
50		1H NMR (CD3OD) δ: 8.44 (d, J = 2.2 Hz, 1H), 8.02-8.09 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.09-7.46 (m, 5H), 4.83-4.85 (m, 1H), 4.30-4.442 (m, 1H), 3.65 (s, 2H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 525, 527
51		1H NMR (CD3OD) δ: 8.07-8.19 (m, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 3H), 7.63-7.70 (m, 1H), 7.47-7.54 (m, 1H), 7.34-7.45 (m, 3H), 4.63 (d, J = 8.1 Hz, 1H), 4.06-4.21 (m, 1H), 1.54 (d, J = 7.0 Hz, 3H); LC/MS RT 1.73 min, m/z [M − H]− 453
52		1H NMR (CD3OD) δ: 8.52 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 8.4, 2.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 4.8 Hz, 2H), 6.83-6.91 (m, 1H), 4.50 (d, J = 10.3 Hz, 1H), 3.51-3.61 (m, 1H), 2.55-2.96 (m, 4H), 1.54-1.91 (m, 4H), 1.36 (d, J = 6.6 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 447, 449
53		1H NMR (CD3OD) δ: 7.94 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.4, 2.2 Hz, 1H), 6.99-7.02 (m, 1H), 6.91-6.97 (m, 1H), 6.84 (d, J = 7.3 Hz, 1H), 4.54 (d, J = 9.5 Hz, 1H), 3.58-3.69 (m, 4H), 2.63-2.85 (m, 4H), 1.64-1.88 (m, 4H), 1.32 (d, J = 6.6 Hz, 3H); LC/MS RT 1.92 min, m/z [M − H]− 520, 522
54		LC/MS RT 1.94 min, m/z [M − H]− 491, 493
55		1H NMR (CD3OD) δ: 7.66 (d, J = 8.7 Hz, 1H), 6.93-7.00 (m, 2H), 6.83 (d, J = 7.0 Hz, 1H), 6.51-6.56 (m, 2H), 4.25 (d, J = 11.0 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.47-3.61 (m, 1H), 2.60-2.79 (m, 4H), 1.59-1.85 (m, 4H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 472
56		1H NMR (CD3OD) δ: 8.13 (dd, J = 9.5, 5.5 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.37-7.53 (m, 3H), 7.30 (td, J = 8.8, 2.6 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.4, 1.8 Hz, 1H), 4.48 (d, J = 10.3 Hz, 1H), 4.11-4.21 (m, 1H), 3.94 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]− 490, 492
57		1H NMR (CD3OD) δ: 8.00 (d, J = 8.4 Hz, 1H), 7.83-7.91 (m, 2H), 6.91-7.02 (m, 2H), 6.78-6.86 (m, 1H), 4.36 (d, J = 10.6 Hz, 1H), 4.05 (s, 3H), 3.53-3.63 (m, 1H), 2.59-2.87 (m, 4H), 1.62-1.87 (m, 4H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.83 min, m/z [M − H]− 487, 489
58		1H NMR (CD3DO) δ: 8.28-8.34 (m, 1H), 6.92-7.00 (m, 2H), 6.80-6.89 (m, 1H), 4.43 (d, J = 10.6 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.47-3.60 (m, 1H), 2.60-2.85 (m, 4H), 1.60-1.87 (m, 4H), 1.33 (d, J = 6.6 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]− 506
59		1H NMR (CD3OD) δ: 8.12-8.30 (m, 2H), 7.74 (dd, J = 8.8, 7.3 Hz, 1H), 6.72-7.02 (m, 3H), 4.52 (d, J = 10.3 Hz, 1H), 3.30-3.40 (m, 1H), 2.68-2.92 (m, 4H), 1.88-2.01 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]− 456
60		1H NMR (cdcl3) δ: 7.60 (t, J = 8.1 Hz, 1H), 7.31-7.37 (m, 1H), 7.20-7.26 (m, 1H), 7.06-7.10 (m, 1H), 7.01-7.06 (m, 1H), 6.88 (d, J = 7.3 Hz, 1H), 5.46 (br s, 1H), 4.52 (br t, J = 7.9 Hz, 1H), 3.29-3.41 (m, 1H), 2.70-2.90 (m, 4H), 1.95-2.07 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.87 min, m/z [M − H]− 494, 496
61		1H NMR (cdcl3) δ: 7.62-7.69 (m, 1H), 7.52-7.59 (m, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.03 (s, 2H), 6.86-6.92 (m, 1H), 5.46 (br s, 1H), 4.54 (br t, J = 8.1 Hz, 1H), 3.30-3.46 (m, 1H), 2.72-2.91 (m, 4H), 1.96-2.09 (m, 2H), 1.37-1.42 (m, 1H), 1.40 (d, J = 7.0 Hz, 2H); LC/MS RT 1.82 min, m/z [M − H]− 450, 452
62		1H NMR (CD3OD) δ: 7.79-7.87 (m, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.27-7.36 (m, 2H), 7.07 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 8.4, 2.2 Hz, 1H), 4.46 (d, J = 9.9 Hz, 1H), 3.93 (s, 3H), 3.70-3.78 (m, 1H), 1.59 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 478, 480
63		1H NMR (CD3OD) δ: 9.16 (1H, s), 7.91-7.88 (1H, m), 7.66 (1H, d, J = 8.4 Hz), 7.39-7.31 (2H, m), 7.07-7.07 (1H, m), 6.99-6.97 (1H, m), 3.95 (3H, s), 3.49-3.48 (1H, m), 3.15-3.13 (1H, m), 1.66 (3H, d, J = 7.0 Hz); LC/MS RT 1.62 min, m/z [M − H]− 479, 481
64		1H NMR (CD3OD) δ: 7.70 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.08-7.11 (m, 1H), 6.99-7.04 (m, 1H), 6.80 (d, J = 7.0 Hz, 1H), 6.61-6.73 (m, 1H), 4.55 (d, J = 10.6 Hz, 1H), 4.44-4.51 (m, 2H), 3.94 (s, 3H), 3.19-3.28 (m, 1H), 3.09 (t, J = 8.6 Hz, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]− 464, 466
65		1H NMR (CD3OD) δ: 8.07-8.21 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.44-7.53 (m, 1H), 7.31-7.42 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.96-7.06 (m, 1H), 5.16 (d, J = 11.7 Hz, 1H), 4.07-4.15 (m, 1H), 3.95 (s, 3H), 2.49 (s, 3H), 1.77 (d, J = 7.3 Hz, 2.3H), 1.66 (d, J = 7.3 Hz, 0.7H); LC/MS RT 1.82 min, m/z [M − H]− 486, 488
66		1H NMR (CD3OD) δ: 7.67-7.77 (m, 1H), 7.10-7.15 (m, 1H), 7.01-7.05 (m, 1H), 6.97-7.01 (m, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 4.36-4.56 (m, 2H), 4.30 (d, J = 11.4 Hz, 1H), 3.94 (s, 3H), 3.21-3.29 (m, 1H), 3.13 (t, J = 8.6 Hz, 2H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]− 464, 466
67		1H NMR (CD3OD) δ: 7.71 (dd, J = 8.4, 0.7 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 2H), 6.91-6.99 (m, 2H), 4.29 (dd, J = 11.2, 1.6 Hz, 1H), 3.94 (s, 3H), 3.30-3.36 (m, 1H), 2.91-3.16 (m, 2H), 2.28-2.55 (m, 3H), 1.44 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 6.4 Hz, 1.5H), 1.0 (d, J = 6.4 Hz, 1.5H); LC/ MS RT 1.89 min, m/z [M − H]− 476, 478
68		1H NMR (CD3OD) δ: 8.62 (d, J = 8.8 Hz, 1H), 8.19 (dd, J = 7.3, 1.1 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.64-7.71 (m, 1H), 7.56-7.62 (m, 1H), 7.48-7.56 (m, 1H), 6.92 (d, J = 4.8 Hz, 2H), 6.83 (d, J = 4.4 Hz, 1H), 4.20 (d, J = 10.6 Hz, 1H), 3.20-3.30 (m, 1H), 2.68-2.83 (m, 4H), 1.83-1.89 (m, 2H), 1.33 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 448
69		LC/MS RT 1.86 min, m/z [M − H]− 476, 478
70		1H NMR (CD3OD) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.26-7.43 (m, 3H), 7.09-7.21 (m, 5H), 7.04 (dd, J = 8.4, 1.8 Hz, 1H), 6.96 (dd, J = 7.1, 1.6 Hz, 1H), 4.37 (d, J = 10.6 Hz, 1H), 3.95 (s, 3H), 3.61-3.68 (m, 1H), 2.13 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.93 min, m/z [M − H]− 512, 514
71		1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.59-7.62 (m, 1H), 7.46 (d, J = 6.2 Hz, 1H), 7.31-7.37 (m, 1H), 7.21-7.29 (m, 2H), 7.06 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.4, 1.8 Hz, 1H), 4.61-4.74 (m, 1H), 4.37 (d, J = 10.6 Hz, 1H), 3.90 (s, 3H), 2.96 (s, 3H), 1.67 (d, J = 7.0 Hz, 3H); LC/MS RT 1.81 min, m/z [M − H]− 486, 488
72		1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.01-7.09 (m, 2H), 6.71 (d, J = 7.7 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 4.28-4.33 (m, 1H), 4.23 (d, J = 11.0 Hz, 1H), 4.07-4.15 (m, 1H), 3.94 (s, 3H), 3.41-3.50 (m, 1H), 3.33-3.39 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]− 478, 480
73		1H NMR (CD3OD) δ: 7.76 (d, J = 8.4 Hz, 1H), 7.10-7.14 (m, 1H), 6.97-7.09 (m, 2H), 6.62-6.67 (m, 1H), 6.51-6.62 (m, 1H), 4.50-4.57 (m, 1H), 4.38-4.48 (m, 1H), 4.11-4.16 (m, 1H), 3.94 (s, 3H), 3.33-3.46 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H), 1.20-1.24 (m, 3H); LC/MS RT 1.66 min, m/z [M − H]− 478, 480
74		1H NMR (CD3OD) δ: 7.71 (d, J = 8.4 Hz, 1H), 6.98-7.17 (m, 5H), 4.54 (d, J = 11.0 Hz, 0.34H), (d, J = 11.0 Hz, 0.68H), 3.95 (s, 1H), 3.85 (s, 2H), 3.48-3.59 (m, 1H), 1.51 (d, J = 7.0 Hz, 2H), 1.17 (d, J = 7.0 Hz, 1H),; LC/MS RT 1.67 min, m/z [M − H]− 458, 460
75		1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.08-7014 (m, 2H), 6.95-7.06 (m, 1H), 6.95-7.06 (m, 1H), 6.84 (t, J = 9.0 Hz, 1H), 4.34 (d, J = 11.0 Hz, 1H), 3.94 (s, 3H), 3.52-3.63 (m, 1H), 2.17 (d, J = 2.2 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]− 454, 456
76		LC/MS RT 1.78 min, m/z [M − H]− 490, 492
77		1H NMR (CD3OD) δ: 7.71 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.94-7.06 (m, 2H), 6.73-6.86 (m, 1H), 4.30 (d, J = 10.6 Hz, 1H), 3.94 (s, 3H), 3.54-3.64 (m, 1H), 2.20 (s, 3H), 2.10 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]− 468, 470
78		1H NMR (CD3OD) δ: 7.68 (d, J = 7.3 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.28-7.37 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.09-7.15 (m, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 8.4, 1.8 Hz, 1H), 4.39 (dd, J = 9.0, 6.4 Hz, 1H), 3.89-3.99 (m, 1H), 3.88 (s, 3H), 3.62-3.69 (m, 1H), 2.89 (s, 3H); LC/MS RT 1.80 min, m/z [M − H]− 472, 474
79		1H NMR (CD3OD) δ: 7.73 (d, J = 8.4 Hz, 0.5H), 7.66 (d, J = 8.4 Hz, 0.5H), 6.98-7.17 (m, 3H), 6.75 (t, J = 9.3 Hz, 1H), 4.66 (d, J = 11.0 Hz, 0.5H), 4.57 (d, J = 11.4 Hz, 0.5H), 3.95 (s, 1.5H), 3.82 (s, 1.5H), 3.61-3.78 (m, 1H), 2.15 (s, 3H), 1.52 (d, J = 7.0 Hz, 1.5H), 1.15 (d, J = 7.0 Hz, 1.5H); LC/MS RT 1.76 min, m/z [M − H]− 472, 474
80		1H NMR (CD3OD) δ: 7.61-7.80 (m, 1H), 6.76-7.19 (m, 5H), 4.55 (d, J = 11.0 Hz, 0.33H), 4.40 (d, J = 11.0 Hz, 0.67H), 3.94 (s, 2H), 3.80 (s, 1H), 3.39-3.49 (m, 1H), 2.15-2.20 (m, 3H), 1.48 (d, J = 7.0 Hz, 2H), 1.14 (d, J = 7.0 Hz, 1H); LC/MS RT 1.73, 1.76 min, m/z [M − H]− 454, 456
81		1H NMR (CD3OD) δ: 7.80 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.43-7.50 (m, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.22-7.29 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 4.64-4.76 (m, 1H), 4.36-4.49 (m, 3H), 2.96 (s, 3H), 2.47-2.58 (m, 2H), 1.68 (d, J = 7.0 Hz, 3H); LC/MS RT 1.88 min, m/z [M − H]− 548, 550
82		1H NMR (DMSO-d6) δ: 11.63 (br s, 1H), 7.31 (br dd, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.46-7.62 (m, J = 8.4 Hz, 4H), 7.30 (dd, J = 10.4, 7.9 Hz, 1H), 7.10-7.26 (m, 2H), 7.01 (dd, J = 8.6, 1.6 Hz, 1H), 4.33-4.50 (m, 1H), 4.60-4.22 (m, 1H), 3.86 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]+ 490, 492
83		1H NMR (CD3OD) δ: 7.74 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.03-7.07 (m, 1H), 6.96 (dd, J = 8.2, 5.7 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 4.68 (br d, J = 11.0 Hz, 1H), 3.95 (s, 3H), 3.61-3.68 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 468, 470
84		1H NMR (CD3OD) δ: 7.87 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 1.8 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.52-3.63 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 463, 465
85		1H NMR (CD3OD) δ: 7.73 (d, J = 8.1 Hz, 1H), 7.08-7.16 (m, 1H), 6.89-7.07 (m, 4H), 4.40 (d, J = 10.3 Hz, 1H), 3.95 (s, 3H), 3.71-3.83 (m, 1H), 3.45-3.58 (m, 1H), 2.33 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.24 (d, J = 7.3 Hz, 6H); LC/MS RT 1.88 min, m/z [M − H]− 478, 480
86		1H NMR (CD3OD) δ: 7.73 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.92-7.05 (m, 4H), 4.35 (d, J 11.0 Hz, 1H), 3.95 (s, 3H), 3.52-3.62 (m, 1H), 2.55-2.78 (m, 2H), 2.24 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.08 (t, J = 7.3 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 464, 466
87		1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.98-7.06 (m, 3H), 6.94 (d, J = 2.2 Hz, 1H), 4.29 (d, J = 10.6 Hz, 1H), 3.94 (s, 3H), 3.58-3.63 (m, 1H), 2.51-2.66 (m, 2H), 2.21 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.08 (t, J = 7.5 Hz, 3H); LC/MS RT 1.84 min, m/z [M − H]− 464, 466
88		1H NMR (CD3OD) δ: 7.88 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.87-7.06 (m, 1H), 6.67-6.77 (m, 1H), 4.70-4.78 (m, 3H), 3.63-3.71 (m, 1H), 2.84-2.95 (m, 2H), 2.22 (s, 3H), 2.17 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]− 508, 510
89		1H NMR (CD3OD) δ: 7.74 (d, J = 8.4 Hz, 1H), 7.10-7.27 (m, 2H), 7.04 (dd, J = 8.4, 1.8 Hz, 1H), 4.64-4.75 (m, 1H), 4.06-4.22 (m, 1H), 3.96 (s, 3H), 2.32 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.84 min, m/z [M − H]− 550, 552
90		1H NMR (CD3OD) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.4, 1.8 Hz, 1H), 6.89 (dd, J = 9.8 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 3.95 (s, 3H), 3.63-3.72 (m, 1H), 2.18 (s, 3H), 2.17 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]− 486, 488
91		1H NMR (CD3OD) δ: 8.51 (d, J = 1.8 Hz, 1H), 8.09-8.21 (m, 1H), 7.768-7.73 (m, 2H), 6.92-7.01 (m, 2H), 6.63-6.78 (m, 1H), 4.61-4.71 (m, 1H), 3.53-3.75 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 505, 507
92		LC/MS RT 1.79 min, m/z [M − H]− 507, 509
93		1H NMR (CD3OD) δ: 7.45 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J = 8.4 Hz), 6.96 (1H, dd, J = 8.6, 5.9 Hz), 6.70 (1H, dd, J = 12.1, 8.6 Hz), 4.66-4.80 (4H, m), 3.46 (3H, s), 2.19 (3H, s), 2.16 (3H, s), 1.49 (3H, d, J = 6.6 Hz); LC/MSRT 1.71 min, m/z [M − H]− 523, 525
94		1H-NMR (CDCl3) δ: 7.77 (1H, s), 7.42 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 8.3, 5.9 Hz), 6.69 (1H, dd, J = 1.15, 8.3 Hz), 5.43 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 4.34-4.29 (1H, m), 4.23-4.19 (1H, m), 3.41 (1H, br s), 3.10-3.07 (2H, m), 2.98-2.83 (2H, m), 2.18-2.17 (6H, m), 1.56-1.53 (3H, m), 1.27-1.23 (3H, m).; LC/MS RT 1.85 min, m/z [M − H]− 523, 525
95		1H-NMR (CDCl3) δ: 8.88 (1H, s), 7.68-7.64 (1H, m), 6.98-6.92 (2H, m), 6.73-6.68 (1H, m), 5.48-5.43 (1H, m), 4.95-4.81 (1H, m), 4.55-4.49 (1H, m), 4.34-4.20 (1H, m), 3.45 (1H, s), 2.92-2.82 (1H, m), 2.20-2.18 (6H, m), 2.08 (2H, s), 2.02 (1H, s), 1.98-1.93 (1H, m), 1.86 (1H, s), 1.76 (2H, s), 1.57-1.51 (3H, m).; LC/MS RT 1.82, 1.87 min, m/z [M − H]− 566, 568
96		1H NMR (CD3OD) δ: 7.74-7.78 (m, 3H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.75 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.51-3.63 (m, 1H), 2.47-2.68 (m, 2H), 2.24 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H); LC/MS RT 1.75 min, m/z [M − H ]− 539, 541
97		1H-NMR (CDCl3) δ: 8.06-7.99 (2H, m), 7.80 (1H, s), 7.07 (1H, t, J = 7.7 Hz), 6.93 (1H, dd, J = 8.5, 5.9 Hz), 6.69 (1H, dd, J = 11.5, 8.5 Hz), 5.28 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 3.46 (1H, br s), 2.92 (1H, d, J = 16.9 Hz), 2.69 (1H, d, J = 16.9 Hz), 2.20 (3H, s), 2.18 (3H, s), 1.64 (3H, s), 1.58-1.56 (3H, m), 1.46 (3H, s).; LC/MS RT 1.77 min, m/z [M − H]− 502
98		LC/MS RT 1.66 min, m/z [M − H]− 429
99		1H-NMR (CDCl3) δ: 8.11 (1H, br s), 7.66-7.63 (2H, m), 6.98-6.90 (2H, m), 6.71-6.66 (1H, m), 5.44 (1H, d, J = 10.5 Hz), 4.82 (1H, t, J = 10.5 Hz), 4.56-4.52 (1H, m), 4.47-4.42 (1H, m), 4.01-3.95 (1H, m), 3.44-3.37 (1H, m), 2.17-2.16 (6H, m), 1.89 (1H, br s), 1.55 (3H, d, J = 7.0 Hz), 1.21-1.10 (2H, m), 0.92-0.89 (2H, m); LC/MS RT 1.69 min, m/z [M − H]− 529
100		LC/MS RT 1.83, 1.90 min, m/z [M − H]− 586, 588
101		1H NMR (CD3OD) δ: 7.51 (1H, d, J = 8.6 Hz), 7.24 (1H, d, J = 8.6 Hz), 6.97 (1H, dd, J = 8.2, 5.7 Hz), 6.71 (1H, dd, J = 11.9, 8.2 Hz), 6.04 (1H, tt, J = 55.5, 3.9 Hz), 4.82-4.58 (7H), m), 3.67-3.62 (1H, m), 2.19 (3H, s), 2.16 (3H, s), 1.47 (3H, d, J = 7.0 Hz); LC/MS RT 1.76 min, m/z [M − H]− 573, 575
102		1H-NMR (CDCl3) δ: 7.67 (1H, br s), 7.46 (1H, d, J = 8.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.94 (1H, dd, J = 8.4, 5.5 Hz), 6.70 (1H, dd, J = 11.4, 8.4 Hz), 6.24 (1H, tt, J = 56.3, 4.5 Hz), 5.41 (1H, d, J = 10.5 Hz), 4.88 (1H, t, J = 10.5 Hz), 4.42-4.37 (1H, m), 4.29-4.25 (1H, m), 3.42 (1H, br s), 3.32-3.17 (4H, m), 2.19-2.17 (6H, m), 1.55-1.54 (3H, m).; LC/MS RT 1.87 min, m/z [M − H]− 559, 561
103		LC/MS RT 1.87 min, m/z [M − H]− 496, 498
104		1H-NMR (CDCl3) δ: 8.21 (1H, br s), 7.79 (1H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 8.6, 5.3 Hz), 7.04-7.01 (1H, m), 6.96-6.92 (2H, m), 5.60-5.56 (1H, m), 4.79 (1H, t, J = 10.6 Hz), 3.95 (3H, s), 3.43 (1H, br s), 2.53 (3H, s), 1.55 (3H, d, J = 7.0 Hz).; LC/MS RT 1.64 min, m/z [M − H]− 479, 481
105		LC/MS RT 1.71 min, m/z [M − H]− 464, 466
106		1H-NMR (CDCl3) δ: 7.92-7.86 (1H, m), 7.56-7.46 (1H, m), 7.08-7.00 (1H, m), 6.97-6.92 (1H, m), 6.73-6.67 (1H, m), 5.52-5.45 (1H, m), 4.96-4.83 (1H, m), 4.61-4.37 (3H, m), 3.49 (1H, br s), 2.90-2.82 (1H, m), 2.54-2.48 (1H, m), 2.19- 2.16 (6H, m), 2.09-2.09 (3H, m), 1.57-1.50 (2H, m); LC/MS RT 1.81 1.85 min, m/z [M − H]− 586
107		LC/MS RT 1.90 min, m/z [M − H]− 506, 508
108		LC/MS RT 1.98 min, m/z [M − H]− 568, 570
109		LC/MS RT 1.71 min, m/z [M − H]− 497, 499
110		1H NMR (CD3OD) δ: 7.53-7.63 (m, 1H), 7.02-7.19 (m, 2H), 6.95-7.01 (m, 1H), 6.72 (dd, J = 11.9, 8.6 Hz, 1H), 4.82-4.98 (m, 1H), 3.65-3.74 (m, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]− 440
111		LC/MS RT 1.79 min, m/z [M − H]− 474, 476
112		1H NMR (CD3OD) δ: 8.05 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.82 (d, J = 11.4 Hz, 1H), 3.99 (s, 3H), 3.66-3.76 (m, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]− 469, 471
113		1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.6, 6.0 Hz, 1H), 6.73 (dd, J = 11.9, 8.6 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 3.75-3.83 (m, 4H), 3.63-3.72 (m, 2H), 3.55-3.62 (m, 1H), 3.22-3.27 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.47 (d, J = 7.3 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]− 552, 554
114		1H NMR (CD3OD) δ: 8.17 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.4 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 3.58-3.66 (m, 3H), 3.21-3.29 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.94-2.01 (m, 4H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 536, 538
115		1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.93-8.02 (m, 1H), 6.99 (dd, J = 8.2, 6.0 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.94 (dd, J = 11.2, 3.1 Hz, 1H), 3.53-3.64 (m, 3H), 3.29-3.36 (m, 2H), 3.23-3.29 (m, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 1.92-2.08 (m, 6H), 1.46 (br d, J = 7.0 Hz, 3H); LC/MS RT 1.83 min, m/z [M − H]− 576, 578
116		1H NMR (CD3OD) δ: 8.16 (dd, J = 8.4, 5.1 Hz, 1H), 7.97 (dd, J = 11.7, 8.4 Hz, 1H), 6.96-7.02 (m, 1H), 6.73 (dd, J = 11.5, 8.4 Hz, 1H), 4.88-4.99 (m, 1H), 4.43-4.50 (m, 1H), 4.21-4.28 (m, 2H), 3.56-3.64 (m, 1H), 3.37-3.49 (m, 1H), 3.16 (d, J = 12.8 Hz, 1H), 2.96 (d, J = 12.8 Hz, 1H), 2.21 (s, 3H, 2.18 (s, 3H), 1.88-2.07 (m, 4H), 1.47 (d, J = 7.0 Hz, 3H); LC/MC RT 1.61 min, m/z [M − H]− 578, 580
117		1H NMR (CD3OD) δ: 8.17 (dd, J = 8.4, 2.6 Hz, 1H), 7.97 (dd, J = 8.4, 2.2 Hz, 1H), 6.99 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 11.5, 8.4 Hz, 1H), 4.91-4.97 (m, 1H), 4.66-4.73 (m, 1H), 3.80-3.90 (m, 2H), 3.54-3.77 (m, 4H), 2.19-2.22 (m, 3H), 2.18 (s, 3H), 2.03-2.12 (m, 4H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]− 578, 580
118		LC/MS RT 1.72 min, m/z [M − H]− 497, 499
119		LC/MS RT 1.73 min, m/z [M − H]− 541, 543
120		LC/MS RT 1.80 min, m/z [M − H]− 555, 557
121		LC/MS RT 1.93 min, m/z [M − H]− 514, 516
122		LC/MS RT 1.91 min, m/z [M − H]− 526, 528
123		1H-NMR (CDCl3) δ: 8.56 (0.5H, s), 8.04 (0.5H, s), 7.83-7.78 (1H, m), 7.07- 7.04 (1H, m), 6.96-6.93 (1H, m), 6.74-6.68 (1H, m), 5.43-5.40 (1H, m), 4.97- 4.91 (0.5H, m), 4.84-4.79 (0.5H, m), 4.60-4.42 (2H, m), 3.51 (1H, s), 2.94 (1H, s), 2.53-2.44 (1H, m), 2.22-2.17 (9H, m), 1.57-1.50 (3H, m).; LC/MS RT 1.89, 1.94 min, m/z [M − H]− 620, 622
124		1H NMR (CD3OD) δ: 7.88 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.8, 5.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 11.2, 9.0 Hz, 1H), 4.69-4.80 (m, 3H), 3.63-3.79 (m, 1H), 2.85-2.92 (m, 2H), 2.44 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 527, 574
125		1H-NMR (CDCl3) δ: 8.47 (1H, br s), 7.67 (1H, d, J = 8.4 Hz), 6.96-6.93 (2H, m), 6.82-6.82 (1H, m), 6.65 (1H, dd, J = 14.5, 8.2 Hz), 5.67 (1H, d, J = 9.6 Hz), 5.01 (1H, dd, J = 9.6, 1.6 Hz), 3.88 (3H, s), 2.29 (3H, s), 2.15 (3H, s), 1.66 (3H, d, J = 4.0 Hz), 1.58 (3H, d, J = 3.7 Hz).; LC/MS RT 1.87 min, m/z [M − H]− 482, 484
126		1H NMR (CD3OD) δ: 7.63 (1H, d, J = 8.4 Hz), 7.07 (1H, s), 6.98-6.94 (2H, m), 6.70-6.66 (1H, m), 4.40 (1H, t, J = 7.7 Hz), 3.94 (3H, s), 3.26-3.23 (1H, m), 3.16-3.11 (1H, m), 2.17 (3H, s), 2.14 (3H, s); LC/MS RT 1.76 min, m/z [M − H]− 454, 456
127		1H NMR (CD3OD) δ: 7.72 (1H, dd, J = 14.3, 8.4 Hz), 7.12-7.06 (1H, m), 7.05-6.99 (2H, m), 6.72-6.63 (1H, m), 4.34-4.16 (1H, m), 3.86-3.81 (3H, m), 2.37-2.30 (3H, m), 2.19 (3H, s), 1.57-1.54 (1H, m), 1.35-1.28 (1H, m), 0.93-0.87 (1H, m), 0.72-0.67 (1H, m); LC/MS RT 1.85 min, m/z [M − H]− 480, 482
128		1H-NMR (CDCl3) δ: 7.84 (1H, br s), 7.78 (1H, d, J = 8.1 Hz), 7.00 (1H, dd, J = 8.4, 1.8 Hz), 6.95-6.91 (2H, m), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 5.46 (1H, d, J = 10.3 Hz), 4.82 (1H, t, J = 10.6 Hz), 3.94 (3H, s), 3.28-3.22 (1H, m), 2.27-2.25 (1H, m), 2.19-2.16 (6H, m), 1.96-1.87 (1H, m), 0.79 (3H, t, J = 7.3 Hz).; LCMS RT 1.85 min, m/z [M − H]− 482, 484
129		1H NMR (CD3OD) δ: 7.58-7.73 (m, 1H), 6.91-7.11 (m, 2H), 6.62-6.81 (m, 1H), 4.71-4.82 (m, 1H), 4.49-4.61 (m, 2H), 3.57-3.79 (m, 1H), 2.70-2.95 (m, 1H), 2.28-2.38 (m, 0.5H), 2.20-2.25 (m, 3H), 2.16-2.24 (m, 3H), 2.08-2.14 (m, 0.5H), 1.98-2.02 (m, 3H), 1.42-1.56 (m, 3H); LC/MS RT 1.81, 1.87 min, m/z [M − H]− 569, 571
130		1H NMR (CD3OD) δ: 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H), 8.12-8.36 (m, 1H), 7.98 (dd, J = 8.2, 2.4 Hz, 1H), 7.69-7.86 (m, 1H), 7.55-7.68 (m, 2H), 7.42-7.51 (m, 2H), 5.21 (d, J = 7.7 Hz, 1H), 4.40-4.53 (m, 1H), 1.55 (d, J = 7.3 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 488, 490
131		1H NMR (CD3OD) δ: 8.28 (dd, J = 6.2, 2.6 Hz, 1H), 8.08 (ddd, J = 8.7, 4.5, 2.6 Hz, 1H), 7.43-7.54 (m, 1H), 7.00-7.09 (m, 2H), 6.98 (d, J = 2.2 Hz, 1H), 4.42 (d, J = 10.6 Hz, 1H), 3.31-3.41 (m, 1H), 3.28 (s, 3H), 2.79-2.87 (m, 4H), 1.92-2.07 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 494
132		1H NMR (CD3OD) δ: 9.01 (dd, J = 4.2, 1.6 Hz, 1H), 8.28-8.45 (m, 2H), 8.15 (d, J = 7.0 Hz, 1H), 7.64-7.71 (m, 1H), 7.57-7.63 (m, 1H), 6.91-7.00 (m, 2H), 6.85-6.91 (m, 1H), 4.45 (d, J = 10.6 Hz, 1H), 3.28-3.42 (m, 1H), 2.68-2.94 (m, 4H), 1.78-2.08 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 449
133		1H NMR (CD3OD) δ: 8.88 (s, 1H), 8.59 (s, 1H), 8.01-8.08 (m, 1H), 7.56-7.65 (m, 1H), 7.45-7.54 (m, 1H), 7.36-7.42 (m, 1H), 6.98-7.06 (m, 2H), 6.85-6.93 (m, 1H), 4.23 (d, J = 11.0 Hz, 1H), 3.19-3.31 (m, 1H), 2.75-2.82 (m, 4H), 1.82-2.08 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]− 465
134		1H NMR (ccl3) δ: 7.81 (dd, J = 7.7, 1.8 Hz, 1H), 7.73 (br s, 1H), 7.43-7.50 (m, 1H), 7.03-7.07 (m, 2H), 7.00 (t, J = 7.7 Hz, 1H), 6.90-6.95 (m, 2H), 5.48 (d, J = 10.6 Hz, 1H), 4.47 (t, J = 10.3 Hz, 1H), 3.95 (s, 3H), 3.14-3.33 (m, 1H), 2.77-2.88 (m, 4H), 1.95-2.10 (m, 2H), 1.49 (td, J = 7.0 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]− 428
135		1H NMR (CD3OD) δ: 7.72 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.4, 2.2 Hz, 1H), 6.98-7.03 (m, 2H), 6.89-6.95 (m, 1H), 4.28 (d, J = 10.3 Hz, 1H), 3.25-3.33 (m, 1H), 2.88-3.11 (m, 2H), 2.75-2.85 (m, 4H), 1.84-2.10 (m, 2H), 1.39 (d, J = 7.0 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H); LC/MS RT 2.02 min, m/z [M − H]− 506, 508
136		1H NMR (CD3OD) δ: 8.86 (d, J = 2.2 Hz, 1H), 8.24 (dd, J = 7.3, 1.5 Hz, 1H), 8.12 (s, 1H), 8.06 (dd, J = 8.1, 1.5 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 6.82-7.03 (m, 3H), 4.40 (d, J = 11.0 Hz, 1H), 3.32-3.40 (m, 1H), 2.70-2.89 (m, 4H), 2.54 (s, 3H), 1.79-2.13 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.79 min, m/z [M − H]− 463
137		1H NMR (CD3OD) δ: 7.64 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.18 (dd, J = 8.4, 1.8 Hz, 1H), 6.97-7.07 (m, 2H), 6.90-6.96 (m, 1H), 4.30 (d,J = 11.0 Hz, 1H), 3.94 (s, 3H), 3.32-3.38 (m, 1H), 2.78-2.89 (m, 4H), 1.90-2.11 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 506, 508
138		1H NMR (CD3OD) δ: 7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.59 (td, J = 8.0, 1.6 Hz, 1H), 7.26-7.33 (m, 3H), 6.99-7.05 (m, 2H), 6.92-6.96 (m, 1H), 4.41 (d, J = 10.6 Hz, 1H), 3.36-3.42 (m, 1H), 2.78-2.91 (m, 4H), 1.91-2.04 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]− 464
139		1H NMR (CD3OD) δ: 8.00 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.99-7.07 (m, 2H), 6.95-6.99 (m, 1H), 4.41 (d, J = 10.3 Hz, 1H), 3.56-3.60 (m, 2H), 3.39-3.46 (m, 2H), 3.25-3.29 (m, 1H), 2.78-2.87 (m, 4H), 1.93-2.06 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.60 min, m/z [M − H]− 488
140		1H NMR (CD3OD) δ: 7.39-7.43 (m, 1H), 7.36-3.38 (m, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.00-7.06 (m, 2H), 6.93-6.98 (m, 1H), 4.30 (d, J = 11.0 Hz, 1H), 3.30-3.35 (m, 1H), 2.74-2.87 (m, 8H), 1.91-2.10 (m, 2H), 1.77-1.82 (m, 4H), 1.41 (d, J = 6.6 Hz, 3H); LC/MS RT 1.91 min, m/z [M − H]− 452
141		1H NMR (CD3OD) δ: 8.53-8.55 (m, 1H), 8.23-8.31 (m, 1H), 8.10 (dd, J = 7.5, 2.0 Hz, 1H), 7.39-7.50 (m, 1H), 7.00-7.05 (m, 2H), 4.32 (d, J = 10.6 Hz, 1H), 4.03 (s, 3H), 3.45-3.52 (m, 1H), 2.76-2.93 (m, 4H), 1.93-2.12 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 429
142		LC/MS RT 1.80 min, m/z [M − H]− 519, 521
143		1H NMR (CD3OD) δ: 8.86-9.01 (m, 1H), 8.29-8.55 (m, 1H), 7.95-8.24 (m, 1H), 7.37-7.52 (m, 1H), 6.63-7.24 (m, 4H), 4.26-4.46 (m, 1H), 3.14-3.39 (m, 1H), 2.71-2.88 (m, 4H), 1.81-2.10 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]− 494
144		LC/MS RT 1.92 min, m/z [M − H]− 554, 556
145		LC/MS RT 1.86 min, m/z [M − H]− 518, 520
146		1H NMR (CD3OD) δ: 7.90 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 1.8 Hz, 1H), 7.33-7.35 (m, 1H), 6.88-7.05 (m, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 5.29-5.43 (m, 1H), 4.74 (d, J = 11.4 Hz, 1H), 3.59-3.75 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.86 min, m/z [M − H]− 504, 506
147		LC/MS RT 1.83 min, m/z [M − H]− 480, 482
148		1H NMR (CD3OD) δ: 8.10 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.03 (s, 3H), 3.60-3.74 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.77 min, m/z [M − H]− 469, 471
149		1H NMR (CD3OD) δ: 8.14-8.23 (m, 2H), 8.05-8.10 (m, 1H), 6.99 (dd, J = 8.4, 6.0 Hz, 1H), 6.75 (dd, J = 11.9, 8.4 Hz, 1H), 5.40 (d, J = 11.4 Hz, 1H), 3.65-3.77 (m, 1H), 2.23 (s, 3H), 2.20 (s, 3H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 522, 524
150		1H NMR (cdcl3) δ: 8.28-8.53 (m, 1H), 7.54 (br d, J = 8.1 Hz, 2H), 7.18 (br d, J = 8.1 Hz, 2H), 6.90-7.08 (m, 3H), 5.17 (br d, J = 9.2 Hz, 1H), 4.40 (t, J = 9.9 Hz, 1H), 3.49 (s, 2H), 3.44-3.61 (m, 1H), 2.38 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 400
151		1H NMR (cdcl3) δ: 5.27 (d, J = 9.9 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.7 Hz, 4H), 6.94 (dd, J = 8.1, 5.9 Hz, 1H), 6.71 (dd, J = 11.4, 8.4 Hz, 1H), 5.27 (br d, J = 9.9 Hz, 1H), 4.79 (t, J = 10.3 Hz, 1H), 3.31-3.48 (m, 1H), 2.38 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.42 (br d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 418
152		1H-NMR (CDCl3) δ: 8.75 (1H, s), 7.72 (1H, d, J = 7.7 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.38-7.37 (1H, m), 7.22 (1H, t, J = 7.9 Hz), 6.91-6.86 (2H, m), 6.66-6.61 (1H, m), 5.48 (1H, d, J = 10.4 Hz), 4.74 (1H, t, J = 10.4 Hz), 3.34 (1H, br s), 2.12 (3H, s), 2.08 (3H, s), 1.36 (3H, d, J = 6.6 Hz); LC/MS RT 1.60 min, m/z [M − H]− 443
153		1H NMR (CD3OD) δ: 9.09 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70-7.76 (m, 1H), 6.91 (dd, J = 8.4, 5.9 Hz, 1H), 6.55-6.68 (m, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.62-3.70 (m, 1H), 2.18 (s, 3H), 2.13 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); LC/MS RT 1.80 min, m/z [M − H]− 489, 491
154		1H-NMR (CDCl3) δ: 8.63 (1H, s), 6.98-6.93 (1H, m), 6.92 (1H, s), 6.71 (1H, dd, J = 11.7, 8.4 Hz), 5.57 (1H, br s), 4.94-4.90 (1H, m), 4.03 (3H, s), 3.45 (1H, s), 2.18 (6H, s), 1.53 (3H, d, J = 7.0 Hz); LC/MS RT 1.65 min, m/z [M − H]− 469, 471
155		1H-NMR (CDCl3) δ: 7.95-7.91 (2H, m), 6.96-6.92 (1H, m), 6.70 (1H, dd, J = 11.5, 8.4 Hz), 4.98 (1H, t, J = 11.5 Hz), 4.76 (1H, d, J = 6.2 Hz), 4.62 (2H, t, J = 6.2 Hz), 4.58-4.55 (1H, m), 4.05-3.77 (1H, m), 3.70-3.66 (2H, m), 3.52-3.25 (4H, m), 2.31-2.21 (2H, m), 2.18 (3H, s), 2.14 (3H, d, J = 9.2 Hz), 1.53 (3H, d, J = 6.6 Hz).; LC/MS RT 1.54 min, m/z [M − H]− 578, 580
156		1H-NMR (CDCl3) δ: 7.95-7.92 (2H, m), 6.94 (1H, dd, J = 8.3, 5.9 Hz), 6.68 (1H, dd, J = 11.4, 8.3 Hz), 4.95 (1H, d, J = 10.6 Hz), 4.51-4.45 (4H, m), 3.82-3.80 (1H, m), 3.58-3.51 (1H, m), 3.44 (1H, br s), 3.16-3.03 (2H, m), 2.18 (3H, s), 2.15 (3H, s), 2.02-1.98 (2H, m), 1.92-1.88 (2H, m), 1.53 (3H, d, J = 7.0 Hz); LC/MS RT 1.56 min, m/z [M − H]− 592, 594
157		1H-NMR (CDCl3) δ: 10.23 (1H, s), 7.64 (1H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.92 (1H, dd, J = 8.4, 5.9 Hz), 6.68 (1H, dd, J =11.7, 8.4 Hz), 6.30 (1H, d, J = 6.2 Hz), 5.58 (1H, d, J = 10.3 Hz), 5.23 (1H, s), 4.79 (1H, t, J = 10.4 Hz), 4.54-4.51 (1H, m), 4.21-4.17 (1H, m), 3.54 (1H, s), 3.48 (1H, s), 2.19 (3H, s), 2.18 (3H, s), 1.96 (3H, s), 1.53 (3H, d, J = 7.0 Hz); LC/MS RT 1.61 min, m/z [M − H]− 551, 553
158		1H-NMR (CDCl3) δ: 8.12 (1H, br s), 7.37 (1H, d, J = 4.0 Hz), 6.97 (1H, dd, J = 8.3, 5.7 Hz), 6.86 (1H, d, J = 4.0 Hz), 6.72 (1H, dd, J = 11.7, 8.3 Hz), 5.24 (1H, br s), 4.84 (1H, t, J = 10.1 Hz), 3.48-3.43 (1H, m), 2.19 (3H, s), 2.17 (3H, s), 1.45 (3H, d, J = 7.0 Hz).; LC/MS RT 1.79 min, m/z [M − H]− 444, 446
159		; LC/MS RT 1.65 min, m/z [M − H]− 492
160		1H-NMR (CDCl3) δ: 8.52 (1H, br s), 7.48 (1H, s), 6.96-6.92 (1H, m), 6.73-6.68 (1H, m), 5.53 (1H, d, J = 9.5 Hz), 4.80 (1H, t, J = 9.5 Hz), 3.66 (3H, s), 3.48 (1H, br s), 2.21 (3H, s), 2.19 (3H, s), 1.56-1.55 (3H, m).; LC/MS RT 1.53 min, m/z [M − H]− 442, 444
161		1H-NMR (CDCl3) δ: 8.34-8.54 (1H, m), 7.98 (1H, dd, J = 8.5, 2.4 Hz), 7.65 (1H, d, J = 8.5 Hz), 6.93-6.89 (1H, m), 6.67 (1H, dd, J = 11.4, 8.4 Hz), 6.16-6.14 (1H, m), 4.91 (1H, t, J = 10.3 Hz), 3.51 (2H, br s), 2.16 (1H, s), 2.14 (3H, s), 2.12 (3H, s), 1.53 (3H, t, J = 7.0 Hz).; LC/MS RT 1.58 min, m/z [M − H]− 506, 508
162		1H NMR (CD3OD) δ: 7.64 (dd, J = 8.1, 1.8 Hz, 1H), 7.60 (s, 1H), 6.97 (dd, J = 8.4, 5.5 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.71 (dd, J = 11.9, 8.1 Hz, 1H), 4.67 (d, J = 11.0 Hz, 1H), 3.53-3.56 (m, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.46 (d, J = 6.6 Hz, 3H); LC/MS RT 1.49 min, m/z [M − H]− 459
163		1H NMR (CD3OD) δ: 8.11-8.21 (m, 2H), 7.90-7.98 (m, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.77 (d, J = 11.0 Hz, 1H), 3.53-3.72 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]− 473
164		1H NMR (CD3OD) δ: 7.30 (dd, J = 8.1, 1.5 Hz, 1H), 7.01 (dd, J = 8.1, 1.5 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 11.9, 8.6 Hz, 1H), 4.74 (d, J = 11.0 Hz, 1H), 4.37-4.45 (m, 2H), 4.19-4.34 (m, 2H), 3.61-3.77 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 462
165		1H NMR (CD3OD) δ: 7.47 (dd, J = 8.4, 1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.96 (dd, J = 8.3, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 3.53 (br dd, J = 10.8, 7.1 Hz, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.42 min, m/z [M − H]− 460
166		LC/MS RT 1.59 min, m/z [M − H]− 494
167		LC/MS RT 1.87, 1.92 min, m/z [M − H]− 630, 632
168		1H NMR (CD3OD) δ: 7.40 (dd, J = 8.1, 1.5 Hz, 1H), 7.16 (dd, J = 8.1, 1.1 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.7 Hz, 1H), 6.72 (dd, J = 1.15, 8.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.63-4.66 (m, 2H), 3.50-3.59 (m, 1H), 2.17 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 475
169		1H NMR (CD3OD) δ: 8.30 (dd, J = 6.2, 2.2 Hz, 1H), 8.12 (ddd, J = 8.7, 4.5, 2.6 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.4 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 3.52-3.64 (m, 1H), 3.28 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 500
170		1H NMR (CD3OD) δ: 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.68-6.78 (m, 2H), 6.59-6.67 (m, 1H), 4.80 (d, J = 11.4 Hz, 1H), 3.94 (s, 3H), 3.63-3.75 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]− 470
171		1H NMR (CD3OD) δ: 8.22 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.1, 2.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.93-7.03 (m, 1H), 6.66-6.80 (m, 1H), 4.71 (d, J = 11.3 Hz, 1H), 3.51-3.64 (m, 1H), 3.07-3.26 (m, 4H), 2.64 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 1.55-1.71 (m, 6H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.89 min, m/z [M − H]− 565
172		1H NMR (CD3OD) δ: 7.59 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.6, 1.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 3.51-3.58 (m, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.39 min, m/z [M − H]− 488
173		1H NMR (CD3OD) δ: 7.19-7.25 (m, 2H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 4.22-4.31 (m, 4H), 3.40-3.65 (m, 1H), 2.16 (s, 6H), 1.44 (d, J = 7.3 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 462
174		LC/MS RT 1.68 min, m/z [M − H]− 472
175		1H NMR (CD3OD) δ: 8.05 (dd, J = 7.5, 2.0 Hz, 2H), 7.73 (t, J = 7.7 Hz, 1H), 6.97 (dd, J = 8.6, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.6 Hz, 1H), 5.52-5.71 (m, 2H), 4.72-4.79 (m, 1H), 3.54-3.61 (m, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 460
176		1H NMR (CD3OD) δ: 8.43 (d, J = 2.2 Hz, 1H), 7.88-7.95 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.4, 8.4 Hz, 1H), 4.23 (d, J = 10.6 Hz, 1H), 3.43-3.55 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/M S RT 1.61 min, m/z [M − H]− 517, 519
177		1H NMR (cdcl3) δ: 8.27 (brs, 1H), 7.77-7.89 (m, 2H), 7.40-7.59 (m, 3H), 6.94 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 5.31 (br d, J = 10.3 Hz, 1H), 4.82 (t, J = 10.3 Hz, 1H), 3.36-3.47 (m, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 1.43 (d, J = 5.9 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 404
178		LC/MS RT 1.75 min, m/z [M − H]− 498
179		LC/MS RT 1.64 min, m/z [M − H]− 474
180		LC/MS RT 1.90 min, m/z [M − H]− 541, 543
181		1H NMR (CD3OD) δ: 8.38 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.83 (dd, J = 8.8, 1.8 Hz, 1H), 6.95 (dd, J = 8.3, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.3 Hz, 1H), 4.75 (d, J = 11.0 Hz, 1H), 3.50-3.65 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.50 min, m/z [M − H]− 445
182		1H NMR (CD3OD) δ: 8.28 (s, 1H), 8.19 (s, 1H), 7.73 (dd, J = 8.8, 1.5 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 8.4, 5.9 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 4.72 (d, J = 11.4 Hz, 1H), 3.47-3.65 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H); LC/MS RT 1.53 min, m/z [M − H]− 444
183		1H NMR (CD3OD) δ: 7.40-7.48 (m, 2H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.69-6.79 (m, 2H), 4.65 (d, J = 11.4 Hz, 1H), 4.16-4.22 (m, 2H), 3.48-3.60 (m, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H), 1.94-2.04 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 460
184		1H NMR (CD3OD) δ: 6.84-7.00 (m, 4H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 3.47-3.56 (m, 1H), 3.20-3.28 (m, 2H), 2.89 (s, 3H), 2.72 (t, J = 6.4 Hz, 2H), 2.15-2.18 (m, 6H), 1.85-1.99 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.73 min, m/z [M − H]− 473
185		1H-NMR (CDCl3) δ: 8.47 (1H, br s), 7.70 (1H, d, J = 8.8 Hz), 7.02 (1H, dd, J = 8.2, 6.0 Hz), 6.97 (1H, dd, J = 8.4, 1.8 Hz), 6.90-6.89 (1H, m), 6.72 (1H, t, J = 8.8 Hz), 5.74-5.73 (1H, m), 5.67 (1H, br s), 5.30-5.30 (1H, m), 5.14 (1H, d, J = 9.2 Hz), 3.92 (3H, s), 2.19 (3H, s), 2.11 (3H, s).; LC/MS RT 1.80 min, m/z [M − H]− 466, 468
186		1H NMR (CD3OD) δ: 7.69-7.82 (m, 1H), 6.91-7.10 (m, 2H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.74 (d, J = 11.0 Hz, 1H), 3.59-3.71 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.66 (s, 6H), 1.46 (d, J = 6.6 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]− 498
187		1H NMR (CD3OD) δ: 7.94 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.98-7.07 (m, 2H), 6.90-6.98 (m, 1H), 4.43 (d, J = 10.3 Hz, 1H), 3.19-3.27 (m, 1H), 2.74-2.91 (m, 4H), 1.90-2.08 (m, 2H), 1.71 (s, 3H), 1.65 (s, 3H), 1.42 (d, J = 7.0 Hz, 3H); LC/MS RT 1.93 min, m/z [M − H]− 490, 492
188		1H NMR (CD3OD) δ: 8.29 (d, J = 2.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.45 (dd, J = 8.2, 2.4 Hz, 1H), 6.90-7.10 (m, 3H), 4.34 (d, J = 10.6 Hz, 1H), 3.24-3.31 (m, 1H), 2.79-2.84 (m, 4H), 1.90-2.09 (m, 2H), 1.70 (s, 6H), 1.39 (d, J = 7.0 Hz, 3H); LC/MS RT 1.8 min, m/z [M − H]− 534, 536
189		1H NMR (CD3OD) δ: 7.69-7.76 (m, 1H), 6.89-7.14 (m, 4H), 4.39 (d, J = 11.0 Hz, 1H), 3.24-3.31 (m, 1H), 2.77-2.97 (m, 4H), 1.91-2.07 (m, 2H), 1.67 (s, 6H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]− 492
190		1H NMR (CD3OD) δ: 7.37-7.50 (m, 1H), 7.03 (s, 2H), 6.91-6.99 (m, 1H), 4.41 (d, J = 10.6 Hz, 1H), 4.06 (s, 3H), 3.32-3.36 (m, 1H), 2.77-2.96 (m, 4H), 1.93-2.06 (m, 2H), 1.54 (s, 3H), 1.50 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 492
191		1H NMR (CD3OD) δ: 7.76 (d, J = 9.2 Hz, 1H), 6.97-7.08 (m, 2H), 6.81-6.95 (m, 2H), 4.32 (d, J = 11.0 Hz, 1H), 3.91 (s, 6H), 3.33-3.40 (m, 1H), 2.70-2.98 (m, 4H), 1.91-2.13 (m, 2H), 1.66 (s, 3H), 1.65 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]− 516
192		1H NMR (CD3OD) δ: 8.45-8.43 (2H, m), 8.02 (1H, d, J = 8.1 Hz), 7.82 (1H, d, J = 8.1 Hz), 7.04-7.02 (2H, m), 6.98-6.95 (1H, m), 4.63 (1H, s), 4.51 (1H, d, J = 11.0 Hz), 2.92-2.82 (4H, m), 2.05-1.97 (2H, m), 1.69 (3H, s), 1.68 (3H, s), 1.42 (3H, d, J = 7.0 Hz); LC/MS RT 1.74 min, m/z [M − H]− 491, 493
193		1H NMR (CD3OD) δ: 8.04 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.83 (d, J = 11.4 Hz, 1H), 3.55-3.68 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.67 (d, J = 6.6 Hz, 6H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]− 497, 499
194		1H NMR (CD3OD) δ: 8.01-8.15 (m, 1H), 7.46-7.69 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.93-7.01 (m, 1H), 6.66-6.76 (m, 1H), 4.69 (d, J = 11.4 Hz, 1H), 3.47-3.61 (m, 1H), 2.72-2.88 (m, 2H), 2.07-2.25 (m, 6H), 1.76-1.94 (m, 4H), 1.39-1.52 (m, 6H); LC/MS RT 1.66 min, m/z [M − H]− 488
195		1H NMR (CD3OD) δ: 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.50 (dt, J = 8.7, 2.6 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.77-6.83 (m, 1H), 6.68-6.76 (m, 1H), 4.67 (dd, J = 11.2, 3.1 Hz, 1H), 4.29-4.38 (m, 1H), 4.21-4.28 (m, 1H), 3.47-3.62 (m, 1H), 2.13-2.24 (m, 6H), 2.02-2.11 (m, 2H), 1.58 (d, J = 11.0 Hz, 3H), 1.39-1.49 (m, 3H); LC/MS RT 1.60 min, m/z [M − H]− 490
196		1H NMR (CD3OD) δ: 8.25 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 11.0 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.51-3.62 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.57 (s, 6H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]− 523
197		1H NMR (CD3OD) δ: 8.02 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.49-3.62 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.53 (s, 6H), 1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.52 min, m/z [M − H]− 505
198		1H NMR (CD3OD) δ: 8.41 (s, 1H), 7.60 (s, 1H), 6.97 (dd, J = 8.3, 6.0 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.52-3.64 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.68 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 539, 541
199		1H NMR (CD3OD) δ: 8.25 (d, J = 1.8 Hz, 1H), 7.95 (dd, J = 7.9, 2.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 6.93-7.02 (m, 1H), 6.66-6.75 (m, 1H), 4.75-4.85 (m, 1H), 3.52-3.62 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.88 (s, 6H), 1.40 (d, J = 6.2 Hz, 3H); LC/MS RT 1.63 min, m/z [M − H]− 553
200A		1H NMR (CD3OD) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.96 (dd, J = 8.2, 5.7 Hz, 1H), 6.70 (dd, J = 11.7, 8.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.40-4.46 (m, 1H), 4.26 (td, J = 10.8, 2.6 Hz, 1H), 3.62-3.71 (m, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 2.05-2.13 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]− 527, 529
200B		1H NMR (CD3OD) δ: 7.59 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.41-4.48 (m, 1H), 4.32 (td, J = 10.7, 2.7 Hz, 1H), 3.63-3.73 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 2.05-2.13 (m, 2H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]− 527, 529
201		1H NMR (CD3OD) δ: 7.90 (dd, J = 8.6, 2.7 Hz, 1H), 7.47 (dd, J = 8.4, 2.2 Hz, 1H), 6.98-7.05 (m, 2H), 6.91-6.95 (m, 1H), 5.67 (dd, J = 6.8, 5.3 Hz, 1H), 4.34 (d, J = 11.0 Hz, 1H), 3.39-3.48 (m, 1H), 2.75-2.95 (m, 4H), 1.92-2.05 (m, 2H), 1.57 (d, J = 7.0 Hz, 3H), 1.44 (dd, J = 6.6, 1.5 Hz, 3H); LC/MS RT 1.74 min, m/z [M − H]− 510, 512
202		1H NMR (CD3OD) δ: 7.98 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.00-7.04 (m, 2H), 6.93-6.98 (m, 1H), 5.19-5.29 (m, 1H), 4.48-4.54 (m, 1H), 3.33-3.42 (m, 1H), 2.70-3.01 (m, 4H), 1.97-2.10 (m, 2H), 1.38-1.52 (m, 6H); LC/MS RT 1.66 min, m/z [M − H]− 477, 479
203		1H NMR (CD3OD) δ: 7.64-7.72 (m, 1H), 7.27 (dd, J = 8.4, 1.5 Hz, 1H), 6.95-7.02 (m, 2H), 6.90-6.94 (m, 1H), 5.34-5.48 (m, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.00 (s, 3H), 3.60-3.76 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 1.57-1.65 (m, 3H), 1.37 (d, J = 7.0 Hz, 3H); LC/MS RT 1.68, 1.74 min, m/z [M − H]− 494, 496
204		1H NMR (CD3OD) δ: 7.69 (dd, J = 8.4, 7.0 Hz, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (dd, J = 8.5, 5.7 Hz, 1H), 6.69 (dd, J = 11.7, 8.5 Hz, 1H), 5.30-5.52 (m, 1H), 4.70-4.77 (m, 1H), 4.01 (d, J = 1.5 Hz, 3H), 3.61-3.74 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.57-1.64 (m, 3H), 1.41-1.48 (m, 3H); LC/MS RT 1.70, 1.75 min m/z [M − H]− 512, 514
205		1H NMR (CD3OD) δ: 8.09-8.21 (m, 1H), 7.74-7.92 (m, 2H), 7.68-7.73 (m, 1H), 7.39-7.64 (m, 2H), 7.24-7.30 (m, 1H), 7.15-7.23 (m, 1H), 5.30-5.55 (m, 1H), 4.16-4.35 (m, 1H), 4.03 (d, J = 2.6 Hz, 3H), 3.80 (d, J = 9.5 Hz, 1H), 1.55-1.67 (m, 3H), 1.27-1.41 (m, 3H); LC/MS RT 1.72 1.77 min, m/z [M − H]− 534, 536
206A		1H NMR (CD3OD) δ: 7.69 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 11.7, 8.3 Hz, 1H), 5.40-5.48 (m, 1H), 4.72 (d, J = 11.5 Hz, 1H), 4.01 (s, 3H), 3.64-3.75 (m, 1H), 2.51-2.60 (m, 2H), 2.25 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.46 (d, J = 6.1 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H); LC/MS RT 1.78 min, m/z [M − H]+ 526, 528
207A		1H-NMR (CDCl3) δ: 7.78 (1H, br s), 7.67 (1H, d, J = 8.4 Hz), 6.99 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 8.3, 5.9 Hz), 6.70 (1H, dd, J = 11.5, 8.3 Hz), 5.41 (1H, d, J = 10.4 Hz), 4.89 (1H, t, J = 10.4 Hz), 4.49-4.44 (1H, m), 4.32-4.25 (1H, m), 3.46 (1H, br s), 3.25 (1H, s), 2.36-2.29 (1H, m), 2.19 (3H, s), 2.18 (3H, s), 2.10-2.05 (1H, m), 1.79 (3H, s), 1.55-1.53 (3H, m); LC/MS RT 1.64 min, m/z [M − H]− 524, 526
207B		1H-NMR (CDCl3) δ: 8.41 (1H, s), 7.64 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.93 (1H, dd, J = 8.2, 5.9 Hz), 6.70 (1H, dd, J = 11.5, 8.2 Hz), 5.40 (1H, d, J = 11.0 Hz), 4.85 (1H, t, J = 11.0 Hz), 4.45-4.44 (1H, m), 4.33-4.30 (1H, m), 3.48 (1H, s), 3.40 (1H, s), 2.32-2.30 (1H, m), 2.19-2.16 (6H, m), 2.14-2.12 (1H, m), 1.78 (3H, s), 1.57-1.55 (3H, m); LC/MS RT 1.71 min, m/z [M − H]− 524, 526
208A		1H NMR (cd3od) δ: 7.75 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.3, 6.0 Hz, 1H), 6.69 (dd, J = 11.7, 8.3 Hz, 1H), 5.49 (q, J = 6.6 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.00 (s, 3H), 3.60-3.74 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]− 512, 514
208B		1H NMR (CD3OD) δ: 7.70 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.3, 6.0 Hz, 1H), 6.69 (dd, J = 11.7, 8.3 Hz, 1H), 5.38 (q, J = 6.6 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.00 (s, 3H), 3.60-3.74 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]− 512, 514
209A		1H-NMR (CDCl3) δ: 8.15 (1H, s), 7.66 (1H, d, J = 8.4 Hz), 7.19 (1H, dd, J = 8.6, 5.1 Hz), 6.99 (1H, d, J = 8.6 Hz), 6.78 (1H, dd, J = 10.8, 9.0 Hz), 5.52 (1H, d, J = 11.0 Hz), 4.87 (1H, t, J = 10.4 Hz), 4.47-4.44 (1H, m), 4.28-4.25 (1H, m), 3.48 (1H, s), 3.29 (1H, s), 2.37 (3H, s), 2.32-2.28 (1H, m), 2.09-2.06 (1H, m), 1.78 (3H, s), 1.54 (3H, d, J = 7.0 Hz).; LC/MS RT 1.68 min, m/z [M − H]− 544, 546
209B		1H-NMR (CDCl3) δ: 8.68 (1H, br s), 7.64 (1H, d, J = 8.8 Hz), 7.19 (1H, dd, J = 8.8, 4.9 Hz), 7.01 (1H, d, J = 8.8 Hz), 6.78 (1H, dd, J = 10.8, 8.8 Hz), 5.47-5.42 (1H, m), 4.81 (1H, t, J = 10.9 Hz), 4.45-4.42 (1H, m), 4.32 (1H, t, J = 10.9 Hz), 3.53 (1H, br s), 3.40 (1H, br s), 2.35 (3H, s), 2.33-2.27 (1H, m), 2.15-2.10 (1H, m), 1.78 (3H, s), 1.59-1.58 (3H, m).; LC/MS RT 1.74 min, m/z [M − H]− 544, 546
210		LC/MS RT 1.66 min, m/z [M − H]− 482, 484
211A		1H-NMR (CDCl3) δ: 8.04 (1H, s), 7.86 (1H, dd, J = 8.2, 1.5 Hz), 7.77 (1H, d, J = 8.2 Hz), 7.03 (1H, t, J = 8.2 Hz), 6.92 (1H, dd, J = 8.3, 5.9 Hz), 6.68 (1H, dd, J = 11.5, 8.3 Hz), 5.58 (1H, d, J = 10.2 Hz), 4.86 (1H, t, J = 10.2 Hz), 4.48-4.43 (2H, m), 3.60 (1H, s), 3.25 (1H, s), 2.40-2.33 (1H, m), 2.24-2.20 (1H, m), 2.20 (3H, s), 2.18 (3H, s), 1.53 (3H, d, J = 7.0 Hz).; LC/MS RT 1.67 min, m/z [M − H]− 544
212		1H NMR (CD3OD) δ: 7.68 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.94-7.06 (m, 1H), 6.67-6.76 (m, 1H), 4.73-4.80 (m, 1H), 3.92 (s, 3H), 3.67-3.77 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H), 1.78 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.84 min, m/z [M − H]− 526, 528
213		LC/MS RT 1.47 min, m/z [M − H]− 483, 485
214		LC/MS RT 1.49 min, m/z [M − H]− 527, 529
215		LC/MS RT 1.49 min, m/z [M − H]− 483, 485
216		1H NMR (CD3OD) δ: 8.19 (d, J = 5.9 Hz, 1H), 6.98 (dd, J = 8.1, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 5.35-5.44 (m, 1H), 4.86-4.91 (m, 1H), 4.03-4.06 (m, 3H), 3.66-3.77 (m, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 1.56-1.63 (m, 3H), 1.51 (d, J = 6.6 Hz, 3H); LC/MS RT 1.62 min, m/z [M − H]− 513, 515
217		LC/MS RT 1.73 min, m/z [M − H]− 500, 502
218		LC/MS RT 1.74 min, m/z [M − H]− 496, 498
219		LC/MS RT 1.59 min, m/z [M − H]− 500, 502
220A		1H-NMR (CDCl3) δ: 8.07 (1H, s), 7.86 (1H, d, J = 8.8 Hz), 7.07 (1H, d, J = 8.8 Hz), 6.94 (1H, dd, J = 8.3, 5.7 Hz), 6.70 (1H, dd, J = 11.7, 8.3 Hz), 5.49 (1H, d, J = 9.9 Hz), 4.86 (1H, t, J = 10.1 Hz), 4.74 (1H, s), 4.61-4.51 (1H, m), 4.39 (1H, t, J = 12.5 Hz), 3.49 (1H, s), 2.57-2.53 (1H, m), 2.36-2.34 (1H, m), 2.20-2.17 (6H, m), 1.52 (3H, d, J = 7.0 Hz).; LC/MS RT 1.74 min, m/z [M − H]− 578, 580
220B		1H-NMR (CDCl3) δ: 8.26 (1H, s), 7.79 (1H, d, J = 8.6 Hz), 7.06 (1H, d, J = 8.6 Hz), 6.96-6.93 (1H, m), 6.73-6.68 (1H, m), 5.40 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 4.53-4.46 (3H, m), 3.41 (1H, s), 2.61-2.57 (1H, m), 2.37-2.34 (1H, m), 2.19-2.16 (6H, m), 1.52 (3H, d, J = 7.0 Hz).; LC/MS RT 1.80 min, m/z [M − H]− 578, 580
221		1H-NMR (CDCl3) δ: 8.51-8.51 (1H, m), 8.28-8.27 (1H, m), 6.93 (1H, dd, J = 8.4, 5.9 Hz), 6.71-6.64 (1H, m), 6.05 (1H, br s), 5.60-5.55 (1H, m), 5.03-4.98 (1H, m), 3.54 (1H, s), 2.17 (6H, d, J = 3.7 Hz), 1.49 (3H, d, J = 7.0 Hz); LC/MS RT 1.72 min, m/z [M − H]− 537, 539
222A		1H NMR (CD3OD) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 9.0, 5.3 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 11.2, 9.0 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.39-4.47 (m, 1H), 4.22-4.33 (m, 1H), 3.63-3.78 (m, 1H), 2.44 (s, 3H), 2.17-2.24 (m, 1H), 2.05-2.15 (m, 1H), 1.75 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]− 588, 590
222B		1H NMR (CD3OD) δ: 7.60 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.9, 5.1 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 11.2, 8.9 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.39-4.47 (m, 1H), 4.33 (td, J = 10.8, 2.6 Hz, 1H), 3.65-3.77 (m, 1H), 2.44 (s, 3H), 2.22-2.31 (m, 1H), 2.05-2.12 (m, 1H), 1.75 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]− 588, 590
223		LC/MS RT 1.61 min, m/z [M − H]− 506
224A		1H NMR (CD3OD) δ: 7.70 (dd, J = 8.6, 5.9 Hz, 1H), 6.96 (dd, J = 8.6, 5.9 Hz, 1H), 6.61-6.82 (m, 2H), 4.70 (d, J = 11.4 Hz, 1H), 4.29-4.49 (m, 2H), 3.60-3.79 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 2.04-2.12 (m, 2H), 1.67 (d, J = 1.8 Hz, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.6 min, m/z [M − H]− 508
224B		1H NMR (CD3OD) δ: 7.70 (dd, J = 8.8, 5.9 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.68-6.75 (m, 2H), 4.74 (d, J = 1.14 Hz, 1H), 4.38 (t, J = 5.5 Hz, 2H), 3.63-3.71 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.03-2.12 (m, 2H), 1.66 (d, J = 1.8 Hz, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 508
225A		1H NMR (CD3OD) δ: 7.79 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.64-4.69 (m, 1H), 4.42-4.49 (m, 1H), 3.61-3.76 (m, 1H), 2.25-2.41 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 2.01-2.11 (m, 1H), 1.62 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 558
226A		1H NMR (CD3OD) δ: 7.61 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.6, 5.1 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.81 (dd, J = 11.4, 8.6 Hz, 1H), 4.69 (d, J = 11.0 Hz, 1H), 4.35-4.46 (m, 1H), 4.26 (td, J = 10.9, 2.7 Hz, 1H), 3.66-3.75 (m, 1H), 2.44 (s, 3H), 2.15-2.26 (m, 1H), 2.05-2.13 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H); LC/MS RT 1.70 min, m/z [M − H]− 591, 593
226B		LC/MS RT 1.76 min, m/z [M − H]− 591, 593
227A		1H NMR (CD3OD) δ: 7.70 (dd, J = 8.8, 5.9 Hz, 1H), 7.42 (dd, J = 8.8, 5.1 Hz, 1H), 6.80 (dd, J = 11.0, 9.0 Hz, 1H), 6.72 (dd, J = 11.0, 9.0 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.31-4.42 (m, 2H), 3.66-3.74 (m, 1H), 2.42 (s, 3H), 2.04-2.15 (m, 2H), 1.67 (d, J = 1.8 Hz, 3H), 1.52 (d, J = 7.0 Hz, 3H); LC/MS RT 1.66 min, m/z [M − H]− 572, 574
227B		1H NMR (CD3OD) δ: 7.71 (dd, J = 8.8, 5.9 Hz, 1H), 7.43 (dd, J = 9.0, 5.3 Hz, 1H), 6.82 (dd, J = 11.4, 8.8 Hz, 1H), 6.73 (dd, J = 10.6, 8.8 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.38 (t, J = 5.5 Hz, 2H), 3.65-3.72 (m, 1H), 2.44 (s, 3H), 2.05-2.13 (m, 2H), 1.66 (d, J = 1.8 Hz, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]+ 572, 574
228A		1H NMR (CD3OD) δ: 7.61 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.8, 5.1 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 11.0, 8.8 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.41-4.47 (m, 1H), 4.26 (td, J = 10.9, 2.4 Hz, 1H), 3.65-3.72 (m, 1H), 2.39 (s, 3H), 2.15-2.25 (m, 1H), 2.05-2.13 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H); LC/MS RT 1.68 min, m/z [M − H]− 547, 549
228B		1H NMR (CD3OD) δ: 7.60 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 9.0, 4.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 11.2, 9.0 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.41-4.46 (m, 1H), 4.29-4.36 (m, 1H), 3.64-3.74 (m, 1H), 2.38 (s, 3H), 2.22-2.29 (m, 1H), 2.05-2.13 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.74 min, m/z [M − H]− 547, 549
229A		1H NMR (CD3OD) δ: 7.70 (dd, J = 8.8, 5.9 Hz, 1H), 7.42 (dd, J = 8.8, 5.1 Hz, 1H), 6.80 (dd, J = 11.2, 9.0 Hz, 1H), 6.72 (dd, J = 10.8, 9.0 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 4.31-4.42 (m, 2H), 3.66-3.74 (m, 1H), 2.44 (s, 3H), 2.05-2.11 (m, 2H), 1.67 (d, J = 1.8 Hz, 3H), 1.52 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]− 528, 530
229B		1H NMR (CD3OD) δ: 7.71 (dd, J = 8.9, 5.9 Hz, 1H), 7.43 (dd, J = 8.9, 5.3 Hz, 1H), 6.82 (dd, J = 11.4, 8.8 Hz, 1H), 6.73 (dd, J = 10.6, 8.8 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.38 (t, J = 5.5 Hz, 2H), 3.63-3.78 (m, 1H), 2.44 (s, 3H), 2.04-2.16 (m, 2H), 1.66 (d, J = 1.8 Hz, 3H), 1.50 (d, J = 6.6 Hz, 3H); LC/MS RT 1.69 min, m/z [M − H]− 528, 530
230A		1H NMR (CD3OD) δ: 7.73 (dd, J = 8.8, 6.2 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.66-6.77 (m, 2H), 4.69 (d, J = 11.4 Hz, 1H), 4.84-4.90 (m, 1H), 4.53-4.60 (m, 1H), 4.35 (ddd, J = 13.1, 10.9, 2.4 Hz, 1H), 3.62-3.71 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.95-2.12 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]− 494
230B		1H NMR (CD3OD) δ: 7.77 (dd, J = 8.8, 6.2 Hz, 1H), 6.97 (dd, J = 8.2, 5.7 Hz, 1H), 6.68-6.78 (m, 2H), 4.85-4.93 (m, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.51-4.60 (m, 1H), 4.33 (td, J = 11.5, 3.3 Hz, 1H), 3.62-3.71 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.96-2.09 (m, 2H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 494
231		1H NMR (CD3OD) δ: 804-8.10 (m, 1H), 7.54-7.61 (m, 1H), 7.38-7.46 (m, 1H), 6.94-7.09 (m, 3H), 5.17 (q, J = 6.5 Hz, 1H), 4.36 (dd, J = 10.6, 5.1 Hz, 1H), 3.24-3.33 (m, 1H), 2.77-2.91 (m, 4H), 1.90-2.07 (m, 2H), 1.38-1.42 (m, 6H); LC/MS RT 1.72 min, m/z [M − H]− 476, 478
232		1H NMR (CD3OD) δ: 7.59-7.69 (m, 3H), 7.46 (dd, J = 7.3, 1.1 Hz, 1H), 7.30-7.38 (m, 1H), 7.22-7.29 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 4.85-4.90 (m, 1H), 4.63-4.72 (m, 1H), 4.50-4.59 (m, 1H), 4.39 (d, J = 10.6 Hz, 1H), 4.26-4.35 (m, 1H), 2.96 (s, 3H), 1.97-2.05 (m, 2H), 1.68 (d, J = 6.6 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 528, 530
233		1H NMR (CD3OD) δ: 8.10 (d, J = 8.4 Hz, 1H), 7.75-7.93 (m, 2H), 7.63-7.75 (m, 1H), 7.51-7.60 (m, 1H), 7.39-7.48 (m, 1H), 7.16-7.29 (m, 1H), 7.05 (t, J = 9.0 Hz, 1H), 4.91-4.93 (m, 1H), 4.56-4.64 (m, 2H), 4.28-4.45 (m, 1H), 4.17-4.27 (m, 1H), 1.98-2.13 (m, 2H), 1.64 (d, J = 6.6 Hz, 3H); LCMS RT 1.63, 1.68 min, m/z [M − H]− 532, 534
234A		1H-NMR (CDCl3) δ: 7.99 (1H, d, J = 8.8 Hz), 7.78 (1H, d, J = 8.1 Hz), 7.72-7.68 (2H, m), 7.65 (1H, s), 7.56 (1H, t, J = 7.9 Hz), 7.43 (1H, t, J = 7.3 Hz), 7.18-7.12 (1H, m), 6.99 (1H, d, J = 8.4 Hz), 5.57 (1H, d, J = 10.6 Hz), 5.05-5.00 (1H, m), 4.93 (1H, s), 4.51-4.48 (1H, m), 4.40-4.33 (1H, m), 4.00 (1H, s), 2.47 (1H, s), 2.16-2.07 (2H, m), 1.69-1.68 (3H, m).; LC/MS RT 1.63 min, m/z [M − H]− 532, 534
235A		1H NMR (CD3OD) δ: 7.66 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.1, 5.5 Hz, 1H), 6.69 (dd, J = 11.7, 8.4 Hz, 1H), 4.86-4.93 (m, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.53-4.61 (m, 1H), 4.29-4.39 (m, 1H), 3.63-3.71 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 2.01-2.06 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 510, 512
235B		1H NMR (CD3OD) δ: 7.70 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.92-4.95 (m, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.53-4.60 (m, 1H), 4.26-4.39 (m, 1H), 3.58-3.75 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.95-2.15 (m, 2H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 510, 512
236		1H NMR (CD3OD) δ: 7.71-7.88 (m, 2H), 7.31-7.42 (m, 1H), 6.93-7.04 (m, 1H), 6.65-6.77 (m, 1H), 5.53-5.80 (m, 1H), 4.72-4.89 (m, 1H), 3.54-3.66 (m, 1H), 2.20 (d, J = 2.2 Hz, 3H), 2.17 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H), 1.42-1.47 (m, 3H); LC/MS RT 1.70, 1.75 min, m/z [M − H]− 482, 484
237A		1H-NMR (CDCl3) δ: 7.72-7.69 (1H, m), 7.61-7.59 (1H, m), 7.45 (1H, s), 6.99-6.90 (2H, m), 6.70-6.65 (1H, m), 5.34-5.32 (1H, m), 4.89-4.81 (2H, m), 3.49 (1H, br s), 2.35 (1H, s), 2.25 (1H, dd, J = 14.4, 6.0 Hz), 2.19 (3H, s), 2.17 (3H, s), 1.97 (1H, dd, J = 14.4, 7.3 Hz), 1.55-1.54 (6H, m), 1.48 (3H, s).; LC/MS RT 1.66 min, m/z [M − H]− 504, 506
238A		1H NMR (CD3OD) δ: 7.67 (d, J = 8.5 Hz, 1H), 7.08-7.17 (m, 1H), 7.04-7.07 (m, 1H), 6.86 (dd, J = 11.1, 8.9 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.89-4.94 (m, 1H), 4.53-4.61 (m, 1H), 4.29-4.40 (m, 1H), 3.64-3.77 (m, 1H), 2.38 (s, 3H), 2.00-2.12 (m, 2H), 1.51 (d, J = 7.6 Hz, 3H); LC/MS RT 1.65 min, m/z [M − H]− 530, 532
239A		1H NMR (CD3OD) δ: 7.67 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.4 Hz, 1H), 4.89-4.94 (m, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.51-4.61 (m, 1H), 4.27-4.43 (m, 1H), 3.59-3.77 (m, 1H), 2.47-2.68 (m, 2H), 2.25 (s, 3H), 2.03-2.13 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]− 524, 526
240		1H NMR (CD3OD) δ: 7.76 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.3, 6.0 Hz, 1H), 6.70 (dd, J = 11.7, 8.3 Hz, 1H), 5.60 (t, J = 3.1 Hz, 1H), 4.67 (d, J = 11.0 Hz, 1H), 3.44-3.51 (m, 1H), 2.96-3.06 (m, 1H), 2.52-2.65 (m, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 1.97-2.10 (m, 2H), 1.78-1.84 (m, 1H), 1.66-1.77 (m, 1H), 1.41 (d, J = 7.0 Hz, 3H); LC/MS RT 1.89 min, m/z [M − H]− 508, 510
241		1H NMR (CD3OD) δ: 7.69-7.88 (m, 1H), 6.93-7.11 (m, 1H), 6.66-6.84 (m, 2H), 4.88-4.93 (m, 1H), 4.64-4.80 (m, 1H), 4.48-4.64 (m, 1H), 4.22-4.43 (m, 1H), 3.62-3.69 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 1.93-2.09 (2H, m), 1.44-1.52 (m, 3H); LC/MS RT 1.57, 161 min, m/z [M − H]− 494
242		1H NMR (CD3OD) δ: 6.94-7.02 (m, 1H), 6.67-6.78 (m, 1H), 6.53-6.65 (m, 1H), 4.79-4.87 (m, 1H), 4.48-4.71 (m, 2H), 4.25-4.42 (m, 1H), 3.57-3.82 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.95-2.11 (m, 2H), 1.50 (d, J = 6.2 Hz, 3H); LC/MS RT 1.59, 1.62 min, m/z [M − H]− 512
243A		1H NMR (CD3OD) δ: 7.67 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.8, 5.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 11.0, 8.8 Hz, 1H), 4.90-4.95 (m, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.54-4.59 (m, 1H), 4.30-4.37 (m, 1H), 3.63-3.78 (m, 1H), 2.43 (s, 3H), 2.03-2.19 (m, 2H), 1.51 (d, J = 7.0 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 574, 576
243B		1H NMR (CD3OD) δ: 7.70 (d, J = 8.7 Hz, 1H), 7.43 (dd, J = 8.8, 5.1 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.82 (dd, J = 11.2, 8.8 Hz, 1H), 4.92-4.95 (m, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.53-4.58 (m, 1H), 4.28-4.37 (m, 1H), 3.65-3.75 (m, 1H), 2.44 (s, 3H), 1.95-2.13 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 574, 576
244B		1H NMR (CD3OD) δ: 7.89 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 5.04-5.07 (m, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.46-4.65 (m, 2H), 3.63-3.77 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.95-2.14 (m, 2H), 1.47 (d, J = 6.6 Hz, 3H); LC/MS RT 1.76 min, m/z [M − H]− 544
245		1H NMR (CD3OD) δ: 8.51 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 6.98 (dd, J = 8.3, 6.0 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.89-4.94 (m, 1H), 3.63-3.70 (m, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); LC/MS RT 1.47 min, m/z [M − H]− 482, 484
246		1H NMR (CD3OD) δ: 7.73-7.97 (m, 1H), 7.51-7.68 (m, 1H), 7.46 (s, 1H), 6.99 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 11.8, 8.4 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 3.54-3.66 (m, 1H), 3.11 (s, 3H), 2.88 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H), 1.44-1.54 (m, 3H); LC/MS RT 1.79 min, m/z [M − H]− 509, 511
247		1H NMR (CD3OD) δ: 7.84 (d, J = 8.1 Hz, 1H), 7.58 (dd, J = 8.4, 2.2 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 6.96-7.01 (m, 1H), 6.71-6.75 (m, 1H), 4.74-4.85 (m, 1H), 3.93-4.32 (m, 4H), 3.53-3.67 (m, 1H), 2.32-2.46 (m, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 1.43 (d, J = 7.3 Hz, 3H); LC/MS RT 1.81 min, m/z [M − H]− 521, 523
248		1H NMR (CD3OD) δ: 7.52-7.89 (m, 3H), 6.94-7.03 (m, 1H), 6.66-6.78 (m, 1H), 4.79 (d, J = 11.4 Hz, 1H), 3.43-3.88 (m, 5H), 2.21 (s, 3H), 2.15 (s, 3H), 1.49 (d, J = 7.7 Hz, 3H).; LC/MS RT 1.61, 1.66 min, m/z [M − H]− 525, 527
249		1H NMR (CD3OD) δ: 8.51 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.9, 5.1 Hz, 1H), 6.88 (dd, J = 11.2, 8.9 Hz, 1H), 4.92 (d, J = 11.4 Hz, 1H), 3.61-3.74 (m, 1H), 2.42 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.51 min, m/z [M − H]− 502, 504
250		1H NMR (CD3OD) δ: 8.61 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.92 (d, J = 11.0 Hz, 1H), 3.56-3.83 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H); LC/MS RT 1.49 min, m/z [M − H]− 526, 528
251		1H NMR (CD3OD) δ: 8.60 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.2, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.88-4.93 (m, 1H), 3.55-3.75 (m, 1H), 2.93 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]− 542, 544
252		1H NMR (CD3OD) δ: 8.17 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 8.6, 5.7 Hz, 1H), 6.66-6.79 (m, 1H), 4.83-4.90 (m, 1H), 3.56-3.71 (m, 1H), 2.94 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]− 496, 498
253		1H NMR (CD3OD) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 6.96-7.18 (m, 1H), 6.73 (dd, J = 11.7, 8.8 Hz, 1H), 4.92-4.98 (m, 1H), 3.57-3.67 (m, 1H), 3.12 (s, 3H), 2.85 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]− 510, 512
254		1H NMR (CD3OD) δ: 8.61 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 9.0, 4.9 Hz, 1H), 6.88 (dd, J = 11.2, 9.0 Hz, 1H), 4.91 (d, J = 11.0 Hz, 1H), 3.61-3.76 (m, 1H), 2.42 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.53 min, m/z [M − H]− 546, 548
255		1H NMR (CD3OD) δ: 7.76-7.80 (m, 1H), 7.69-7.73 (m, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.73 (dd, J = 11.7, 8.3 Hz, 1H), 4.82 (d, J = 11.0 Hz, 1H), 3.51-3.65 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.71 min, m/z [M − H]− 499, 501
256		1H NMR (CD3OD) δ: 7.66 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.70 (dd, J = 11.5, 8.3 Hz, 1H), 4.92-5.00 (m, 1H), 3.67-3.79 (m, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H ]− 515, 517
257		1H NMR (CD3OD) δ: 7.73 (s, 1H), 7.61 (s, 1H), 6.98 (dd, J = 8.1, 5.9 Hz, 1H), 6.68-6.77 (m, 1H), 4.79-4.85 (m, 1H), 3.52-3.65 (m, 1H), 2.42 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.7 min, m/z [M − H]− 495, 497
258		1H NMR (CD3OD) δ: 7.43 (dd, J = 10.3, 2.2 Hz, 1H), 7.30 (d, J = 1.1 Hz, 1H), 6.98 (dd, J = 8.3, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.3 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 3.60-3.75 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]− 499, 501
259		1H NMR (CD3OD) δ: 7.66 (s, 1H), 7.48 (s, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.72 (dd, J = 11.9, 8.3 Hz, 1H), 4.80-4.85 (m, 1H), 3.97 (s, 3H), 3.52-3.60 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.46-1.50 (m, 3H); LC/MS RT 1.67 min, m/z [M − H]− 511, 513
260		1H NMR (CD3OD) δ: 7.35 (s, 1H), 7.16 (s, 1H), 6.97 (dd, J = 8.5, 5.7 Hz, 1H), 6.72 (dd, J = 11.7, 8.5 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.47-3.56 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]− 507
261		1H NMR (CD3OD) δ: 7.26 (s, 1H), 7.10 (s, 1H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.29-4.32 (m, 4H), 3.44-3.60 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 505
262		1H NMR (CD3OD) δ: 8.36 (s, 1H), 7.90 (s, 1H), 6.98 (dd, J = 8.3, 5.9 Hz, 1H), 6.73 (dd, J = 11.9, 8.3 Hz, 1H), 4.82-4.86 (m, 1H), 3.55-3.65 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); LC/MS RT 1.72 min, m/z [M − H]− 526, 528
263		1H NMR (CD3OD) δ: 7.60 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 8.6, 2.7 Hz, 1H), 6.98 (dd, J = 8.4, 5.9 Hz, 1H), 6.72 (dd, J = 11.7, 8.4 Hz, 1H), 6.20 (tt, J = 55.0, 3.7 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 4.31 (tdd, J = 13.6, 3.7, 2.6 Hz, 2H), 3.51-3.58 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.46 (d, J = 6.6 Hz, 3H); LC/MS RT 1.67 min, m/z [M − H]− 527
264		1H NMR (CD3OD) δ: 8.51 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.8, 5.5 Hz, 1H), 6.77-6.91 (m, 1H), 4.89-4.95 (m, 1H), 3.65-3.75 (m, 1H), 2.48 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H); LC/MS RT 1.54 min, m/z [M − H]− 546, 548
265		1H NMR (CD3OD) δ: 8.10 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75-7.79 (m, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.39-7.45 (m, 2H), 7.20 (dd, J = 11.7, 9.2 Hz,1H), 6.11-6.24 (m, 2H), 4.73 (d, J = 11.4 Hz, 1H), 4.12-4.30 (m, 1H), 3.85 (s, 3H), 1.62 (d, J = 6.6 Hz, 3H); LC/MS RT 1.56 min, m/z [M − H]− 471
266		1H NMR (CD3OD) δ: 7.37-7.45 (m, 2H), 6.94-7.08 (m, 2H), 6.85 (d, J = 6.6 Hz, 1H), 6.51-6.62 (m, 2H), 4.24 (d, J = 10.6 Hz, 1H), 3.36-3.48 (m, 1H), 2.59-2.75 (m, 4H), 1.59-1.85 (m, 4H), 1.29-1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.61 min, m/z [M − H]− 427
267		1H NMR (CD3OD) δ: 7.52 (d, J = 9.2 Hz, 1H), 7.01 (s, 2H), 6.87-6.96 (m, 1H), 6.35-6.48 (m, 2H), 4.17 (d, J = 10.6 Hz, 1H), 3.20-3.35 (m, 1H), 2.75-2.84 (m, 4H), 2.42 (s, 3H), 1.85-2.09 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]− 427
268		1H NMR (CD3OD) δ: 8.82-8.91 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.36-7.45 (m, 1H), 6.83-7.06 (m, 3H), 6.68 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.34-3.46 (m, 1H), 2.72-2.82 (m, 4H), 1.81-2.10 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.57 min, m/z [M − H]− 464
269		1H NMR (CD3OD) δ: 7.64 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 7.6, 1.9 Hz, 1H), 7.43-7.47 (m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.21-7.27 (m, 2H), 6.12-6.16 (m, 2H), 4.59-4.66 (m, 1H), 4.26 (d, J = 10.9 Hz, 1H), 3.80 (s, 3H), 2.95 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H); LC/MS RT 1.58 min, m/z [M − H]− 467
270		1H NMR (CD3OD) 7.38 (d, J = 8.4 Hz, 1H), 6.98-7.07 (m, 2H), 6.91-6.95 (m, 1H), 6.20 (d, J = 1.8 Hz, 1H), 6.16 (dd, J = 8.6, 2.0 Hz, 1H), 4.57-4.63 (m, 1H), 4.21 (d, J = 11.0 Hz, 1H), 3.83 (s, 3H), 2.73-2.91 (m, 4H), 1.89-2.04 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H); LC/MS RT 1.55 min, m/z [M − H]− 443
271		LC/MS RT 1.75 min, m/z [M − H]− 453, 455
272		LC/MS RT 1.8 min, m/z [M − H]− 511, 513
273		1H NMR (CD3OD) δ: 7.46 (1H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 6.98-6.95 (1H, m), 6.71 (1H, dd, J = 11.9, 8.2 Hz), 4.79-4.66 (3H, m), 4.41-4.34 (1H, m), 4.24-4.18 (1H, m), 3.75-3.62 (3H, m), 2.19 (3H, s), 2.16 (3H, s), 1.49 (3H, d, J = 6.6 Hz); LC/MS RT 1.61 min, m/z [M − H]− 553, 555
274		1H NMR (CD3OD) δ: 7.53 (d, J = 8.8 Hz, 1H), 6.96-7.04 (m, 1H), 6.71-6.81 (m, 2H), 6.55-6.60 (m, 1H), 4.66 (d, J = 11.4 Hz, 1H), 3.50-3.66 (m, 1H), 2.23 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H); LC/MS RT 1.92 min, m/z [M − H]− 495, 497
275		1H-NMR (CDCl3) δ: 7.63 (1H, s), 7.10 (1H, d, J = 8.4 Hz), 6.94-6.88 (2H, m), 6.69 (1H, dd, J = 11.5, 8.6 Hz), 5.38 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.8 Hz), 4.41-4.40 (4H, m), 3.53-3.52 (2H, m), 2.18-2.17 (6H, m), 1.57-1.54 (3H, m).; LC/MS RT .71 min, m/z [M − H]− 495, 497
276		1H-NMR (CDCl3) δ: 8.07 (1H, br s), 7.64 (1H, d, J = 8.8 Hz), 7.07-7.06 (2H, m), 6.95-6.93 (1H, m), 6.38 (1H, d, J = 8.8 Hz), 5.68 (2H, s), 5.45 (1H, d, J = 10.4 Hz), 4.37 (1H, t, J = 10.4 Hz), 3.95 (3H, s), 3.88 (3H, s), 3.28-3.21 (1H, m), 2.88-2.83 (4H, m), 2.04-1.99 (2H, m), 1.49 (3H, d, J = 7.0 Hz).; LC/MS RT 1.67 min, m/z [M − H]− 501
277		1H NMR (CD3OD) δ: 7.83 (d, J = 8.4 Hz, 1H), 7.58-7.60 (m, 1H), 7.55-7.57 (m, 1H), 6.94-7.02 (m, 1H), 6.67-6.77 (m, 1H), 4.76-4.82 (m, 1H), 3.57-3.76 (m, 1H), 2.92 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); LC/MS RT 1.74 min, m/z [M − H]− 495, 497
278		LC/MS RT 1.34 min, m/z [M − H]− 509, 511
279		LC/MS RT 1.4 min, m/z [M − H]− 493, 495
280		1H-NMR (CDCl3) δ: 8.12 (1H, br s), 7.15-7.13 (1H, m), 6.93-6.90 (1H, m), 6.75-6.64 (3H, m), 5.51 (1H, d, J = 10.6 Hz), 4.87 (1H, t, J = 10.6 Hz), 4.37-4.35 (2H, m), 3.93 (1H, br s), 3.43-3.40 (3H, m), 2.19 (3H, s), 2.17 (3H, s), 1.54 (3H, d, J = 7.0 Hz).; LC/MS RT 1.6 min, m/z [M − H]− 461
281		1H NMR (CD3OD) δ: 7.90 (d, J = 1.0 Hz, 1H), 7.35-7.49 (m, 2H),
		6.97 (t, J = 1.0 Hz, 1H), 6.73 (dd, J = 1.0 Hz, 1H), 4.70 (br d, J = 11.4 Hz,
		1H), 4.28-4.52 (m, 2H), 3.38-3.83 (m, 5H), 2.17 (s, 5H), 1.49 (d, J =
		1.0 Hz, 3H); LC/MS RT 1.29 min, m/z [M − H]− 459
282		LC/MS RT 1.94 min, m/z [M − H]− 587, 589
283		1H NMR (CD3OD) δ: 7.94-7.99 (m, 1H), 7.84-7.91 (m, 1H), 6.81-6.93 (m, 1H), 6.61 (dd, J = 11.5, 8.6 Hz, 1H), 4.75 (d, J = 10.3 Hz, 1H), 3.37-3.89 (m, 5H), 2.88-3.03 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H), 1.75-1.85 (m, 1H), 1.36-1.53 (m, 4H); LC/MS RT 1.25 min, m/z [M − H]− 551, 553
284		1H-NMR (CDCl3) δ: 7.08 (1H, d, J = 8.8 Hz), 7.02-6.97 (3H, m), 6.88 (1H, d, J = 8.4 Hz), 5.42 (1H, d, J = 10.8 Hz), 4.56 (1H, t, J = 10.8 Hz), 4.47-4.36 (3H, m), 3.55-3.44 (3H, m), 2.24 (3H, s), 2.22 (3H, s), 2.17 (3H, s), 1.47 (3H, d, J = 7.0 Hz).; LC/MS RT 1.88 min, m/z [M − H]− 519, 521
285		1H NMR (CD3OD) δ: 7.84-7.95 (m, 1H), 7.50-7.66 (m, 3H), 6.97 (dd, J = 8.4, 5.9 Hz, 1H), 6.71 (dd, J = 11.7, 8.4 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.50-3.63 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H); LC/MS RT 1.48 min, m/z [[M − H]− 463
286		1H NMR (CD3OD) δ: 7.87 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.2, 5.7 Hz, 1H), 6.72 (dd, J = 11.9, 8.2 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.53-3.63 (m, 1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H); LC/MS RT 1.59 min, m/z [M − H]− 497, 499
287		1H-NMR (CDCl3) δ: 8.70 (1H, s), 8.51-8.48 (1H, m), 7.87-7.84 (2H, m), 7.44 (1H, dd, J = 8.6, 2.1 Hz), 7.39 (1H, d, J = 2.1 Hz), 6.93 (1H, dd, J = 8.4, 5.9 Hz), 6.71-6.65 (2H, m), 4.87 (1H, t, J = 10.1 Hz), 3.53-3.48 (1H, m), 2.18-2.17 (6H, m), 1.43 (3H, d, J = 7.0 Hz).; LC/MS RT 1.72 min, m/z [M − H]− 497, 499
288		LC/MS RT 1.76 min, m/z [M − H]− 509, 511
289		LC/MS RT 1.8 min, m/z [M − H]− 529, 531
290		1H NMR (CD3OD) δ: 7.73 (1H, d, J = 8.1 Hz), 7.16-7.15 (1H, m), 7.06-7.01 (2H, m), 6.71 (1H, dd, J = 10.6, 8.4 Hz), 5.38 (1H, d, J = 9.5 Hz), 4.68 (1H, d, J = 9.5 Hz), 3.96 (3H, s), 3.33 (1H, s), 2.25 (3H, s), 2.16 (3H, s); LC/MS RT 1.53 min, m/z [M − H]− 470, 472
291		LC/MS RT 1.75, 1.76 min, m/z [M − H]− 472, 474
292		1H-NMR (CDCl3) δ: 7.98 (1H, d, J = 8.8 Hz), 7.94 (1H, s), 7.86-7.84 (1H, m), 7.78 (1H, d, J = 8.1 Hz), 7.72-7.70 (1H, m), 7.55 (1H, t, J = 7.7 Hz), 7.42 (1H, t, J = 7.3 Hz), 7.17-7.12 (1H, m), 7.08 (1H, d, J = 8.4 Hz), 5.79-5.67 (1H, m), 5.62 (1H, d, J = 10.4 Hz), 4.94 (1H, t, J = 10.4 Hz), 4.60-4.56 (1H, m), 4.23-4.20 (1H, m), 3.99 (1H, s), 3.67-3.51 (1H, m), 2.38-2.35 (1H, m), 1.69 (3H, d, J = 5.9 Hz).; LC-MS RT 1.8 min, m/z [M − H]− 534, 536
293		1H-NMR (CDCl3) δ: 8.56-8.54 (1H, m), 8.37-8.35 (1H, m), 8.10 (1H, s), 6.97-6.90 (1H, m), 6.71-6.64 (1H, m), 5.82 (1H, br s), 5.03-4.97 (1H, m), 3.54-3.52 (1H, m), 2.19-2.17 (6H, m), 1.53-1.44 (3H, m).; LC/MS RT 1.64 min, m/z [M − H]− 535, 537
294		LC/MS RT 1.83 min, m/z [M − H]− 510, 512
295		1H NMR (CD3OD) δ: 7.48 (d, J = 8.8 Hz, 1H), 6.91-7.03 (m, 4H), 6.70 (dt, J = 10.3, 2.0 Hz, 1H), 6.01 (dt, J = 10.3, 3.7 Hz, 1H), 4.98-5.04 (m, 2H), 4.33 (d, J = 10.6 Hz, 1H), 3.60-3.68 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H); LC/MS RT 1.82 min, m/z [M − H]− 474, 476
296		LC/MS RT 1.73 min, m/z [M − H]− 462, 464
297		1H NMR (CD3OD) δ: 7.69-7.80 (m, 1H), 7.30-7.40 (m, 1H), 6.93-7.06 (m, 1H), 6.69-6.82 (m, 1H), 5.38-5.49 (m, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 11.7 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 4.02 (s, 3H), 3.68-3.75 (m, 1H), 2.86 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H), 1.48 (d, J = 7.1 Hz, 3H); LC/MS RT 1.92 min, m/z [M − H]− 556, 558
298		1H-NMR (CDCl3) δ: 7.81 (1H, d, J = 8.4 Hz), 7.06-6.88 (7H, m), 6.82 (1H, dd, J = 11.4, 8.4 Hz), 5.40 (1H, d, J = 10.4 Hz), 4.86 (1H, t, J = 10.4 Hz), 3.96 (3H, s), 3.83 (3H, s), 3.42 (1H, br s), 2.16 (3H, s), 1.59 (3H, d, J = 7.0 Hz); LC/MS RT 1.93 min, m/z [M − H]− 560, 562
299		1H-NMR (CDCl3) δ: 7.89 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.04-6.98 (2H, m), 6.93 (1H, s), 6.88-6.75 (2H, m), 6.68-6.66 (2H, m), 5.44 (1H, d, J = 10.7 Hz), 4.85 (1H, t, J = 10.7 Hz), 3.96 (3H, s), 3.41 (1H, br s), 2.16 (3H, s), 1.59-1.57 (3H, m).; LC/MS RT 1.96 min, m/z [M − H]− 566, 568
300		1H-NMR (CDCl3) δ: 8.57-8.55 (1H, m), 8.45-8.43 (1H, m), 7.82 (1H, d, J = 8.4 Hz), 7.64-7.61 (1H, m), 7.44-7.41 (1H, m), 7.05-7.00 (2H, m), 6.94-6.88 (2H, m), 5.60-5.57 (1H, m), 4.82 (1H, t, J = 10.4 Hz), 3.96 (3H, s), 3.92 (1H, s), 3.46 (1H, s), 2.15 (3H, s), 1.61 (3H, d, J = 6.6 Hz).; LC/MS RT 1.4 min, m/z [M − H]− 531, 533
301		1H-NMR (CDCl3) δ: 7.82 (1H, d, J = 8.1 Hz), 7.59 (1H, s), 7.19-7.16 (1H, m), 7.02 (1H, d, J = 8.8 Hz), 6.92 (1H, s), 6.87-6.82 (1H, m), 6.28 (1H, s), 5.85 (1H, br s), 4.84 (1H, t, J = 10.1 Hz), 3.90 (3H, s), 3.45 (1H, br s), 2.24 (3H, s), 1.56 (3H, d, J = 6.6 Hz); LC/MS RT 1.56 min, m/z [M − H]− 520, 522
302		1H-NMR (CDCl3) δ: 7.91 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.07-6.97 (4H, m), 6.86-6.81 (1H, m), 6.84 (1H, t, J = 9.9 Hz), 5.44 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 3.96 (3H, s), 3.41 (1H, br s), 2.14 (3H, s), 1.58 (3H, d, J = 7.0 Hz).; LC/MS RT 2.05 min, m/z [M − H]− 564, 566
303		1H-NMR (CDCl3) δ: 7.81 (1H, d, J = 8.4 Hz), 7.52-7.51 (2H, m), 7.09-6.99 (4H, m), 6.93-6.93 (1H, m), 6.85-6.80 (1H, m), 5.49-5.46 (1H, m), 4.88-4.83 (1H, m), 3.96 (3H, s), 3.43 (1H, br s), 2.27 (3H, s), 1.58 (3H, d, J = 7.0 Hz).; LC/MS RT 1.54 min, m/z [M − H]− 520, 522
304		1H-NMR (CDCl3) δ: 8.06 (1H, br s), 7.81 (1H, d, J = 8.4 Hz), 7.73 (1H, s), 7.59 (1H, s), 7.57-7.54 (1H, m), 7.41-7.36 (1H, m), 7.03-7.00 (1H, m), 6.93-6.92 (1H, m), 6.84 (1H, dd, J = 11.0, 8.4 Hz), 5.45 (1H, d, J = 10.4 Hz), 4.86 (1H, t, J = 10.4 Hz), 3.96 (3H, s), 3.44 (1H, br s), 2.27 (3H, s), 1.58 (3H, d, J = 9.5 Hz).; LC/MS RT 1.75 min, m/z [M − H]− 570, 572
305		1H-NMR (CDCl3) δ: 8.81 (1H, br s), 7.80 (1H, d, J = 8.8 Hz), 7.36 (1H, s), 7.23-7.20 (1H, m), 7.01 (1H, d, J = 8.4 Hz), 6.93 (1H, s), 6.82 (1H, t, J = 9.7 Hz), 6.19 (1H, s), 5.50 (1H, d, J = 10.4 Hz), 4.86 (1H, t, J = 10.4 Hz), 3.95 (3H, s), 3.90 (3H, s), 3.45 (1H, br s), 2.30 (3H, s), 1.56 (3H, d, J = 6.6 Hz).; LC/MS RT 1.64 min, m/z [M − H]− 534, 536
306		1H-NMR (CDCl3) δ: 8.48 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.39 (1H, s), 7.28 (1H, s), 7.06-6.99 (2H, m), 6.92-6.92 (1H, m), 6.80 (1H, dd, J = 11.2, 8.6 Hz), 5.56 (1H, d, J = 10.6 Hz), 4.84 (1H, t, J = 10.6 Hz), 3.94 (3H, s), 3.91 (3H, s), 3.44 (1H, s), 2.27 (3H, s), 1.57 (3H, d, J = 7.0 Hz).; LC/MS RT 1.62 min, m/z [M − H]− 534, 536
307		LC/MS RT 1.65 min, m/z [M − H]− 534, 536
308		LC/MS RT 1.82 min, m/z [M − H]− 534, 536
309		LC/MS RT 1.94 min, m/z [M − H]− 597, 599
310		1H-NMR (CDCl3) δ: 8.50 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.40 (1H, s), 7.32 (1H, s), 7.05 (1H, dd, J = 8.5, 5.9 Hz), 7.01 (1H, dd, J = 8.4, 1.5 Hz), 6.92 (1H, d, J = 1.8 Hz), 6.80 (1H, dd, J = 11.2, 8.5 Hz), 5.56 (1H, d, J = 10.3 Hz), 4.85 (1H, t, J = 10.8 Hz), 4.18 (2H, q, J = 7.3 Hz), 3.94 (3H, s), 3.44 (1H, br s), 2.28 (3H, s), 1.57 (3H, d, J = 7.0 Hz), 1.50 (3H, t, J = 7.3 Hz).; LC/MS RT 1.68 min, m/z [M − H]+ 548, 550
311		LC/MS RT 1.71 min, m/z [M − H]− 560, 562
312		1H-NMR (CDCl3) δ: 7.80 (1H, d, J = 8.4 Hz), 7.42 (1H, s), 7.36 (1H, s), 7.06-6.99 (2H, m), 6.92 (1H, s), 6.82-6.77 (1H, m), 5.53 (1H, d, J = 10.7 Hz), 4.85 (1H, t, J = 10.7 Hz), 4.75 (1H, t, J = 8.4 Hz), 3.94 (3H, s), 3.44 (1H, br s), 2.55-2.46 (4H, m), 2.28 (3H, s), 1.89-1.82 (2H, m), 1.56 (3H, d, J = 7.0 Hz); LC/MS RT 1.8 min, m/z [M − H]− 574, 576
313		1H-NMR (CDCl3) δ: 8.20 (1H, d, J = 2.0 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.47-7.44 (1H, m), 7.35 (1H, d, J = 8.4 Hz), 7.05-7.02 (1H, m), 7.01-6.99 (1H, m), 6.94 (1H, d, J = 2.0 Hz), 6.92-6.87 (1H, m), 5.43 (1H, d, J = 10.6 Hz), 4.86 (1H, t, J = 10.6 Hz), 3.96 (3H, s), 3.42 (1H, br s), 2.16 (3H, s), 1.59 (3H, d, J = 7.0 Hz); LC/MS RT 1.82 min, m/z [M − H]− 565, 567
314		1H-NMR (CDCl3) δ: 8.94 (1H, br s), 7.91 (1H, d, J = 2.0 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.39-7.36 (1H, m), 7.01-6.97 (2H, m), 6.93 (1H, d, J = 1.0 Hz), 6.85 (1H, dd, J = 11.4, 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 5.60 (1H, d, J = 10.4 Hz), 4.84 (1H, t, J = 10.4 Hz), 3.94 (3H, s), 3.93 (3H, s), 3.44 (1H, br s), 2.16 (3H, s), 1.58 (3H, d, J = 7.0 Hz).; LC/MS RT 1.82 min, m/z [M − H]− 561, 563
315		1H-NMR (CDCl3) δ: 7.95 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J = 8.5 Hz), 7.32 (1H, dd, J = 8.5, 2.4 Hz), 7.00-6.95 (2H, m), 6.92 (1H, d, J = 2.0 Hz), 6.83 (1H, dd, J = 11.2, 8.7 Hz), 6.65 (1H, d, J = 8.7 Hz), 5.61 (1H, d, J = 10.5 Hz), 4.84 (1H, t, J = 10.5 Hz), 3.93 (3H, s), 3.84-3.80 (4H, m), 3.51-3.44 (5H, m), 2.17 (3H, s), 1.57 (3H, d, J = 7.0 Hz); LC/MS RT 1.48 min, m/z [M − H]− 616, 618
316		1H NMR (CD3OD) δ: 8.53 (1H, s), 7.74 (1H, d, J = 8.4 Hz), 7.61 (1H, s), 7.12-7.09 (1H, m), 7.05-6.98 (2H, m), 6.88-6.83 (1H, m), 4.70-4.60 (2H, m), 3.94 (3H, s), 2.08 (3H, s), 1.52 (3H, d, J = 7.0 Hz); LC/MS RT 1.68 min, m/z [M − H]+ 588, 590
317		1H NMR (CD3OD) δ: 8.27 (1H, br s), 7.75 (1H, d, J = 8.4 Hz), 7.34 (1H, s), 7.12 (1H, d, J = 1.8 Hz), 7.04 (1H, dd, J = 8.4, 1.8 Hz), 6.96 (1H, dd, J = 8.4, 5.9 Hz), 6.84 (1H, dd, J = 11.4, 8.4 Hz), 4.68 (1H, d, J = 11.4 Hz), 3.94 (3H, s), 3.82 (3H, s), 3.67-3.62 (1H, m), 2.13 (3H, s), 1.88 (3H, s), 1.52 (3H, d, J = 7.0 Hz); LC/MS RT 1.63 min, m/z [M − H]+ 548, 550
318		1H-NMR (CDCl3) δ: 9.20 (1H, s), 8.60 (2H, s), 8.02 (1H, br s), 7.82 (1H, d, J = 8.1 Hz), 7.05-7.03 (2H, m), 6.97-6.92 (2H, m), 5.53 (1H, d, J = 11.1 Hz), 4.87 (1H, t, J = 11.1 Hz), 3.96 (3H, s), 3.45 (1H, br s), 2.20 (3H, s), 1.61 (3H, d, J = 7.0 Hz).; LC/MS RT 1.55 min, m/z [M − H]− 532, 534
319		1H-NMR (CDCl3) δ: 8.34 (2H, s), 7.81 (1H, d, J = 8.4 Hz), 7.03-6.88 (4H, m), 5.57 (1H, d, J = 10.6 Hz), 4.85 (1H, t, J = 10.6 Hz), 4.04 (3H, s), 3.95 (3H, s), 3.44 (1H, br s), 2.18 (3H, s), 1.59 (3H, d, J = 7.0 Hz); LC/MS RT 1.66 min, m/z [M − H]− 562, 564
320		1H-NMR (CDCl3) δ: 8.12 (1H, br s), 7.99 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.03-6.93 (3H, m), 6.87-6.81 (1H, m), 6.72 (1H, d, J = 8.4 Hz), 5.52 (1H, d, J = 10.6 Hz), 4.79 (1H, t, J = 10.6 Hz), 3.94 (3H, s), 3.57-3.55 (4H, m), 3.45 (1H, br s), 2.17 (3H, s), 1.69-1.66 (6H, m), 1.59 (3H, d, J = 6.6 Hz).; LC/MS RT 1.49 min, m/z [M − H]− 614, 616
321		1H-NMR (CDCl3) δ: 8.19-8.08 (2H, m), 7.80 (1H, d, J = 8.4 Hz), 7.37-7.27 (1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.95-6.92 (2H, m), 6.88-6.83 (1H, m), 5.50 (1H, d, J = 10.3 Hz), 4.83 (1H, t, J = 11.0 Hz), 3.95-3.94 (3H, m), 3.77 (3H, s), 3.42 (1H, br s), 2.04-2.03 (3H, m), 1.58 (3H, d, J = 6.6 Hz).; LC/MS RT 1.96 min, m/z [M − H]− 595, 597
322		1H-NMR (CDCl3) δ: 8.08-8.05 (2H, m), 7.80 (1H, d, J = 8.1 Hz), 7.53 (1H, s), 7.02-6.93 (2H, m), 6.85-6.81 (2H, m), 5.55 (1H, d, J = 10.9 Hz), 4.80 (1H, t, J = 10.9 Hz), 4.28-4.25 (2H, m), 3.94 (3H, s), 3.51 (2H, s), 3.44 (1H, br s), 3.14 (3H, s), 2.17 (3H, s), 1.59 (3H, d, J = 6.2 Hz),.; LC/MS RT 1.44 min, m/z [M − H]− 602, 604
323		1H NMR (CD3OD) δ: 8.60 (1H, s), 8.45 (1H, s), 7.76 (1H, d, J = 8.4 Hz), 7.68 (1H, s), 7.14-7.10 (2H, m), 7.05 (1H, dd, J = 8.4, 1.8 Hz), 6.97 (1H, dd, J = 11.2, 8.4 Hz), 4.70 (1H, d, J = 11.2 Hz, 1H), 3.94 (3H, s), 3.77-3.74 (4H, m), 3.69-3.63 (4H, m), 3.48-3.46 (1H, m), 2.20 (3H, s), 1.55 (3H, d, J = 7.0 Hz); LC/MS RT 1.52 min, m/z [M − H]− 644, 646
324		1H-NMR (CDCl3) δ: 7.96 (1H, d, J = 8.1 Hz), 7.55-7.51 (2H, m), 7.40 (1H, s), 7.28 (1H, s), 7.04 (1H, dd, J = 8.4, 5.9 Hz), 6.84-6.79 (2H, m), 6.05-6.03 (1H, m), 5.98-5.96 (1H, m), 4.95-4.90 (1H, m), 3.92 (3H, s), 3.50 (1H, br s), 2.28 (3H, s), 1.49 (3H, d, J = 7.3 Hz); LC/MS RT 1.46 min, m/z [M − H]− 547, 549
325		1H-NMR (CDCl3) δ: 9.65 (1H, br s), 7.81-7.79 (2H, m), 7.74 (1H, s), 7.60-7.59 (1H, m), 7.50-7.48 (1H, m), 6.95-6.91 (1H, m), 6.73-6.68 (1H, m), 6.20 (1H, d, J = 10.0 Hz), 4.90 (1H, t, J = 10.0 Hz), 3.92 (3H, s), 3.47 (1H, br s), 2.15 (3H, s), 2.13 (3H, s), 1.50 (3H, d, J = 6.6 Hz).; LC/MS RT 1.69 min, m/z [M − H]− 518, 520
326		1H-NMR (CDCl3) δ: 7.81-7.79 (2H, m), 7.76 (1H, dd, J = 8.5, 2.2 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.46-7.42 (1H, m), 7.31-7.28 (2H, m), 7.17 (1H, t, J = 8.8 Hz), 6.97-6.93 (1H, m), 6.71 (1H, dd, J = 11.7, 8.3 Hz), 5.05 (1H, d, J = 10.0 Hz), 4.85 (1H, t, J = 10.0 Hz), 3.43 (1H, br s), 2.18 (3H, s), 2.16 (3H, s), 1.47 (3H, d, J = 5.9 Hz).; LC/MS RT 1.96 min, m/z [M − H]− 532, 534
327		1H-NMR (CDCl3) δ: 7.80 (1H, d, J = 87.1 Hz), 7.50-7.47 (2H, m), 7.36-7.33 (5H, m), 7.02 (1H, dd, J = 8.4, 1.8 Hz), 6.93 (1H, d, J = 1.5 Hz), 6.81 (1H, dd, J = 11.4, 8.4 Hz), 5.41 (1H, d, J = 10.5 Hz), 4.82 (1H, t, J = 10.5 Hz), 3.97 (3H, s), 3.42 (1H, br s), 2.51 (3H, s), 1.57-1.54 (3H, m).; LC/MS RT 2.06 min, m/z [M − H]− 554,556
328		1H NMR (CD3OD) δ: 8.34 (1H, br s), 7.76-7.65 (1H, m), 7.25-7.22 (1H, m), 7.17-7.09 (1H, m), 6.90-6.85 (1H, m), 4.79-4.70 (2H, m), 4.59-4.51 (2H, m), 4.41-4.26 (2H, m), 3.72-3.66 (1H, m), 2.38-2.37 (6H, m), 2.33-2.23 (2H, m), 1.86 (3H, d, J = 28.2 Hz).; LC/MS RT 1.39 min, m/z [M − H]− 543, 545
329		1H NMR (CD3OD) δ: 7.68-7.79 (m, 1H), 7.42-7.46 (m, 1H), 7.12-7.20 (m, 1H), 6.79-6.88 (m, 1H), 4.71-4.82 (m, 1H), 4.54-4.65 (m, 1H), 4.25-43.46 (m, 1H), 3.63-3.77 (m, 1H), 2.44 (s, 3H), 2.32-2.38 (m, 2H), 1.89-1.94 (m, 3H), 1.51-1.56 (m, 3H); LC/MS RT 1.39 min, m/z [M − H]− 587, 589
330A		LC/MS RT 1.37 min, m/z [M − H]− 543, 545
330B		LC/MS RT 1.37 min, m/z [M − H]− 543, 545
331		1H-NMR (CDCl3) δ: 8.54 (2H, s), 8.42 (1H, s), 8.32-8.30 (1H, m), 7.75 (1H, d, J = 8.1 Hz), 6.96-6.88 (2H, m), 6.67 (1H, dd, J = 11.4, 8.4 Hz), 6.30 (1H, s), 6.10 (1H, s), 4.97 (1H, t, J = 10.3 Hz), 3.48 (1H, s), 2.16 (3H, s), 2.15 (3H, s), 1.48 (3H, d, J = 7.0 Hz).; LC/MS RT 1.5 min, m/z [M − H]− 515
332		1H NMR (CD3OD) δ: 7.68-7.79 (m, 3H), 6.97 (dd, J = 8.5, 5.7 Hz, 1H), 6.71 (dd, J = 11.7, 8.5 Hz, 1H), 4.89-5.02 (m, 1H), 3.58-3.65 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.47 (d, J = 7.3 Hz, 3H); LC/MS RT 1.75 min, m/z [M − H]− 541, 543
333		1H NMR (CD3OD) δ: 7.73 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.81-6.99 (m, 3H), 4.15 (d, J = 6.2 Hz, 1H), 3.98 (s, 3H), 3.38-3.43 (m, 1H), 2.75-2.92 (m, 4H), 1.92-2.13 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H); LC/MS RT 1.95 min, m/z [M − H]− 540, 542
334		LC/MS RT 1.89 min, m/z [M − H]− 506, 508
335		1H NMR (CD3OD) δ: 7.65-7.74 (m, 2H), 7.57-7.64 (m, 1H), 7.50 (d, J = 3.3 Hz, 1H), 6.98-7.18 (m, 2H), 6.79-6.84 (m, 1H), 3.99 (d, J = 9.9 Hz, 1H), 3.40-3.50 (m, 1H), 2.70-2.86 (m, 1H), 2.57-2.66 (m, 1H), 2.32-2.51 (m, 2H), 1.82 (s, 3H), 1.45-1.54 (m, 2H), 1.44 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H); LC/MS RT 2.11 min, m/z [M − H]− 534, 536
336		1H NMR (CD3OD) δ: 8.02 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 6.97-6.99 (m, 3H), 6.88-6.90 (m, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.34-3.46 (m, 1H), 2.71-2.97 (m, 4H), 2.14 (s, 6H), 1.93-2.02 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H); LC/MS RT 1.87 min, m/z [M − H]− 506, 508
337		1H NMR (CD3OD): 7.93 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 8.1, 5.9 Hz, 1H), 6.76 (dd, J = 11.9, 8.6 Hz, 1H), 5.58 (dd, J = 11.7, 1.8 Hz, 1H), 3.76-3.90 (m, 1H), 3.06 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H); LC/MS RT 1.64 min, m/z [M − H]− 495, 497
338		1H-NMR (CDCl3) δ: 8.15 (1H, s), 7.86 (1H, d, J = 8.4 Hz), 7.52 (1H, dd, J = 8.4, 1.5 Hz), 7.48-7.47 (1H, m), 6.94 (1H, dd, J = 8.2, 5.7 Hz), 6.69 (1H, dd, J = 11.7, 8.4 Hz), 5.33 (1H, d, J = 9.9 Hz), 4.85 (1H, t, J = 10.3 Hz), 3.50-3.45 (1H, m), 2.18 (6H, s), 1.47 (3H, d, J = 7.0 Hz).; LC/MS RT 1.95 min, m/[M − H]− 566, 568
339		1H-NMR (CDCl3) δ: 7.97 (1H, s), 7.64-7.61 (1H, m), 7.40 (1H, dd, J = 8.8, 5.1 Hz), 6.96 (1H, dd, J = 8.1, 5.9 Hz), 6.70 (1H, dd, J = 11.4, 8.4 Hz), 5.40 (1H, d, J = 9.2 Hz), 4.89 (1H, t, J = 9.3 Hz), 3.52-3.47 (1H, m), 2.19 (6H, s), 1.48 (3H, d, J = 7.3 Hz).; LC/MS RT 1.86 min, m/[M − H]− 519, 521
340		1H-NMR (CDCl3) δ: 8.31-8.28 (2H, m), 8.13 (1H, s), 8.02-7.98 (2H, m), 6.95 (1H, dd, J = 8.4, 5.9 Hz), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 5.32-5.29 (1H, m), 4.87 (1H, t, J = 9.9 Hz), 3.48-3.44 (1H, m), 2.17 (3H, s), 2.16 (3H, s), 1.43 (3H, d, J = 7.0 Hz).; LC/MS RT 1.73 min, m/[M − H]− 449
341		1H-NMR (CDCl3) δ: 8.42 (1H, s), 7.94-7.92 (2H, m), 7.77-7.75 (2H, m), 6.95 (1H, dd, J = 8.4, 5.9 Hz), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 5.45 (1H, d, J = 9.5 Hz), 4.84 (1H, t, J = 9.7 Hz), 3.48-3.42 (1H, m), 2.18 (3H, s), 2.15 (3H, s), 1.42 (3H, d, J = 7.0 Hz).; LC/MS RT 1.67 min, m/[M − H]− 429
342		1H-NMR (CDCl3) δ: 8.62 (1H, br s), 7.98 (1H, d, J = 8.1 Hz), 7.33 (1H, dd, J = 8.1, 1.1 Hz), 7.20 (1H, d, J = 1.1 Hz), 6.93 (1H, dd, J = 8.4, 5.9 Hz), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 5.55 (1H, d, J = 10.3 Hz), 4.84 (1H, t, J = 10.6 Hz), 4.01 (3H, s), 3.43 (1H, br s), 2.17 (6H, s), 1.52 (3H, d, J = 7.0 Hz).; LC/MS RT 1.71 min, m/[M − H]− 459, 461
343		1H-NMR (CD3OD) δ: 8.25 (1H, s), 8.09 (1H, d, J = 2.2 Hz), 7.95-7.86 (2H, m), 7.00-6.96 (1H, m), 6.72 (1H, dd, J = 11.5, 8.2 Hz), 4.74 (1H, d, J = 11.4 Hz), 3.57-3.54 (1H, m), 2.18 (3H, s), 2.17 (3H, s), 1.45 (3H, d, J = 7.0 Hz).; LC/MS RT 1.78 min, m/[M − H]− 507, 509
344		1H-NMR (CDCl3) δ: 7.98 (1H, s), 7.77 (1H, d, J = 2.6 Hz), 7.65 (1H, dd, J = 8.4, 2.6 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.36-7.34 (2H, m), 6.99-6.92 (4H, m), 6.70 (1H, dd, J = 11.7, 8.4 Hz), 5.11 (1H, d, J = 10.0 Hz), 4.85 (1H, t, J = 10.1 Hz), 3.85 (3H, s), 3.43-3.41 (1H, m), 2.17 (3H, s), 2.15 (3H, s), 1.45 (3H, d, J = 6.2 Hz).; LC/MS RT 1.97 min, m/[M − H]− 544, 546
345		1H-NMR (CDCl3) δ: 8.08 (1H, d, J = 1.8 Hz), 7.71 (2H, dd, J = 7.9, 1.6 Hz), 7.60 (1H, d, J = 8.1 Hz), 7.39-7.35 (1H, m), 7.28-7.26 (2H, m), 7.19 (1H, d, J = 10.3 Hz), 7.07-7.03 (1H, m), 7.00-6.98 (1H, m), 6.89 (1H, dd, J = 8.4, 5.9 Hz), 6.67 (1H, dd, J = 11.4, 8.4 Hz), 6.06 (1H, s), 5.90 (1H, s), 4.95 (1H, t, J = 10.6 Hz), 3.85 (3H, s), 3.46-3.44 (1H, m), 2.16 (3H, s), 2.15 (3H, s), 1.50 (3H, d, J = 7.0 Hz).; LC/MS RT 1.8 min, m/[M − H]− 553, 555
346		1H-NMR (CDCl3) δ: 10.58 (1H, s), 7.93 (1H, d, J = 8.4 Hz), 7.36-7.34 (2H, m), 6.91 (1H, dd, J = 8.2, 5.7 Hz), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 6.44 (2H, s), 5.56 (1H, d, J = 10.3 Hz), 4.84 (1H, t, J = 11.0 Hz), 4.02 (3H, s), 3.42 (1H, br s), 2.17-2.16 (6H, m), 1.56 (3H, d, J = 7.0 Hz).; LC/MS RT 1.51 min, m/[M − H]− 477
347		1H-NMR (CD3OD) δ: 7.96-7.93 (2H, m), 7.86-7.83 (2H, m), 6.96 (1H, dd, J = 8.4, 5.9 Hz), 6.71 (1H, dd, J =11.7, 8.4 Hz), 4.74 (1H, d, J = 11.0 Hz), 3.57-3.53 (1H, m), 2.17 (3H, s), 2.15 (3H, s), 1.42 (3H, d, J = 7.0 Hz).; LC/MS RT 1.46 min, m/[M − H]− 447
348		LC/MS RT min, m/[M − H]− 486, 488
349		1H-NMR (CDCl3) δ: 7.80 (1H, d, J = 8.4 Hz), 7.05 (1H, dd, J = 8.4, 1.8 Hz), 6.96-6.93 (2H, m), 6.68 (1H, dd, J = 11.7, 8.4 Hz), 5.96 (1H, d, J = 9.9 Hz), 4.78 (1H, t, J = 9.7 Hz), 3.91 (3H, s), 3.54-3.49 (1H, m), 2.17 (3H, s), 2.13 (3H, s), 2.49 (3H, d, J = 7.0 Hz).; LC/MS RT 1.77 min, m/[M − H]− 468, 470
350		1H-NMR (CDCl3) δ: 11.70 (1H, s), 11.48 (1H, s), 7.75 (1H, d, J = 8.4 Hz), 6.92-6.89 (2H, m), 6.73-6.68 (1H, m), 6.62 (1H, d, J = 8.4 Hz), 6.16 (1H, d, J = 9.2 Hz), 4.89 (1H, t, J = 10.3 Hz), 3.85 (3H, s), 3.60-3.58 (1H, m), 2.16 (3H, s), 2.13 (3H, s), 1.47 (3H, d, J = 6.6 Hz).; LC/MS RT 1.6 min, m/[M − H]− 483, 485

Test Example

The compound according to the present invention was evaluated using the following test method.

Test Example 1 Human RNR Inhibition Effect

The inhibitory activity against the ribonucleotide reduction reaction (RNR inhibitory activity) of the Example compound was determined by measuring the formation of deoxycytidine diphosphate (hereinafter referred to as dCDP) from cytidine diphosphate (hereinafter referred to as CDP) by the following method.

Human M1 subunit (isoform 1, GenBank accession No: NM_001033), to which a histidine tag is fused at the amino terminus, and human M2 subunit (mutant lacking amino terminal 59 amino acids of isoform 2, GenBank accession No: NM_001034), to which a histidine tag is fused, were overexpressed in Escherichia coli and were solubilized after collection, and histidine tagged human M1 and histidine tagged human M2 proteins were purified on a nickel chelate column. A mixture of the histidine tagged human M1 and histidine tagged human M2 proteins was used as RNR in the ribonucleotide reduction reaction. [to]

For measuring the inhibitory activity of the Example compound against the ribonucleotide reduction reaction, the method described in the document [CANCER RESEARCH 64, 1-6, 2004] was referred to.

First, Example compounds were serially diluted with DMSO. Next, human M1 protein and human M2 protein were added to a 0.02% aqueous albumin solution derived from fetal bovine serum, a DMSO solution of the Example compound or the control DMSO solution (final concentration of DMSO was 1%) was added, and the mixture was allowed to stand for 20 minutes. Thereafter, the reaction buffer [50 mM HEPES buffer (pH 7.2) at the final concentration, 4 mM magnesium acetate at the final concentration, 100 mM potassium chloride at the final concentration, 6 mM dithiothreitol at the final concentration, 2 mM adenosine triphosphate at the final concentration, 0.24 mM nicotinamide adenine dinucleotide phosphate at final concentration] and 10 μM CDP at the final concentration were added and incubated at 37° C. for 30 minutes to perform ribonucleotide reduction reaction. Immediately after the reaction, the reaction was stopped by heating at 100° C. for 15 minutes, followed by centrifugation at 10,000 rpm for 10 minutes. After the centrifugation, a portion (5 μL) of the resulting supernatant was analyzed with a high performance liquid chromatography (Shimadzu Corporation, Prominence) using Shim-pack XR-ODS (manufactured by Shimadzu GLC Co., 3.0×100 mm). Elution was carried out at a measurement wavelength of 265 nm at a flow rate of 0.5 mL/min by a 9-minute concentration gradient from the 12:13 mixture of mobile phase A (10 mM potassium dihydrogen phosphate (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate (pH 6.7), 5.6 mM tetrabutylammonium, 30% methanol) to the same 2:3 mixture to measure the substrate CDP (RT 5.9 min) and the reaction product dCDP (RT 6.2 min).

The inhibitory activity of the Example compound was determined by the following equation, and the concentrations of Example compounds inhibiting the ribonucleotide reduction reaction by 50% are shown as IC₅₀ (μM) in Table 22.

$\left[\mathrm{Mathematical}\mathrm{Formula}1\right]$ $\mathrm{Inhibition}\mathrm{rate}\left(\%\right)=\left[1-\frac{\begin{array}{c}\mathrm{Amount}\mathrm{of}\mathrm{produced}\mathrm{dCDP}\mathrm{where}\\ \mathrm{test}\mathrm{compound}\mathrm{added}\left(\mathrm{pmol}\right)\end{array}}{\begin{array}{c}\mathrm{Amount}\mathrm{of}\mathrm{produced}\mathrm{dCDP}\mathrm{of}\\ \mathrm{control}\left(\mathrm{pmol}\right)\end{array}}\right]\times 100$

As a result, it is apparent from the following table that the sulfonamide compound represented by formula (I) has an excellent RNR inhibitory action.

TABLE 22
               RNR inhibitory
Example Number activity IC50 (μM)
1              0.06
3              0.30
4              0.38
5              0.14
6              0.11
7              0.45
9              0.60
10             0.14
11             0.18
12             0.17
13             0.14
14             0.25
15             0.10
16             0.13
17             0.50
18             0.13
19             0.19
20             0.26
21             0.24
22             0.34
23             0.74
25             0.15
26             0.16
27             0.55
28             0.50
30             0.15
31             0.1
32             0.79
35             0.13
36             0.11
37             0.14
38             0.19
39             0.04
40             0.13
41             0.10
42             0.20
43             0.08
46             0.84
48             0.60
49             0.80
50             0.85
52             0.77
60             0.99
67             0.70
71             0.24
76             0.20
81             0.28
83             0.14
84             0.36
85             0.84
86             0.40
87             0.84
88             0.15
89             0.42
90             0.16
91             0.23
92             0.20
93             0.1
94             0.11
95             0.14
96             0.10
97             0.24
98             0.64
99             0.29
100            0.30
101            0.13
102            0.14
103            0.41
104            0.84
105            0.16
106            0.27
107            0.24
108            0.43
109            0.06
110            0.96
111            0.27
112            0.15
113            0.06
114            0.06
115            0.18
116            0.07
117            0.03
118            0.34
119            0.45
120            0.43
123            0.11
124            0.09
129            0.10
137            0.59
142            0.21
144            0.17
145            0.44
146            0.26
147            0.27
148            0.10
151            0.41
152            0.71
153            0.11
155            0.13
156            0.08
157            0.10
158            0.45
159            0.16
161            0.28
162            0.74
164            0.33
165            0.83
167            0.08
169            0.19
171            0.47
172            0.82
173            0.13
174            0.35
176            0.81
178            0.17
179            0.28
181            0.66
182            0.41
183            0.32
184            0.22
185            0.60
186            0.09
188            0.64
189            0.55
192            0.44
193            0.09
194            0.36
195            0.18
196            0.08
197            0.06
198            0.06
199            0.35
200A           0.03
200B           0.08
201            0.17
202            0.40
203            0.18
204            0.15
205            0.08
206A           0.15
207A           0.13
207B           0.09
208A           0.10
208B           0.06
209A           0.10
209B           0.18
210            0.18
211A           0.12
212            0.11
213            0.50
214            0.99
215            0.19
216            0.20
217            0.96
219            0.27
220A           0.06
220B           0.08
222A           0.08
222B           0.06
223            0.79
224A           0.09
224B           0.10
225A           0.12
226A           0.05
226B           0.07
227A           0.05
227B           0.09
228A           0.08
228B           0.14
229A           0.06
229B           0.11
230A           0.12
230B           0.05
231            0.65
232            0.23
233            0.13
234A           0.31
235A           0.08
235B           0.07
236            0.38
237A           0.29
238A           0.11
239A           0.20
240            0.91
241            0.14
242            0.23
243A           0.07
243B           0.10
244A           0.09
244B           0.22
245            0.04
246            0.50
247            0.41
248            0.27
249            0.10
250            0.02
251            0.25
252            0.06
253            0.08
254            0.07
255            0.12
256            0.42
257            0.10
258            0.14
259            0.10
260            0.36
261            0.09
262            0.13
263            0.07
264            0.06
265            0.26
266            0.85
269            0.51
270            0.73
271            0.23
272            0.66
273            0.13
274            0.44
275            0.10
277            0.37
278            0.13
280            0.42
281            0.76
282            0.91
283            0.15
284            0.56
285            0.31
286            0.07
287            0.05
288            0.06
289            0.13
290            0.84
292            0.16
294            0.11
295            0.79
298            0.30
299            0.94
300            0.34
301            0.29
302            0.49
303            0.16
304            0.16
305            0.24
306            0.09
308            0.18
310            0.17
311            0.22
312            0.22
313            0.34
314            0.26
315            0.19
317            0.28
318            0.54
319            0.28
320            0.60
322            0.22
323            0.42
324            0.17
325            0.22
328            0.11
329            0.06
330A           0.12
330B           0.46
331            0.09
332            0.13
333            0.31
334            0.83
337            0.08
338            0.10
339            0.51
340            0.27
341            0.41
342            0.09
343            0.64
344            0.72
345            0.25
346            0.42
349            0.25
350            0.46

Test Example 2 Cell Proliferation Inhibitory Effect on Human Breast Cancer Cell Line

Human derived breast cancer cell line HCC 1806 cells (American Type Culture Collection, ATCC) were daily passaged at a cell density not exceeding 80% in ATCC recommended Roswell Park Memorial Institute medium (RPMI-1640) containing 10% fetal bovine serum (FBS). In order to start the test of cell proliferation inhibitory activity, HCC 1806 cells were suspended in the above medium, after seeing at 180 μL in each well of a 96-well flat bottom plate so that the number of cells per well was 2,000, the cells were cultured at 37° C. for 1 day in an incubator containing 5% carbon dioxide gas.

On the next day, the Example compound was dissolved in DMSO, and 20 μL of a drug additive solution diluted serially with distilled water to 10 times of the final concentration was added to each well of the culture plate of the cells, and the cells were cultured at 37° C. for 72 hours in an incubator containing 5% carbon dioxide gas. After culturing for 72 hours, 20 μL of glutaraldehyde was added to each well and allowed to stand for 30 minutes, then the plate was washed 10 times with water and was dried. 100 μL of a stain solution (0.05% crystal violet in a 20% methanol solution) was added to each well and allowed to stand for 30 minutes, then the plate was washed 10 times with water and was dried. 100 μL of an extract solution (0.1 N NaH₂PO₄: 100% ethanol=1:1) was added to each well and mixed, and the mixture was measured at a wavelength of 540 nm using a plate reader (MTP-450 manufactured by Corona Electric Co., Ltd.).

The growth inhibition rate was calculated from the following formula, and the concentration (IC₅₀ (μM)) of a compound inhibiting 50% was determined. The results are shown in Table 23.

Growth inhibition rate (%){(C-B)−(T-B)}(C-B)×100

T: Absorbance of well to which Example compound was added

C: Absorbance of wells to which no Example compound was added

B: Absorbance of wells to which no cell was added

As a result, as is clear from the following Table 23, it was revealed that all the sulfonamide compounds represented by formula (I) have growth inhibitory activity against human-derived breast cancer cells.

TABLE 23
               Cell growth
Example Number suppression IC50 (μM)
1              0.16
5              0.20
6              0.29
10             0.56
11             0.64
12             0.50
13             0.31
14             0.56
15             0.40
18             0.58
19             0.94
25             0.59
26             0.98
30             0.80
35             0.67
37             0.82
39             0.23
40             0.59
41             0.40
43             0.28
71             0.79
76             0.44
83             0.50
91             0.98
93             0.28
94             0.48
95             0.14
96             0.95
100            0.39
101            0.81
102            0.66
106            0.38
109            0.40
113            0.60
114            0.37
116            0.32
117            0.31
123            0.17
129            0.08
144            0.96
146            0.83
147            0.65
148            0.40
153            0.91
156            0.87
157            0.37
167            0.14
186            0.64
193            0.11
196            0.32
197            0.41
198            0.05
200A           0.05
200B           0.46
203            0.81
204            0.15
205            0.25
206A           0.57
207A           0.07
207B           0.25
208A           0.33
208B           0.05
209A           0.06
209B           0.82
211A           0.85
212            0.26
216            0.67
220A           0.37
220B           0.50
222A           0.06
222B           0.67
224A           0.10
224B           0.77
225A           0.60
226A           0.08
226B           0.30
227A           0.19
228A           0.14
229A           0.31
230A           0.29
230B           0.78
232            0.33
233            0.28
234A           0.57
235A           0.13
235B           0.40
238A           0.44
239A           0.72
241            0.49
243A           0.29
243B           0.70
244A           0.72
245            0.15
249            0.14
250            0.12
252            0.74
253            0.23
254            0.25
255            0.48
257            0.20
258            0.58
259            0.35
261            0.72
262            0.17
264            0.76
273            0.81
275            0.37
278            0.59
288            0.15
289            0.60
292            0.75
294            0.39
303            0.99
304            0.94
308            0.87
310            0.35
311            0.52
312            0.87
315            0.93
328            0.41
329            0.24
330A           0.24
337            0.30

Test Example 3 Cell Proliferation Inhibitory Effect on Human Cancer-Derived Cancer Cell Lines

According to the method of Test Example 2, the cell proliferation inhibitory effect on various cancer cell lines as described in Table 24 was evaluated. NCI-H460, CFPAC-1, MSTO-211H, DU145, ACHN, HCT116, NCI-H2228 and NCI-H2170 cells were purchased from ATCC, A2780 and RPMI7932 cells were purchased from European Collection of Cell Cultures, GB-1 and HLE cells were purchased from JCRB Cell Bank, A673 cells were purchased from DS Pharma Biomedical Co., Ltd., and NUGC-3 cells were purchased from Health Science Research Resources Bank.

As a result, as is clear from the following table, it was revealed that the sulfonamide compounds represented by formula (I) have growth inhibitory activity against various types of cancer cells derived from humans.

	TABLE 24
	cell line
	NUGC-3	NCI-H460
	Carcinoma type
		Stomach	Lung					MSTO-211H
		Cancer	Cancer	CFPAC-1	A673		HLE	Mesothelioma
	Culture medium
			ATCC	Pancreatic	Ewing's	GB-1	Liver	ATCC
			recommended	Cancer	sarcoma	Glioblastoma	Cancer	recommended
		RPMI-1640 +	RPMI-1640 +	IMDM +	DMEM +	DMEM +	DMEM +	RPMI-1640 +
		10% FBS	10% FBS	10% FBS	10% FBS	10% FBS	10% FBS	10% FBS
	cell number (cell/well)
		2000	1000	2000	2000	3000	3000	6000
IC50	Example 5	1.22	0.73	0.94	1.09	1.57	0.79	0.70
(μM)	Example 235A	0.71	0.35	0.35	0.61	1.12	0.42	0.39
	Example 11	3.11	1.50	1.71	2.56	5.22	1.74	1.54
	Example 1	1.12	0.57	0.54	0.92	1.56	0.56	0.65
	Example 14	2.83	1.35	1.42	1.85	4.60	1.30	1.58
	Example 209A	0.40	0.25	0.33	0.32	0.64	0.26	0.32
	Example 222A	0.36	0.18	0.23	0.25	0.46	0.20	0.27
	Example 200A	0.27	0.13	0.17	0.18	0.37	0.14	0.17
	Example 228A	0.51	0.31	0.36	0.40	0.85	0.29	0.37
	cell line
	DU145
	Carcinoma type
		Prostate					NCI-H2228	NCI-H2170
		Cancer					Lung	Lung
	Culture medium
		EMEM + 0.1 mM non-	A2780	ACHN	HCT116		Cancer	Cancer
		essential amino acid +	Ovarian	Kidney	Colorectal	RPMI7932	ATCC	ATCC
		1 mM sodium	Cancer	Cancer	Cancer	Melanoma	recommended	recommended
		pyruvate +	RPMI-1640 +	EMEM +	McCoy's 5A +	RPMI-1640 +	RPMI-1640 +	RPMI-1640 +
		10% FBS	10% FBS	10% FBS	10% FBS	10% FBS	10% FBS	10% FBS
	cell number (cell/well)
		5000	2000	2000	1000	4000	5000	5000
IC50	Example 5	1.04	0.83	0.75	0.91	2.67	1.27	1.89
(μM)	Example 235A	0.53	0.40	0.38	0.48	1.23	0.88	1.10
	Example 11	1.84	2.08	1.50	2.30	4.74	3.21	3.90
	Example 1	0.73	0.63	0.68	0.75	1.74	1.35	1.41
	Example 14	2.22	1.71	0.98	2.20	3.21	3.53	4.18
	Example 209A	0.31	0.30	0.22	0.28	0.72	0.73	0.57
	Example 222A	0.26	0.19	0.17	0.27	0.51	0.48	0.52
	Example 200A	0.17	0.13	0.13	0.22	0.43	0.50	0.49
	Example 228A	0.34	0.38	0.32	0.38	0.65	0.74	0.88

Test Example 4 Evaluation of Antitumor Effect Using Human-Derived Blood Cancer Cell Line (MV-4-11) Subcutaneous Transplantation Model (In Vivo)

A human-derived blood cancer cell line MV-4-11 was transplanted subcutaneously into a nude mouse (BALB/cA Jcl-nu/nu, CLEA Japan, Inc.), and at the time when the tumor volume of the nude mouse on which the engrafted tumor reached 100 to 300 mm³, four mice were assigned to each group by random stratification so that the average of the tumor volumes of each group was uniform (day 0), and the Example compound was orally administered daily at 100 mg/kg/day once per day for 14 days. Example Compound dosing solutions were prepared using 0.5% HPMC.

An electric balance for animals was used in body weight measurement. Rate of change in body weight on day n (BWCn) from body weight on day n (BWn) was calculated according to the following equation.

Rate of change in body weight BWCn (%)=(BWn−BW0)/BW0×100

Tumor volume (TV) was calculated according to the following equation by sandwiching and measuring the major axis and the minor axis with a digital caliper.

Tumor volume (mm³)=Major axis (mm)×Minor axis (mm)×Minor axis (mm)/2

In order to compare the chronological transition of proliferation of tumor for the administration of each compound, relative tumor volume (RTV) setting the tumor volume at the time of grouping as 1 as the tumor proliferation rate was calculated according to the following formula, and the transition of the average value of RTV of each individual are shown in FIGS. 1 to 4.

RTV=(tumor volume at the day of tumor volume measurement)/(tumor volume at the time of the grouping)

When the average RTV value of the Example compound-administered group on the final evaluation day is smaller than the average RTV value of the control group, and a statistically significant difference (Student-t test) is shown, the Example compound was determined to be significantly effective, and the statically significant difference is marked with * in the figure (*: p<0.05).

As a result, it was revealed that all the sulfonamide compounds represented by formula (I) shows a significant antitumor effect.

Test Example 5 Demonstration of Effect of Combination of Sulfonamide Compound and Other Antitumor Agent

Distributors of reagents, distributors of tumor cell lines, media, and the numbers of cells to be seeded, used in this Test Example are shown in the following Tables 25 and 26.

TABLE 25
Reagent                          Supplier
CELLect ® Fetal Bovine Serum     MP Biomedicals, LLC.
(FBS)
Fetal Bovine Serum, dialyzed, US origin Thermo Fisher Scientific, Inc.
(D-FBS)
DMEM (High Glucose) with L-Glutamine Wako Pure Chemical
and Phenol Red                   Industries, Ltd.
(DMEM)
IMDM                             Thermo Fisher Scientific, Inc.
McCoy′s 5A (Modified) Medium     Thermo Fisher Scientific, Inc.
(McCoy′s 5A)
2-Fluoroadenine-9-β-D-arabinofuranoside Sigma-Aldrich Japan
(Fludarabine nucleoside)
Cytosine P-D-arabinofuranoside   Sigma-Aldrich Japan
hydrochloride
(Cytarabine)
5-Aza-2′-deoxycytidine           Sigma-Aldrich Japan
(Decitabine)
SGI-110 (Guadecitabine)          Adooq Bioscience, LLC.
(Guadecitabine)
Gemcitabine                      Taiho Pharmaceutical Co., Ltd.
(Gemcitabine)
FTD                              Yuki Gosei Kogyo Co., Ltd.
(Trifluridine)
5-Fluorouracil                   Wako Pure Chemical
(5-Fluorouracil)                 Industries, Ltd.
5-Azacytidine                    Sigma-Aldrich Japan
(Azacytidine)
AZD6738                          Adooq Bioscience, LLC.
LY2606368                        Medchemexpress Co., Ltd.
(Prexasertib)
SCH900776                        Adooq Bioscience, LLC.
Briplatin ® Injection 10 mg      Bristol-Myers Squibb
(Cisplatin)                      Company
Oxaliplatin                      Tokyo Chemical Industry Co.,
(Oxaliplatin)                    Ltd.
Paraplatin ® Injection 450 mg    Bristol-Myers Squibb
(Carboplatin)                    Company
Etoposide                        Sigma-Aldrich Japan
(Etoposide)
Sunitinib, Free Base             LC Laboratories, Inc.
(Sunitinib)
Cabozantinib (XL-184, salt form) Taiho Pharmaceutical Co., Ltd.
(Cabozantinib)
PKC-412                          Santa Cruz Biotechnology, Inc.
(Midostaurin)
Lapatinib, Di-p-Toluenesulfonate Salt LC Laboratories, Inc.
(Lapatinib)
Luminespib (AUY-922, NVP-AUY922) Selleck Chemicals, LLC.
(Luminespib)
Olaparib (AZD2281, Ku-0059436)   Selleck Chemicals, LLC.
(Olaparib)
BMN-673                          Chemscene, LLC.
(Talazoparib)

TABLE 26
			The number
Tumor			of cells to be
cell			seeded per
line	Distributor		well
(origin)	of cell line	Medium	(number)
A549	Dainippon	DMEM containing	1500
(Human	Pharmaceutical Co.,	10% FBS (DMEM
lung	Ltd. (present DS	containing 10% D-FBS
cancer)	PHARMA	for trifluridine
	BIOMEDICAL	evaluation)
	CO., LTD.)
MV-4-11	ATCC	IMDM containing	1500
(Human		10% FBS
blood
cancer)
CFPAC-1	ATCC	IMDM containing	2000
(Human		10% FBS
pancreatic
cancer)
HCT116	ATCC	McCoy’s 5A containing	1000
(Human		10% FBS
large
intestine
cancer)

Each cell line was seeded at 90 L/well to a 96-well culture plate (Thermo Fisher Scientific, Inc.) according to the above tables. The cell-seeded plate was cultured in an incubator set to 37° C. and 500 CO₂. On the day following seeding, varying concentrations of the sulfonamide compound and the other antitumor agent were added in combination to the cells. Specifically, ten serial dilutions (including 0 nM) was prepared as to the sulfonamide compound (Example Compounds 1, 5, 14, 209A, and 235A) and the other antitumor agent using Otsuka distilled water (Otsuka Pharmaceutical Factory; hereinafter referred to as DW). The serial dilutions of each compound, or DW was added at 5μL/well to the plate such that each compound and DW, or the sulfonamide compound and the other antitumor agent were combined. The common ratio of concentrations was 1.5 for all the drugs, and the highest concentration (indicated by final concentration) of each compound added to each cell line is shown in the following Tables 27-30. The plate after the addition was cultured at 37° C. for 3 days under 5% CO₂ conditions.

Three days later, CellTiter-Glo(R) 2.0 Reagent (Promega Corporation) was added at 100 μL/well, and the amount of luminescence was measured using a plate reader EnSpire(R) Multimode Plate Reader (PerkinElmer Co., Ltd.).

TABLE 27
	Sulfonamide compound	Other antitumor agent
Tumor cell	Compound	Maximum	Compound	Maximum
line	name	concentration (nM)	name	concentration (nM)
A549	Example	7210	Fludarabine	152000
	Compound		nucleoside
	1		Cytarabine	1850
			Decitabine	15200
			Guadecitabine	5570
			Gemcitabine	42.5
			Trifluridine	3270
			5-Fluorouracil	13700
			Azacytidine	20800
			AZD6738	17700
			Prexasertib	50.6
			SCH900776	23300
			Cisplatin	32400
			Oxaliplatin	5370
			Carboplatin	268000
			Etoposide	19200
			Sunitinib	14200
			Cabozantinib	30400
			Midostaurin	1270
			Lapatinib	30400
			Luminespib	68.3
			Olaparib	75000
			Talazoparib	40500
	Example	8830	Fludarabine	101000
	Compound		nucleoside
	5		Cytarabine	841
			Decitabine	15300
			Guadecitabine	5340
			Gemcitabine	42.5
			Trifluridine	3270
			5-Fluorouracil	21800
			Azacytidine	20700
			AZD6738	17700
			Prexasertib	50.6
			SCH900776	23300
			Cisplatin	32400
			Oxaliplatin	5370
			Carboplatin	268000
			Etoposide	19200
			Sunitinib	14200
			Cabozantinib	30400
			Midostaurin	1270
			Lapatinib	30400
			Luminespib	68.3
			Olaparib	75000
			Talazoparib	40500

TABLE 28
	Sulfonamide compound	Other antitumor agent
Tumor cell	Compound	Maximum	Compound	Maximum
line	name	concentration (nM)	name	concentration (nM)
A549	Compound	22400	Fludarabine	152000
	Example		nucleoside
	14		Cytarabine	1850
			Decitabine	15200
			Guadecitabine	5570
			Gemcitabine	42.5
			Trifluridine	3270
			5-Fluorouracil	13700
			Azacytidine	20700
			AZD6738	17700
			Prexasertib	50.6
			SCH900776	23300
			Cisplatin	32400
			Oxaliplatin	5370
			Carboplatin	268000
			Etoposide	19200
			Sunitinib	14200
			Cabozantinib	30400
			Midostaurin	1270
			Lapatinib	30400
			Luminespib	68.3
			Olaparib	75000
			Talazoparib	40500
	Example	4820	Fludarabine	152000
	Compound		nucleoside
	209A		Cytarabine	1850
			Decitabine	15200
			Guadecitabine	5570
			Gemcitabine	42.5
			Trifluridine	3270
			5-Fluorouracil	21800
			Azacytidine	20800
			AZD6738	17700
			Prexasertib	50.6
			SCH900776	23300
			Cisplatin	32400
			Oxaliplatin	5370
			Carboplatin	268000
			Etoposide	19200
			Sunitinib	14200
			Cabozantinib	30400
			Midostaurin	1270
			Lapatinib	30400
			Luminespib	68.3
			Olaparib	75000
			Talazoparib	40500

TABLE 29
	Sulfonamide compound	Other antitumor agent
Tumor cell	Compound	Maximum	Compound	Maximum
line	name	concentration (nM)	name	concentration (nM)
A549	Example	5920	Fludarabine	101000
	Compound		nucleoside
	235A		Cytarabine	841
			Decitabine	15300
			Guadecitabine	5340
			Gemcitabine	42.5
			Trifluridine	3270
			5-Fluorouracil	21800
			Azacytidine	20800
			AZD6738	17700
			Prexasertib	50.6
			SCH900776	23300
			Cisplatin	32400
			Oxaliplatin	5370
			Carboplatin	268000
			Etoposide	19200
			Sunitinib	14200
			Cabozantinib	30400
			Midostaurin	1270
			Lapatinib	30400
			Luminespib	27.5
			Olaparib	75000
			Talazoparib	40500

TABLE 30
	Sulfonamide compound	Other antitumor agent
Tumor cell	Compound	Maximum	Compound	Maximum
line	name	concentration (nM)	name	concentration (nM)
MV-4-11	Example	2070	Fludarabine	46700
	Compound		nucleoside
	1		Cytarabine	1990
			Decitabine	571
			Guadecitabine	203
	Example	2810	Fludarabine	46700
	Compound		nucleoside
	5		Cytarabine	1990
			Decitabine	571
			Guadecitabine	203
	Example	5910	Fludarabine	46700
	Compound		nucleoside
	14		Cytarabine	1990
			Decitabine	571
			Guadecitabine	203
	Example	1100	Fludarabine	46700
	Compound		nucleoside
	209A		Cytarabine	1990
			Decitabine	571
			Guadecitabine	203
	Example	1540	Fludarabine	46700
	Compound		nucleoside
	235A		Cytarabine	1990
			Decitabine	571
			Guadecitabine	203
CFPAC-1	Example	5770	Gemcitabine	40.1
	Compound		AZD6738	15800
	1		Prexasertib	48.5
			SCH900776	4320
	Example	7970	Gemcitabine	40.1
	Compound		AZD6738	15800
	5		Prexasertib	48.5
			SCH900776	4320
	Example	15800	Gemcitabine	40.1
	Compound		AZD6738	15800
	14		Prexasertib	48.5
			SCH900776	4320
	Example	3860	Gemcitabine	40.1
	Compound		AZD6738	15800
	209A		Prexasertib	48.5
			SCH900776	4320
	Example	5480	Gemcitabine	40.1
	Compound		AZD6738	15800
	235A		Prexasertib	48.5
			SCH900776	4320
	Example	5830	AZD6738	3860
	Compound		Prexasertib	122
	1
	Example	6460	AZD6738	3860
	Compound		Prexasertib	122
	5
HCT116	Example	17100	AZD6738	3860
	Compound		Prexasertib	122
	14
	Example	3200	AZD6738	3860
	Compound		Prexasertib	122
	209A
	Example	5410	AZD6738	3860
	Compound		Prexasertib	122
	235A

Enhancement in effect by combined use of drugs was evaluated according to the method described in the known documents (Trends Pharmacol. Sci. 4, 450-454, 1983; and Pharmacol. Rev. 58 (3), 621-681, 2006).

An average value from 3 wells was calculated as to each drug condition from the obtained data, and cell survival rate normalized against control wells supplemented with the vehicle (DW) was calculated. A Fa (fractional inhibition) value was calculated by subtracting the cell survival rate from 1. The Fa value of the concentration at which 0.01<Fa<0.999 held and linear correlation coefficient r of the median-effect plot was larger than 0.92 was input to drug administration effect analysis software CalcuSyn Version 2.0 (Biosoft) based on the Median Effect method to calculate a combination index (CI) value (Synergy 1,3-21, 2014).

The combinatorial effect was determined according to the following Table 31 (Pharmacol. Rev. 58 (3), 621-681, 2006).

TABLE 31
Range of CI (upper limit) Description
0.1                       Very strong synergistic activity
0.3                       Strong synergistic activity
0.7                       Synergistic activity
0.85                      Moderate synergistic activity
0.9                       Slight synergistic activity
1.0                       Almost additive
1.2                       Slight antagonistic activity
1.45                      Moderate antagonistic activity
3.3                       Antagonistic activity
10                        Strong antagonistic activity
>10                       Very strong antagonistic activity

The results are shown in the following Tables 32-51.

TABLE 32
Cell line:A549 (Human lung cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with	Example	Other	Compound 1:
Example	Compound	antitumor	Other
Compound	1	agent	antitumor	Fa	CI
1	(nM)	(nM)	agent)	value	value
Fludarabine	281	5920	1:21.08	0.2653	0.550
nucleoside	422	8900		0.6824	0.388
	633	13300		0.8650	0.367
	949	20000		0.8719	0.537
Cytarabine	422	108	1:0.2566	0.4482	0.770
	633	162		0.6164	0.614
	949	244		0.7886	0.461
	1420	364		0.8557	0.491
Decitabine	633	1330	1:2.108	0.3872	0.532
	949	2000		0.5507	0.501
	1420	2990		0.6575	0.583
Guadecitabine	633	489	1:0.7725	0.4374	0.471
	949	733		0.5583	0.502
	1420	1100		0.6756	0.563
Gemcitabine	1420	8.37	1:0.005895	0.8410	0.858
Trifluridine	949	430	1:0.4535	0.6005	0.890
	1420	644		0.8230	0.717
	2140	970		0.8988	0.761
5-Fluorouracil	1420	2700	1:1.900	0.6426	0.881
Azacytidine	949	2740	1:2.885	0.5060	0.895
	1420	4100		0.7364	0.676
AZD6738	422	1040	1:2.455	0.5145	0.449
	633	1550		0.7602	0.350
	949	2330		0.8849	0.315
	1420	3490		0.8809	0.482
Prexasertib	281	1.97	1:0.007018	0.3570	0.349
	422	2.96		0.7264	0.226
	633	4.44		0.8863	0.193
	949	6.66		0.8866	0.288
SCH900776	281	908	1:3.232	0.6117	0.196
	422	1360		0.7479	0.195
	633	2050		0.8581	0.190
	949	3070		0.8783	0.257
Cisplatin	2140	9620	1:4.494	0.9125	0.848
	3200	14400		0.9675	0.694
Oxaliplatin	1420	1060	1:0.7448	0.7172	0.831
Carboplatin	2140	79500	1:37.17	0.9198	0.632
	3200	119000		0.9734	0.502
	4810	179000		0.9841	0.569
Etoposide	1420	3780	1:2.663	0.6999	0.772
Sunitinib	949	1870	1:1.969	0.6537	0.721
	1420	2800		0.8162	0.688
Cabozantinib	2140	9020	1:4.216	0.9173	0.790
Midostaurin	1420	250	1:0.1761	0.7361	0.871
Lapatinib	1420	5990	1:4.216	0.8412	0.480
Luminespib	1420	13.5	1:0.009473	0.7741	0.894
Olaparib	1420	14800	1:10.40	0.6398	0.761
Talazoparib	1420	7980	1:5.617	0.6630	0.661

TABLE 33
Cell line: MV-4-11 (Human blood cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with	Example	Other	Compound 1:
Example	Compound	antitumor	Other
Compound	1	agent	antitumor	Fa	CI
1	(nM)	(nM)	agent)	value	value
Fludarabine	182	4110	1:22.56	0.1868	0.783
nucleoside	273	6160		0.8795	0.592
Cytarabine	121	116	1:0.9614	0.1611	0.683
	182	175		0.4508	0.603
	273	262		0.7678	0.574
	409	393		0.9443	0.538
Decitabine	613	589	1:0.2758	0.9960	0.419
	182	50.2		0.3873	0.643
	273	75.3		0.5342	0.680
	409	113		0.7570	0.667
	613	169		0.9292	0.672
	920	254		0.9900	0.666
Guadecitabine	121	11.9	1:0.09807	0.2186	0.706
	182	17.8		0.3225	0.741
	273	26.8		0.5192	0.705
	409	40.1		0.7788	0.658
	613	60.1		0.9347	0.671
	920	90.2		0.9921	0.639

TABLE 34
Cell line: CFPAC-1 (Human pancreatic cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with	Example	Other	Compound 1:
Example	Compound	antitumor	Other
Compound	1	agent	antitumor	Fa	CI
1	(nM)	(nM)	agent)	value	value
Gemcitabine	507	3.52	1:0.006950	0.5009	0.821
	760	5.28		0.6416	0.790
AZD6738	338	925	1:2.738	0.4791	0.484
	507	1390		0.7266	0.356
	760	2080		0.7884	0.427
Prexasertib	225	1.89	1:0.008406	0.2319	0.825
	338	2.84		0.6056	0.580
	507	4.26		0.7542	0.633
SCH900776	338	253	1:0.7487	0.4162	0.496
	507	380		0.6944	0.369
	760	569		0.7479	0.472

TABLE 35
Cell line: HCT116 (Human large intestine cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with	Example	Other	Compound 1:
Example	Compound	antitumor	Other
Compound	1	agent	antitumor	Fa	CI
1	(nM)	(nM)	agent)	value	value
AZD6738	768	508	1:0.6621	0.8782	0.264
	1150	761		0.9579	0.218
Prexasertib	341	7.14	1:0.02093	0.6993	0.451
	512	10.7		0.9038	0.243
	768	16.1		0.9579	0.197

TABLE 36
Cell line: A549 (Human lung cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with	Example	Other	Compound 1:
Example	Compound	antitumor	Other
Compound	1	agent	antitumor	Fa	CI
1	(nM)	(nM)	agent)	value	value
Fludarabine	517	5910	1:11.44	0.1823	0.818
nucleoside	775	8870		0.5070	0.559
	1160	13300		0.8089	0.405
	1740	19900		0.8431	0.537
Cytarabine	1160	110	1:0.09524	0.4712	0.842
	1740	166		0.7121	0.619
Decitabine	775	1340	1:1.733	0.3618	0.528
	1160	2010		0.4748	0.573
	1740	3020		0.5994	0.627
Guadecitabine	775	469	1:0.6048	0.3478	0.558
	1160	702		0.4476	0.627
	1740	1050		0.5997	0.640
Gemcitabine	1160	5.58	1:0.004813	0.6357	0.865
	1740	8.37		0.8623	0.757
Trifluridine	1160	430	1:0.3703	0.6401	0.842
	1740	644		0.8343	0.696
	2620	970		0.9017	0.744
5-Fluorouracil	1740	4300	1:2.469	0.7276	0.835
Azacytidine	1740	4080	1:2.344	0.6539	0.820
AZD6738	517	1037	1:2.005	0.5213	0.486
	775	1554		0.7989	0.318
	1160	2326		0.8880	0.309
Prexasertib	345	1.98	1:0.005730	0.4283	0.363
	517	2.96		0.7673	0.207
	775	4.44		0.8934	0.174
SCH900776	345	910	1:2.639	0.5875	0.287
	517	1360		0.7191	0.250
	775	2050		0.8457	0.210
	1160	3060		0.8825	0.255
	1740	4590		0.8708	0.411
Cisplatin	2620	3610	1:3.669	0.9341	0.701
	3920	14400		0.9720	0.608
Oxaliplatin	1740	1060	1:0.6082	0.7638	0.787
Carboplatin	2620	79500	1:30.35	0.8844	0.519
	3920	119000		0.9458	0.474
	5890	179000		0.9560	0.627
	8830	268000		0.9773	0.635
Etoposide	1740	3780	1:2.174	0.7574	0.631
Sunitinib	1160	1870	1:1.608	0.7514	0.740
	1740	2800		0.8380	0.811
Cabozantinib	1740	5990	1:3.443	0.8307	0.688
Midostaurin	1740	250	1:0.1438	0.8366	0.624
Lapatinib	1740	5990	1:3.443	0.8672	0.400
Luminespib	1740	13.5	1:0.007735	0.8341	0.828
Olaparib	1740	14800	1:8.494	0.7460	0.575
Talazoparib	1740	7980	1:4.587	0.7568	0.508

TABLE 37
Cell line: MV-4-11 (Human blood cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 5:
use with	Example	antitumor	Other
Example	Compound 5	agent	antitumor	Fa	CI
Compound 5	(nM)	(nM)	agent)	value	value
Fludarabine	370	6150	1:16.62	0.6600	0.739
nucleoside	555	9220		0.9981	0.293
Cytarabine	247	175	1:0.7082	0.4093	0.638
	370	262		0.6725	0.651
	555	393		0.9212	0.553
	833	590		0.9948	0.366
	1250	885		0.9986	0.386
Decitabine	247	50.2	1:0.2032	0.3382	0.685
	370	75.2		0.4753	0.725
	555	113		0.6924	0.709
	833	169		0.8888	0.693
	1250	254		0.9844	0.608
Guadecitabine	164	11.8	1:0.07224	0.2498	0.640
	247	17.8		0.3527	0.683
	370	26.7		0.4905	0.727
	555	40.1		0.7205	0.690
	833	60.2		0.9023	0.673
	1250	90.3		0.9892	0.557

TABLE 38
Cell line: CFPAC-1 (Human pancreatic cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 5:
use with	Example	antitumor	Other
Example	Compound 5	agent	antitumor	Fa	CI
Compound 5	(nM)	(nM)	agent)	value	value
Gemcitabine	700	3.52	1:0.005031	0.5292	0.814
	1050	5.28		0.6974	0.788
AZD6738	311	616	1:1.982	0.2221	0.640
	466	924		0.5986	0.365
	700	1390		0.7586	0.358
	1050	2080		0.7838	0.495
Prexasertib	311	1.89	1:0.006085	0.3644	0.579
	466	2.84		0.6946	0.413
	700	4.26		0.7564	0.525
SCH900776	466	253	1:0.5420	0.6428	0.283
	700	379		0.7803	0.283

TABLE 39
Cell line: HCT116 (Human large intestine cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 5:
use with	Example	antitumor	Other
Example	Compound 5	agent	antitumor	Fa	CI
Compound 5	(nM)	(nM)	agent)	value	value
AZD6738	567	339	1:0.5975	0.3831	0.649
	851	508		0.9186	0.231
	1280	765		0.9567	0.250
Prexasertib	567	10.7	1:0.01889	0.7563	0.289
	851	16.1		0.9499	0.180

TABLE 40
Cell line: A549 (Human lung cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 14:
use with	Example	antitumor	Other
Example	Compound	agent	antitumor	Fa	CI
Compound 14	14 (nM)	(nM)	agent)	value	value
Fludarabine	874	5930	1:6.786	0.3063	0.549
nucleoside	1310	8890		0.7007	0.387
	1970	13400		0.8610	0.377
	2950	20000		0.8736	0.537
Cytarabine	874	72.2	1:0.08259	0.3745	0.670
	1310	108		0.4356	0.790
	1970	163		0.6170	0.616
	2950	244		0.7754	0.498
	4420	365		0.8591	0.490
Decitabine	1970	1340	1:0.6786	0.3867	0.542
	2950	2000		0.5183	0.577
	4420	3000		0.6737	0.602
Guadecitabine	1310	326	1:0.2487	0.2913	0.561
	1970	490		0.4560	0.503
	2950	734		0.5553	0.582
	4420	1100		0.6875	0.620
Gemcitabine	4420	8.38	1:0.001897	0.8565	0.752
Trifluridine	1970	288	1:0.1460	0.4363	0.892
	2950	431		0.6485	0.844
	4420	645		0.8577	0.678
	6640	969		0.9068	0.791
5-Fluorouracil	4420	2700	1:0.6116	0.6619	0.880
Azacytidine	4420	4080	1:0.9241	0.7570	0.744
AZD6738	1310	1040	1:0.7902	0.5577	0.432
	1970	1560		0.7900	0.331
	2950	2330		0.8857	0.322
	4420	3490		0.8807	0.497
Prexasertib	874	1.97	1:0.002259	0.4973	0.277
	1310	2.96		0.7864	0.193
	1970	4.45		0.8986	0.177
SCH900776	874	909	1:1.040	0.6512	0.194
	1310	1360		0.7883	0.184
	1970	2050		0.8714	0.191
	2950	3070		0.8814	0.271
Cisplatin	6640	9600	1:1.446	0.9244	0.791
	9960	14400		0.9690	0.692
Oxaliplatin	4420	1060	1:0.2397	0.7498	0.829
Carboplatin	6640	79400	1:11.96	0.9157	0.620
	9960	119000		0.9630	0.605
	14900	178000		0.9756	0.734
	22400	268000		0.9882	0.773
Etoposide	4420	3790	1:0.8571	0.7245	0.707
Sunitinib	2950	1870	1:0.6339	0.7017	0.693
	4420	2800		0.8248	0.728
Cabozantinib	4420	6000	1:1.357	0.7829	0.868
Midostaurin	4420	251	1:0.05670	0.8117	0.719
Lapatinib	4420	6000	1:1.357	0.8641	0.512
Luminespib	4420	13.5	1:0.003049	0.8373	0.786
Olaparib	4420	14800	1:3.348	0.7031	0.668
Talazoparib	4420	7990	1:1.808	0.7406	0.540

TABLE 41
Cell line: MV-4-11 (Human blood cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 14:
use with	Example	antitumor	Other
Example	Compound	agent	antitumor	Fa	CI
Compound 14	14 (nM)	(nM)	agent)	value	value
Fludarabine	778	6150	1:7.902	0.5954	0.786
nucleoside	1170	9250		0.9984	0.296
Cytarabine	519	175	1:0.3367	0.2908	0.766
	778	262		0.6118	0.691
	1170	394		0.8743	0.599
	1750	589		0.9860	0.387
	2630	886		0.9984	0.269
Decitabine	519	50.1	1:0.09662	0.3361	0.707
	778	75.2		0.4089	0.872
	1170	113		0.5994	0.849
	1750	169		0.8350	0.717
	2630	254		0.9588	0.599
Guadecitabine	519	17.8	1:0.03435	0.3318	0.767
	778	26.7		0.4449	0.844
	1170	40.2		0.6448	0.797
	1750	60.1		0.8620	0.668
	2630	90.3		0.9686	0.545

TABLE 42
Cell line: CFPAC-1 (Human pancreatic cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 14:
use with	Example	antitumor	Other
Example	Compound	agent	antitumor	Fa	CI
Compound 14	14 (nM)	(nM)	agent)	value	value
Gemcitabine	2080	5.28	1:0.002538	0.6749	0.756
	3120	7.92		0.7790	0.752
AZD6738	925	925	1:1.000	0.5930	0.296
	1390	1390		0.7353	0.259
Prexasertib	616	1.89	1:0.003070	0.2455	0.886
	925	2.84		0.6771	0.452
	1390	4.27		0.7725	0.514
SCH900776	925	253	1:0.2734	0.4714	0.465
	1390	380		0.7231	0.322
	2080	569		0.7671	0.409

TABLE 43
Cell line: HCT116 (Human large intestine cancer cell line)
			Molar ratio
Other			of drugs in
antitumor			combined use
agent in			(Example
combined		Other	Compound 14:
use with	Example	antitumor	Other
Example	Compound	agent	antitumor	Fa	CI
Compound 14	14 (nM)	(nM)	agent)	value	value
AZD6738	1000	226	1:0.2257	0.4422	0.804
	1500	339		0.9071	0.235
	2250	508		0.9646	0.192
	3380	763		0.9574	0.322
Prexasertib	1000	7.14	1:0.007135	0.3054	0.535
	1500	10.7		0.8469	0.208
	2250	16.1		0.9453	0.174

TABLE 44
Cell line: A549 (Human lung cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	209A: Other
Compound	Compound	agent	antitumor	Fa	CI
209A	209A (nM)	(nM)	agent)	value	value
Fludarabine	188	5930	1:31.54	0.3666	0.558
nucleoside	282	8890		0.7059	0.386
	423	13300		0.8660	0.339
	635	20000		0.8634	0.515
Cytarabine	188	72.2	1:0.3838	0.3588	0.777
	282	108		0.4675	0.759
	423	162		0.6516	0.581
	635	244		0.7994	0.474
	952	365		0.8410	0.574
Decitabine	423	1330	1:3.154	0.4274	0.542
	635	2000		0.5615	0.569
Guadecitabine	423	489	1:1.156	0.4525	0.577
	635	734		0.6179	0.522
Gemcitabine	635	5.60	1:0.008817	0.7031	0.792
	952	8.39		0.8749	0.791
Trifluridine	423	287	1:0.6784	0.4046	0.883
	635	431		0.5907	0.897
	952	646		0.8235	0.733
	1430	970		0.9021	0.775
5-Fluorouracil	952	4310	1:4.523	0.7187	0.853
Azacytidine	635	2740	1:4.315	0.6005	0.850
	952	4110		0.8264	0.520
AZD6738	282	1040	1:3.672	0.5590	0.402
	423	1550		0.7925	0.315
	635	2330		0.8851	0.317
Prexasertib	188	1.97	1:0.01050	0.5015	0.258
	282	2.96		0.7685	0.189
	423	4.44		0.8944	0.169
SCH900776	188	909	1:4.834	0.6553	0.180
	282	1360		0.7965	0.170
	423	2040		0.8795	0.177
	635	3070		0.8744	0.273
Cisplatin	1430	9610	1:6.722	0.9358	0.709
	2140	14400		0.9740	0.632
Oxaliplatin	952	1060	1:1.114	0.7832	0.762
Carboplatin	1430	79500	1:55.60	0.9282	0.618
	2140	119000		0.9721	0.528
	3210	178000		0.9813	0.630
Etoposide	952	3790	1:3.983	0.7460	0.635
Sunitinib	635	1870	1:2.946	0.6919	0.688
	952	2800		0.8234	0.723
Cabozantinib	952	6000	1:6.307	0.8982	0.486
Midostaurin	952	251	1:0.2635	0.8520	0.583
Lapatinib	952	6000	1:6.307	0.8816	0.443
Luminespib	952	13.5	1:0.01417	0.8172	0.832
Olaparib	952	14800	1:15.56	0.7947	0.478
Talazoparib	952	8000	1:8.402	0.7998	0.422

TABLE 45
Cell line: MV-4-11 (Human blood cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	209A: Other
Compound	Compound	agent	antitumor	Fa	CI
209A	209A (nM)	(nM)	agent)	value	value
Fludarabine	145	6160	1:42.45	0.9458	0.598
nucleoside
Cytarabine	96.6	175	1:1.809	0.5055	0.739
	145	262		0.8261	0.664
	217	393		0.9736	0.510
	326	590		0.9981	0.330
Decitabine	64.4	33.4	1:0.5191	0.2551	0.793
	96.6	50.1		0.3812	0.839
	145	75.2		0.6143	0.790
	217	113		0.8536	0.715
	326	169		0.9689	0.627
Guadecitabine	96.6	17.8	1:0.1845	0.4376	0.766
	145	26.8		0.6306	0.767
	217	40.0		0.8301	0.753
	326	60.1		0.9675	0.631

TABLE 46
Cell line: CFPAC-1 (Human pancreatic cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	209A: Other
Compound	Compound	agent	antitumor	Fa	CI
209A	209A (nM)	(nM)	agent)	value	value
Gemcitabine	339	3.52	1:0.01039	0.5348	0.855
	508	5.28		0.6998	0.736
AZD6738	226	925	1:4.093	0.5736	0.478
	339	1390		0.7322	0.429
	508	2080		0.7827	0.531
Prexasertib	151	1.90	1:0.01256	0.3163	0.735
	226	2.84		0.6872	0.558
	339	4.26		0.7662	0.704
SCH900776	226	253	1:1.119	0.5579	0.385
	339	379		0.7356	0.348
	508	568		0.7649	0.474

TABLE 47
Cell line: HCT116 (Human large intestine cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	209A: Other
Compound	Compound	agent	antitumor	Fa	CI
209A	209A (nM)	(nM)	agent)	value	value
AZD6738	281	339	1:1.206	0.2770	0.877
	421	508		0.8773	0.289
	632	762		0.9571	0.242
Prexasertib	187	7.13	1:0.03813	0.1703	0.792
	281	10.7		0.8191	0.230
	421	16.1		0.9441	0.173

TABLE 48
Cell line: A549 (Human lung cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	235A: Other
Compound	Compound	agent	antitumor	Fa	CI
235A	235A (nM)	(nM)	agent)	value	value
Fludarabine	520	8870	1:17.06	0.4460	0.568
nucleoside	780	13300		0.7798	0.423
	1170	20000		0.8525	0.504
	1750	29900		0.8595	0.734
Cytarabine	780	111	1:0.1421	0.4015	0.878
	1170	166		0.6327	0.693
	1750	249		0.8184	0.581
Decitabine	520	1340	1:2.584	0.2897	0.570
	780	2020		0.4383	0.567
	1170	3020		0.5537	0.650
Guadecitabine	520	469	1:0.9020	0.2878	0.568
	780	704		0.4237	0.583
	1170	1060		0.5377	0.670
Gemcitabine	780	5.60	1:0.007179	0.6511	0.844
	1170	8.40		0.8624	0.714
Trifluridine	780	431	1:0.5524	0.5850	0.869
	1170	646		0.8250	0.680
	1750	967		0.8950	0.739
5-Fluorouracil	1170	4310	1:3.682	0.6738	0.880
Azacytidine	780	2740	1:3.514	0.5392	0.822
	1170	4110		0.6909	0.767
AZD6738	346	1030	1:2.990	0.5478	0.435
	520	1550		0.7920	0.323
	780	2330		0.8869	0.314
	1170	3500		0.8817	0.486
Prexasertib	231	1.97	1:0.008547	0.4315	0.331
	346	2.96		0.7784	0.191
	520	4.44		0.8915	0.174
SCH900776	231	909	1:3.936	0.6135	0.262
	346	1360		0.7038	0.280
	520	2050		0.8035	0.275
	780	3070		0.8771	0.275
	1170	4610		0.8705	0.430
Cisplatin	1750	9580	1:5.473	0.9113	0.832
	2630	14400		0.9711	0.635
Oxaliplatin	1170	1060	1:0.9071	0.7355	0.793
Carboplatin	1750	79200	1:45.27	0.8325	0.609
	2630	119000		0.9438	0.461
	3950	179000		0.9600	0.575
	5920	268000		0.9739	0.688
Etoposide	1170	3790	1:3.243	0.6978	0.763
Sunitinib	780	1870	1:2.399	0.6775	0.709
	1170	2810		0.8225	0.675
Cabozantinib	1170	6010	1:5.135	0.7659	0.871
Midostaurin	1170	251	1:0.2145	0.7639	0.775
Lapatinib	1170	6010	1:5.135	0.8726	0.417
Luminespib	1750	8.13	1:0.004645	0.8795	0.819
Olaparib	1170	14800	1:12.67	0.6832	0.683
Talazoparib	1170	8000	1:6.841	0.6990	0.585

TABLE 49
Cell line: MV-4-11 (Human blood cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	235A: Other
Compound	Compound	agent	antitumor	Fa	CI
235A	235A (nM)	(nM)	agent)	value	value
Fludarabine	203	6150	1:30.32	0.7607	0.746
nucleoside	304	9220	1:1.292	0.9988	0.320
Cytarabine	90.1	116		0.1704	0.740
	135	174		0.4683	0.645
	203	262		0.7568	0.624
	304	393		0.9522	0.510
	456	589		0.9958	0.365
	684	884		0.9989	0.374
Decitabine	90.1	33.4	1:0.3708	0.2126	0.725
	135	50.1		0.3356	0.757
	203	75.3		0.5302	0.764
	304	113		0.7532	0.760
	456	169		0.9339	0.687
	684	254		0.9935	0.535
Guadecitabine	90.1	11.9	1:0.1318	0.2567	0.633
	135	17.8		0.4131	0.638
	203	26.8		0.5802	0.696
	304	40.1		0.7974	0.689
	456	60.1		0.9524	0.617
	684	90.2		0.9930	0.544

TABLE 50
Cell line: CFPAC-1 (Human pancreatic cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	235A: Other
Compound	Compound	agent	antitumor	Fa	CI
235A	235A (nM)	(nM)	agent)	value	value
Gemcitabine	722	5.28	1:0.007318	0.6762	0.722
AZD6738	214	617	1:2.883	0.2450	0.777
	321	925		0.5873	0.338
	481	1390		0.7446	0.295
	722	2080		0.7899	0.368
Prexasertib	214	1.89	1:0.008850	0.3469	0.645
	321	2.84		0.6687	0.344
	481	4.26		0.7578	0.372
SCH900776	321	253	1:0.7883	0.4978	0.474
	481	379		0.7223	0.382
	722	569		0.7722	0.484

TABLE 51
Cell line: HCT116 (Human large intestine cancer cell line)
Other			Molar ratio
antitumor			of drugs in
agent in			combined use
combined			(Example
use with		Other	Compound
Example	Example	antitumor	235A: Other
Compound	Compound	agent	antitumor	Fa	CI
235A	235A (nM)	(nM)	agent)	value	value
AZD6738	475	339	1:0.7135	0.6249	0.429
	712	508		0.9468	0.182
Prexasertib	317	7.15	1:0.02255	0.3131	0.557
	475	10.7		0.8595	0.224
	712	16.1		0.9459	0.197

It is apparent from these results that all the sulfonamide compounds represented by formula (I) synergistically inhibit the growth of a human lung cancer cell line, a human blood cancer cell line, a human pancreatic cancer cell line, and a human large intestine cancer cell line when used in combination with any of various antitumor agents including an antimetabolite, a platinum drug, a plant alkaloid drug, and a molecular targeting drug.

Furthermore, the combined administration groups of the sulfonamide compound represented by formula (I) and the other antitumor agent in the in vivo test using nude mice (BALB/cA Jcl-nu/nu) in which human tumor cells were transplanted showed a statistically significant antitumor effect as compared with the single administration groups of each drug on the final evaluation day. In addition, the rate of change in body weight in the combined administration groups was less than 20% of the body weight before administration (on day 0) and was change within an acceptable range.

All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

1-15. (canceled)

16: A method of treating and/or preventing tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sulfonamide compound represented by the following formula (I):

17: The method according to claim 16, wherein in formula (I): X1 represents an oxygen atom;X2 represents an oxygen atom;X3 represents —NH—;X4 represents a hydrogen atom;R1 represents —C(R11)(R12)—;R11 and R12 are the same or different and represent a hydrogen atom or a C1-C6 alkyl group;R2 represents a C6-C14 aromatic hydrocarbon group, wherein R2 may have R21 as a substituent;R21 represents a halogen atom or a C1-C6 alkyl group (when two or more of R21 are present, R21 are the same as or different from each other);R3 represents a C6-C14 aromatic hydrocarbon group which may have R31 as a substituent or may be fused with a 4-8 membered saturated heterocyclic ring (wherein the saturated heterocyclic ring may have Rc as a substituent);R31 represents a halogen atom or an aminocarbonyl group (when two or more of R31 are present, R31 are the same as or different from each other);Rc represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group (when two or more of Rc are present, Rc are the same as or different from each other); andR4 represents a hydrogen atom.

18: The method according to claim 16, wherein in formula (I), X1 represents an oxygen atom;X2 represents an oxygen atom;X3 represents —NH—;X4 represents a hydrogen atom;R1 represents —C(R11)(R12)—;one of R11 and R represents a hydrogen atom, and the other represents a C1-C6 alkyl group;R2 represents a phenyl group, wherein R2 may have R21 as a substituent;R21 represents a halogen atom or a C1-C6 alkyl group (when two or more of R21 are present, R21 are the same as or different from each other);R3 represents a phenyl group which may have R31 as a substituent or may be fused with a monocyclic 6 membered saturated heterocyclic ring having one oxygen atom (wherein the saturated heterocyclic ring may have Rc as a substituent);R31 represents a halogen atom or an aminocarbonyl group (when two or more of R31 are present, R31 are the same as or different from each other);Rc represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group (when two or more of Rc are present, Rc are the same as or different from each other); andR4 represents a hydrogen atom.

19: The method according to claim 16, wherein in formula (I), X1 represents an oxygen atom;X2 represents an oxygen atom;X3 represents —NH—;X4 represents a hydrogen atom;R1 represents —C(R11)(R12)—;one of R11 and R12 represents a hydrogen atom, and the other represents a methyl group;R2 represents a phenyl group having R21 as a substituent;R21 represents a halogen atom or a C1-C6 alkyl group (when two or more of R21 are present, R21 are the same as or different from each other);R3 represents a phenyl group having R31 as a substituent or a chromanyl group having Rc as a substituent;R31 represents a halogen atom or an aminocarbonyl group (when two or more of R31 are present, R31 are the same as or different from each other);Rc represents a halogen atom, a hydroxy group, or a C1-C6 alkyl group (when two or more of Rc are present, Rc are the same as or different from each other); andR4 represents a hydrogen atom.

20: The method according to claim 16, wherein the sulfonamide compound is selected from the following compounds (1)-(5): (1) 5-bromo-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;(2) 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;(3) 5-chloro-2-(N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide;(4) 5-chloro-N-((1S,2R)-2-(3-chloro-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxy-4-methylchromane-8-sulfonamide; and(5) 5-chloro-N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-hydroxychromane-8-sulfonamide.

21: The method according to claim 16, wherein the sulfonamide compound represented by formula (I) or a salt thereof and the at least one another antitumor agent are administered concurrently, sequentially, or in a staggered manner.

22: The method according to claim 16, wherein the at least one another antitumor agent is at least one or more selected from an antimetabolite, a platinum drug, a plant alkaloid drug, and a molecular targeting drug.

23: The method according to claim 16, wherein the at least one another antitumor agent is at least one or more selected from 5-fluorouracil (5-FU), trifluridine, fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, decitabine, guadecitabine, azacitidine, cisplatin, oxaliplatin, carboplatin, etoposide, AZD6738, prexasertib, SCH900776, luminespib, olaparib, talazoparib, lapatinib, sunitinib, cabozantinib, and midostaurin.

24: A method of enhancing an antitumor effect of an antitumor agent in a subject in need thereof, comprising administering to the subject a sulfonamide compound represented by the following formula (I):

25: The method according to claim 24, wherein at least one another antitumor agent is administered concurrently, sequentially, or in a staggered manner with the sulfonamide compound or the salt thereof.

26: The method according to claim 24, wherein at least one another antitumor agent is administered as a combination formulation with the sulfonamide compound or the salt thereof.

27: A pharmaceutical composition comprising a sulfonamide compound or a salt thereof and at least one another antitumor agent, wherein the sulfonamide compound is a compound represented by the following formula (I):

28: A method of treating and/or preventing tumor in a patient diagnosed with cancer dosed with an antitumor agent, comprising administering to the patient a sulfonamide compound represented by the following formula (I):