JP2017071603A - Pharmaceutical composition comprising dihydrothiazine or dihydrooxazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having an amyloid β production inhibitory action, particularly a BACE1 inhibitory action, which is useful as a therapeutic or prophylactic agent, for diseases caused by the production, secretion, and/or deposition of amyloid β-protein.SOLUTION: The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. (X is -S- or -O-; Ris an allyl, haloalkyl, and the like; Ris H, halogen, alkyloxy, haloalkyloxy, etc .; Ris H; Ris H or alkyl; ring A and ring B each independently represent a substituted/unsubstituted aromatic carbocyclic ring, substituted/unsubstituted aromatic heterocyclic ring, etc.; and Ris a substituted or unsubstituted alkyl)SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition having an amyloid β production inhibitory effect and useful as a therapeutic or prophylactic agent for diseases induced by the production, secretion and / or deposition of amyloid β protein.

  In the brain of Alzheimer's disease patients, insoluble spots (senile plaques) in which a peptide consisting of about 40 amino acids called amyloid β protein accumulates outside the nerve cells are widely observed. It is believed that Alzheimer's disease develops when this senile plaque kills nerve cells, and amyloid β protein degradation accelerators, amyloid β vaccines, and the like have been studied as therapeutic agents for Alzheimer's disease.

  Secretase is an enzyme that cleaves a protein called amyloid precursor protein (APP) in cells to produce amyloid β protein. The enzyme responsible for generating the N-terminus of amyloid β protein is called β-secret APP (cleaving enzyme 1, BACE 1). By inhibiting this enzyme, amyloid β protein production is suppressed, and it is considered that it can be a therapeutic or preventive agent for Alzheimer's disease.

  Patent Documents 1 to 39 and Non-Patent Document 1 describe compounds similar in structure to the compounds according to the present invention. Although these documents describe that they are useful as therapeutic agents for Alzheimer's disease, Alzheimer-related symptoms, diabetes, etc., all of the disclosed compounds are different from the compounds according to the present invention. It has a structure.

International Publication No. 2007/049532 International Publication No. 2008/133273 International Publication No. 2008/133274 International Publication No. 2009/151098 International Publication No. 2010/047372 International Publication No. 2010/113848 International Publication No. 2011/071057 International Publication No. 2011/058763 International Publication No. 2011/077071 International Publication No. 2011/0777726 International Publication No. 2011-071135 International Publication No. 2011-071109 International Publication No. 2012/057247 International Publication No. 2012/057248 International Publication No. 2012/147762 International Publication No. 2012/147773 Japanese Patent Publication 2012 / 250933A International Publication No. 2014/010748 Japanese Patent Publication No. 2014 / 101354A International Publication No. 2014/065434 Japanese Patent Publication No. 2014 / 101353A International Publication No. 2013/110622 International Publication No. 2014/001228 International Publication No. 2013/041499 International Publication No. 2012/107371 International Publication No. 2011/069934 International Publication No. 2011/070029 International Publication No. 2012/139993 International Publication No. 2012/168164 International Publication No. 2012/168175 International Publication No. 2012/156284 International Publication No. 2014/166906 International Publication No. 2014/114532 International Publication No. 2013/027188 International Publication No. 2014/134341 International Publication No. 2008/103351 US Patent Publication No. 2008/0200445 US Patent Publication No. 2006/0287294 International Publication No. 2014/098831 International Publication No. 2015/156421

Journal of Medicinal Chemistry 2013, 56, 10, 3980-3955

  The present invention relates to a pharmaceutical composition comprising a compound having a suppressive effect on amyloid β protein production, particularly a BACE1 inhibitory effect, and useful as a therapeutic agent for a disease induced by production, secretion and / or deposition of amyloid β protein. provide.

  The present invention provides the following inventions, for example.

（式中、
Ｘは−Ｓ−または−Ｏ−であり、
（ｉ）Ｘが−Ｓ−であるとき、
Ｒ^３ａはアルキル、ハロアルキル、ヒドロキシアルキルまたはアルキルオキシアルキルであり、
Ｒ^２ａはハロゲン、アルキルオキシまたはハロアルキルオキシであり、かつ、
Ｒ^３ａがハロアルキルであるとき、Ｒ^２ａはアルキルでもよく、
Ｒ^２ｂはＨであり、
Ｒ^２ａおよびＲ^２ｂが、それらが結合している炭素原子と一緒になって置換されたシクロアルカンを形成してもよく、
Ｒ^２ａおよびＲ^２ｂが、それらが結合している炭素原子と一緒になって置換されたシクロアルカンを形成するとき、Ｒ^３ａはＨでもよく、
（ｉｉ）Ｘが−Ｏ−であるとき、
Ｒ^３ａはアルキルオキシおよびシクロアルキルから選択される一以上の基で置換されていてもよいハロアルキル、またはハロゲンから選択される一以上の基で置換されているシクロアルキルであり、
Ｒ^２ａはＨ、ハロゲン、アルキル、アルキルオキシまたはハロアルキルオキシであり、
Ｒ^２ｂはＨであり、
Ｒ^２ａおよびＲ^２ｂが、それらが結合している炭素原子と一緒になって置換されたシクロアルカンを形成してもよく、
Ｒ^２ａおよびＲ^２ｂが、それらが結合している炭素原子と一緒になって置換されたシクロアルカンを形成するとき、Ｒ^３ａはＨまたはアルキルでもよく、

Ｒ^３ｂはＨまたはアルキルであり、

であってもよく、
環Ａは置換若しくは非置換の芳香族炭素環、置換若しくは非置換の非芳香族炭素環、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環であり、
環Ｂは置換若しくは非置換の芳香族炭素環、置換若しくは非置換の非芳香族炭素環、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環であり、
Ｒ^１は置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニルまたは置換若しくは非置換のシクロアルキルであり、
Ｒ^５はハロゲンまたは置換若しくは非置換のアルキルであり、
ｎは０〜２の整数であり、
ただし、以下の化合物を除く。
（１）Ｘが−Ｏ−であり、Ｒ^３ａがＣＨ_２ＦまたはＣＦ_３であり、Ｒ^３ｂがＨであり、Ｒ^２ａがＨまたはＦであり、かつＲ^２bがＨである化合物、
（２）Ｘが−Ｏ−であり、Ｒ^３ａがＣＨＦ_２であり、Ｒ^３ｂがＨであり、Ｒ^２ａがＯＭｅであり、かつＲ^２bがＨである化合物、および、
（３）以下の化合物：

）
で示される化合物またはその製薬上許容される塩を含有する医薬組成物。
（１−１）式（Ｉ）：

（式中、
Ｘは−Ｏ−または−Ｓ−であり、
（ｉ）Ｘが−Ｏ−であるとき、
Ｒ^３ａはハロアルキルであり、
Ｒ^２ａはＨ、ハロゲン、アルキル、アルキルオキシまたはハロアルキルオキシであり、
（ｉｉ）Ｘが−Ｓ−であるとき、
Ｒ^３ａはアルキルまたはハロアルキルであり、
Ｒ^２ａはハロゲン、アルキルオキシまたはハロアルキルオキシであり、かつ、
Ｒ^３ａがハロアルキルのとき、Ｒ^２ａはアルキルでもよく、
Ｒ^３ｂはＨまたはアルキルであり、

であってもよく、
環Ａは置換若しくは非置換の芳香族炭素環、置換若しくは非置換の非芳香族炭素環、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環であり、
環Ｂは置換若しくは非置換の芳香族炭素環、置換若しくは非置換の非芳香族炭素環、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環であり、
Ｒ^１は置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニルまたは置換若しくは非置換のシクロアルキルであり、
Ｒ^５はハロゲンまたは置換若しくは非置換のアルキルであり、
ｎは０〜２の整数であり、
ただし、以下の化合物を除く。
（１）Ｘが−Ｏ−であり、Ｒ^３ａがＣＨ_２ＦまたはＣＦ_３であり、Ｒ^３ｂがＨであり、かつＲ^２ａがＨまたはＦである化合物、および、
（２）以下の化合物：

）
で示される化合物またはその製薬上許容される塩を含有する医薬組成物。
（１−２）以下の化合物を除く化合物またはその製薬上許容される塩を含有する、項目（１）記載の医薬組成物。
（１）Ｘが−Ｏ−であり、Ｒ^３ａがＣＨ_２ＦまたはＣＦ_３であり、Ｒ^３ｂがＨであり、かつＲ^２ａがＨ、ＦまたはＯＭｅである化合物、および、
（３）Ｘが−Ｏ−であり、Ｒ^３ａがＣＨＦ_２であり、Ｒ^３ｂがＨであり、かつＲ^２ａがＯＭｅである化合物。 (1) Formula (I):

(Where
X is —S— or —O—;
(I) when X is -S-
R ^3a is alkyl, haloalkyl, hydroxyalkyl or alkyloxyalkyl;
R ^2a is halogen, alkyloxy or haloalkyloxy, and
When R ^3a is haloalkyl, R ^2a may be alkyl;
R ^2b is H;
R ^2a and R ^2b together with the carbon atom to which they are attached may form a substituted cycloalkane;
When R ^2a and R ^2b together with the carbon atom to which they are attached form a substituted cycloalkane, R ^3a may be H;
(Ii) when X is -O-
R ^3a is haloalkyl optionally substituted with one or more groups selected from alkyloxy and cycloalkyl, or cycloalkyl substituted with one or more groups selected from halogen;
R ^2a is H, halogen, alkyl, alkyloxy or haloalkyloxy,
R ^2b is H;
R ^2a and R ^2b together with the carbon atom to which they are attached may form a substituted cycloalkane;
When R ^2a and R ^2b together with the carbon atom to which they are attached form a substituted cycloalkane, R ^3a may be H or alkyl;

R ^3b is H or alkyl;

May be,
Ring A is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted nonaromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted nonaromatic heterocyclic ring,
Ring B is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl;
R ⁵ is halogen or substituted or unsubstituted alkyl;
n is an integer from 0 to 2,
However, the following compounds are excluded.
(1) A compound wherein X is —O—, R ^3a is CH ₂ F or CF ₃ , R ^3b is H, R ^2a is H or F, and R ^2b is H,
(2) a compound wherein X is —O—, R ^3a is CHF ₂ , R ^3b is H, R ^2a is OMe and R ^2b is H, and
(3) The following compounds:

)
Or a pharmaceutically acceptable salt thereof.
(1-1) Formula (I):

(Where
X is —O— or —S—,
(I) when X is -O-
R ^3a is haloalkyl;
R ^2a is H, halogen, alkyl, alkyloxy or haloalkyloxy,
(Ii) when X is -S-
R ^3a is alkyl or haloalkyl;
R ^2a is halogen, alkyloxy or haloalkyloxy, and
When R ^3a is haloalkyl, R ^2a may be alkyl;
R ^3b is H or alkyl;

May be,
Ring A is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted nonaromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted nonaromatic heterocyclic ring,
Ring B is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl;
R ⁵ is halogen or substituted or unsubstituted alkyl;
n is an integer from 0 to 2,
However, the following compounds are excluded.
(1) a compound wherein X is —O—, R ^3a is CH ₂ F or CF ₃ , R ^3b is H, and R ^2a is H or F; and
(2) The following compounds:

)
Or a pharmaceutically acceptable salt thereof.
(1-2) The pharmaceutical composition according to item (1), comprising a compound excluding the following compound or a pharmaceutically acceptable salt thereof:
(1) a compound wherein X is —O—, R ^3a is CH ₂ F or CF ₃ , R ^3b is H, and R ^2a is H, F or OMe, and
(3) A compound wherein X is —O—, R ^3a is CHF ₂ , R ^3b is H, and R ^2a is OMe.

であり、Ｒ^５がハロゲンであり、ｎが１または２である、項目（２）記載の医薬組成物。
（９）式（Ｉ）においてＲ^３ａが置換されたハロアルキルであり、該置換基がアルキルオキシまたはシクロアルキルである、項目（２）または（４）記載の医薬組成物。
（１０）式（Ｉ）においてＸが−Ｓ−であり、Ｒ^２ａがハロゲンまたはアルキルオキシであり、Ｒ^２ｂがＨであり、Ｒ^３ａがアルキル、ハロアルキル、ヒドロキシアルキルまたはアルキルオキシアルキルであり、Ｒ^３ｂがＨである、項目（１）、（１−１）および（１−２）のいずれかに記載の医薬組成物。
（１１）式（Ｉ）においてＸが−Ｓ−であり、Ｒ^２ａがＦであり、Ｒ^２ｂがＨであり、Ｒ^３ａがＣＨ_３またはＣＨ_２Ｆであり、Ｒ^３ｂがＨである、項目（１）記載の医薬組成物。
（１２）式（Ｉ）においてＲ^２ａおよびＲ^２ｂが、それらが結合している炭素原子と一緒になってハロゲンで置換されたシクロアルカンを形成し、Ｒ^３ａがＨまたはアルキルである、項目（１）、（１−１）および（１−２）のいずれかに記載の医薬組成物。
（１３）式（Ｉ）においてＲ^１がアルキルである、項目（１）、（１−１）、（１−２）、（２）〜（５）、（５−１）、（６）、（６−１）、および（７）〜（１２）のいずれかに記載の医薬組成物。
（１４）式（Ｉ）において環Ａが

（式中、Ｒ^４はＨまたはハロゲンであり、−Ｚ＝は−ＣＨ＝または−Ｎ＝である）
である、項目（１）、（１−１）、（１−２）、（２）（５）、（５−１）、（６）、（６−１）、および（７）〜（１３）のいずれかに記載の医薬組成物。
（１５）式（Ｉ）においてＲ^４がハロゲンであり、−Ｚ＝が−ＣＨ＝である、項目（１４）記載の医薬組成物。
（１６）式（Ｉ）において環Ｂが置換若しくは非置換のピリジン、置換若しくは非置換のピラジン、置換若しくは非置換のピリミジン、置換若しくは非置換のピリダジンまたは置換若しくは非置換のオキサゾールである、項目（１）、（１−１）、（１−２）、（２）〜（５）、（５−１）、（６）、（６−１）、および（７）〜（１５）〜（１５）のいずれかに記載の医薬組成物。
（１６−１）式（Ｉ）において環Ｂが置換若しくは非置換のピリジン、置換若しくは非置換のピラジン、または置換若しくは非置換のオキサゾールである、項目（１）、（１−１）、（１−２）、（２）〜（５）、（５−１）、（６）、（６−１）、および（７）〜（１５）のいずれかに記載の医薬組成物。 (2) The pharmaceutical composition according to item (1), (1-1) or (1-2), wherein X is —O— in formula (I).
(3) Item (2) description in which R ^3a in formula (I) is CH ₂ F, CHF ₂ , CF ₃ , CH (F) CH ₃ or CF ₂ CH ₃ , and R ^3b is H or CH ₃ of.
(4) The pharmaceutical composition according to item (2) or (3), wherein in formula (I), R ^2a is H, F, CH ₃ , OCH ₃ or OCH ₂ CF ₃ .
(5) In the formula (I), R ^2a is H, halogen or alkyl, R ^2b is H, R ^3a is CHF ₂ , CH (F) CH ₃ or CF ₂ CH ₃ , Item (2) Or the pharmaceutical composition of (3) description.
(5-1) In item (2) or (3), in formula (I), R ^2a is H or halogen, and R ^3a is CHF ₂ , CH (F) CH ₃ or CF ₂ CH ₃ Pharmaceutical composition.
(6) In formula (I), R ^2a is H or halogen, R ^2b is H, R ^3a is CH ₂ F or CF ₃ , R ^3b is alkyl, and R ¹ is unsubstituted alkyl The pharmaceutical composition according to item (2), wherein
(6-1) The pharmaceutical composition according to item (2), wherein in formula (I), R ^2a is H or halogen, R ^3a is CH ₂ F or CF ₃ , and R ^3b is alkyl.
(7) The pharmaceutical composition according to item (2) or (3), wherein in formula (I), R ^2a is alkyl, alkyloxy or haloalkyloxy.
(8)
In formula (I)

The pharmaceutical composition according to item (2), wherein R ⁵ is halogen and n is 1 or 2.
(9) The pharmaceutical composition according to item (2) or (4), wherein in formula (I), R ^3a is a substituted haloalkyl, and the substituent is alkyloxy or cycloalkyl.
(10) In the formula (I), X is —S—, R ^2a is halogen or alkyloxy, R ^2b is H, R ^3a is alkyl, haloalkyl, hydroxyalkyl or alkyloxyalkyl, R The pharmaceutical composition according to any one of items (1), (1-1) and (1-2), wherein ^3b is H.
(11) In the formula (I), X is —S—, R ^2a is F, R ^2b is H, R ^3a is CH ₃ or CH ₂ F, and R ^3b is H. (1) The pharmaceutical composition as described.
(12) In formula (I), R ^2a and R ^2b together with the carbon atom to which they are attached form a cycloalkane substituted with halogen, and R ^3a is H or alkyl, 1) The pharmaceutical composition according to any one of (1-1) and (1-2).
(13) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), wherein R ¹ is alkyl in formula (I), The pharmaceutical composition according to any one of (6-1) and (7) to (12).
(14) In formula (I), ring A is

(Wherein R ⁴ is H or halogen, -Z = is -CH = or -N =)
Items (1), (1-1), (1-2), (2) (5), (5-1), (6), (6-1), and (7) to (13) ) The pharmaceutical composition according to any one of
(15) The pharmaceutical composition according to item (14), wherein in formula (I), R ⁴ is halogen and -Z = is -CH =.
(16) Item (I) wherein ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, or substituted or unsubstituted oxazole; 1), (1-1), (1-2), (2) to (5), (5-1), (6), (6-1), and (7) to (15) to (15) ) The pharmaceutical composition according to any one of
(16-1) Items (1), (1-1), (1) in which ring B in formula (I) is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, or substituted or unsubstituted oxazole -2), (2)-(5), (5-1), (6), (6-1), and the pharmaceutical composition in any one of (7)-(15).

(17) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), (6-1), (6-1) having BACE1 inhibitory activity The pharmaceutical composition according to any one of 7) to (16) and (16-1).
(18) Items (1), (1-1), (1-2), (2) to (5) for the treatment or prevention of a disease induced by production, secretion or deposition of amyloid β protein, The pharmaceutical composition according to any one of (5-1), (6), (6-1), (7) to (16) and (16-1).
(19) Alzheimer-type dementia, mild cognitive impairment or amnestic mild cognitive impairment treatment or prevention, Alzheimer-type dementia, mild cognitive impairment or amnestic mild cognitive impairment progression, or Alzheimer Items (1), (1-1), (1-2), (2) to (2) for prevention of progression in asymptomatic patients at risk for type dementia (a patient asymptomatic at risk for Alzheimer dementia) The pharmaceutical composition according to any one of (5), (5-1), (6), (6-1), (7) to (16) and (16-1).
(20) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), (6) for treatment or prevention of Alzheimer's dementia The pharmaceutical composition according to any one of 6-1), (7) to (16) and (16-1).
(21) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), (6-1), (7) to (16) ) And (16-1), or a pharmaceutical composition for oral administration comprising the compound or a pharmaceutically acceptable salt thereof.
(22) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions or tinctures (21) The pharmaceutical composition of description.
(23) Sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets, orally disintegrating tablets, dry syrups, soft capsules, microcapsules or sustained-release capsules The pharmaceutical composition according to (22), wherein
(24) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), (6-1), (7) to (16) ) And a pharmaceutical composition for parenteral administration comprising the compound according to any one of (16-1) or a pharmaceutically acceptable salt thereof.
(25) The pharmaceutical composition according to (24), for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.
(26) Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellies, The pharmaceutical composition according to (24) or (25), which is a cream, a patch, a poultice, a powder for external use or a suppository.
(27) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), (6-1), (7) to (16) ) And a pharmaceutical composition for children or the elderly, comprising the compound according to any one of (16-1) and (16-1), or a pharmaceutically acceptable salt thereof.
(28) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), (6-1), (7) to (16) ) And (16-1), or a pharmaceutically acceptable salt thereof, and a combination of an acetylcholinesterase inhibitor, an NMDA antagonist, or other medicaments for Alzheimer-type dementia Composition.
(29) Items (1), (1-1), (1-2), (2) for combination therapy with acetylcholinesterase inhibitors, NMDA antagonists, or other drugs for Alzheimer-type dementia ) To (5), (5-1), (6), (6-1), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising

  The composition of the present invention has BACE1 inhibitory activity and is useful as a therapeutic and / or prophylactic agent for diseases (such as Alzheimer type dementia) induced by production, secretion or deposition of amyloid β protein.

The meaning of each term used in this specification will be described below. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.
In this specification, the term “consisting of” means having only constituent elements.
In the present specification, the term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.
In the present specification, “halogen” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
In the present specification, “alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and the like can be mentioned.
In one embodiment, “alkyl” is methyl, ethyl, n-propyl, isopropyl, tert-butyl.
“Alkenyl” refers to a straight or branched chain having 2 to 15 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more double bonds at any position. Includes branched hydrocarbon groups. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc. For example, vinyl, allyl, propenyl, isopropenyl, butenyl are mentioned.

  “Alkynyl” has 2 to 15 carbon atoms, such as 2 to 10 carbon atoms, for example 2 to 8 carbon atoms, for example 2 to 6 carbon atoms, for example 2 to 2 carbon atoms, having one or more triple bonds at any position. Includes 4 straight chain or branched alkynyl. Specific examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. These may further have a double bond at an arbitrary position. Examples include ethynyl, propynyl, butynyl, pentynyl.

“Alkylene” includes a straight or branched divalent carbon chain having 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, for example 1 to 4 carbon atoms. Examples include methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
The alkylene part of “alkylenedioxy” is the same as the above “alkylene”. Examples include methylenedioxy and dimethylenedioxy.

The “aromatic carbocyclic group” includes a monocyclic or two or more cyclic aromatic hydrocarbon group. For example, it is a C6-C14 cyclic aromatic hydrocarbon group, and specific examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
One embodiment of the “aromatic carbocyclic group” includes phenyl.

「単環非芳香族炭素環」は、炭素数３〜１６の基を包含し、例えば炭素数３〜１２、例えば炭素数３〜８、例えば炭素数３〜５である。例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン、シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロヘキサジエン等が挙げられる。
２環以上の非芳香族炭素環式基は炭素数６〜１４の基を包含し、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocyclic group” includes a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The non-aromatic carbocyclic group having two or more rings includes a monocyclic non-aromatic carbocyclic ring or a group in which two or more non-aromatic carbocyclic rings are condensed to the ring in the above “aromatic carbocyclic group”. .
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.

“Monocyclic non-aromatic carbocycle” includes a group having 3 to 16 carbon atoms, for example, 3 to 12 carbon atoms, for example 3 to 8 carbon atoms, for example 3 to 5 carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
Two or more non-aromatic carbocyclic groups include groups having 6 to 14 carbon atoms, and examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.

“Cycloalkyl” is a carbocyclic group having 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, for example 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. , Cyclononyl, cyclodecyl and the like.
A “cycloalkane” is a carbocyclic ring having 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, for example 3 to 5 carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane and cyclodecane.
The cycloalkyl part of “cycloalkylalkyl”, “cycloalkylamino” and “cycloalkylalkyloxy” is the same as the above “cycloalkane”.

The “aromatic heterocyclic group” includes monocyclic or bicyclic or more aromatic cyclic groups having one or more heteroatoms independently selected from O, S and N.
The aromatic heterocyclic group having two or more rings is a monocyclic aromatic heterocyclic group or a non-aromatic heterocyclic group containing two or more rings condensed with the above “aromatic carbocyclic group”. Is included.
The monocyclic aromatic heterocyclic group includes a 5- to 8-membered cyclic group, for example, a 5-membered or 6-membered group. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
Bicyclic aromatic heterocyclic groups include 9-10 membered cyclic groups such as indolinyl, isoindolinyl, indazolinyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, Benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolo Examples include pyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl and the like.
The aromatic heterocyclic group having 3 or more rings includes a 13 to 14 membered cyclic group, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.

単環の非芳香族複素環式基は、３〜８員環を包含し、例えば、４員、５員または６員環である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル等が挙げられる。
２環以上の非芳香族複素環式基としては、９〜１４員環式基を包含し、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 “Non-aromatic heterocyclic group” includes a monocyclic or bicyclic or more non-aromatic cyclic group having one or more heteroatoms independently selected from O, S and N.
The non-aromatic heterocyclic group having two or more rings is a monocyclic non-aromatic heterocyclic group or a non-aromatic heterocyclic group having two or more rings, the above “aromatic carbocyclic group” or “non-aromatic”. Also included are those fused to the ring of “Aromatic carbocyclic group” and / or “Aromatic heterocyclic group”.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.

Monocyclic non-aromatic heterocyclic groups include 3-8 membered rings, for example, 4 membered, 5 membered or 6 membered rings. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl Furyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl Aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thii Le, triazinyl, and the like.
Non-aromatic heterocyclic groups having two or more rings include 9 to 14 membered cyclic groups, and examples thereof include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.

“Alkyloxy” includes a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
In one embodiment, “alkyloxy” is methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.

“Alkenyloxy” includes a group in which the above “alkenyl” is bonded to an oxygen atom.
Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.

“Alkynyloxy” includes a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.

The “haloalkyl” includes a group in which one or more hydrogen atoms bonded to one or more carbon atoms of the “alkyl” are replaced with one or more “halogen”. For example,
Monofluoromethyl, monofluoroethyl, monofluoropropyl,
Difluoromethyl, difluoroethyl, difluoropropyl,
Trifluoromethyl, trifluoroethyl, trifluoropropyl, pentafluoropropyl,
Monochloromethyl, monochloroethyl, monochloropropyl,
Dichloromethyl, dichloroethyl, dichloropropyl,
Trichloromethyl, trichloroethyl, trichloropropyl, pentachloropropyl,
1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
1-chloroethyl, 2-chloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl,
Examples include 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl, 2,2,3,3,3-pentafluoropropyl and the like.
For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like can be mentioned. For example, monofluoromethyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like can be mentioned.
The “haloalkenyl” includes a group in which one or more hydrogen atoms bonded to one or more carbon atoms of the “alkenyl” are replaced with one or more “halogen”. For example, monofluorovinyl, monofluoroallyl, monofluoropropenyl, difluorovinyl, difluoroallyl, difluoropropenyl and the like can be mentioned.
The “haloalkynyl” includes a group in which one or more hydrogen atoms bonded to one or more carbon atoms bonded to the “alkynyl” are replaced with one or more “halogen”. Examples include fluoroethynyl, monofluoropropynyl, difluoropropynyl, monofluorobutynyl, chloroethynyl, monochloropropynyl, monochlorobutynyl, dichloropropynyl and the like.

“Haloalkyloxy” includes a group in which the above “haloalkyl” is bonded to an oxygen atom. For example, monofluoromethyloxy, monofluoroethyloxy, difluoromethyloxy, 1,1-difluoroethyloxy, 2,2-difluoroethyloxy, trifluoromethyloxy, trichloromethyloxy, 2,2,2-trifluoroethyl Examples include oxy and trichloroethyloxy.
In one embodiment, “haloalkyloxy” includes difluoromethyloxy, 2,2,2-difluoroethyloxy, trifluoromethyloxy, 2,2,2-trifluoroethyloxy, trichloromethyloxy.
“Cyanoalkyloxy” includes a group in which a cyano group is bonded to the above “alkyloxy”. Examples thereof include cyanomethyloxy and cyanoethyloxy.

  The “alkyloxyalkyl” includes a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.

The “alkyloxyalkyloxy” includes a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methyloxymethyloxy, methyloxyethyloxy, ethyloxymethyloxy, ethyloxyethyloxy and the like.
The “cycloalkylalkyloxy” includes a group in which the “alkyloxy” is bonded to the “cycloalkyl”. For example, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, cyclobutylethyloxy and the like can be mentioned.

  “Alkylcarbonyl” includes a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Examples include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.

  “Alkenylcarbonyl” includes a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl, butenylcarbonyl and the like can be mentioned.

  “Alkynylcarbonyl” includes a group wherein the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl and the like can be mentioned.

The “monoalkylamino” includes a group in which one hydrogen atom bonded to the nitrogen atom of the amino group is replaced with the above “alkyl”. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
In one embodiment, “monoalkylamino” is methylamino or ethylamino.

The “dialkylamino” includes a group in which two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above two “alkyl”. Two alkyl groups may be the same or different. For example, dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like can be mentioned.
In one embodiment, “dialkylamino” is dimethylamino or diethylamino.

“Alkylsulfonyl” includes a group wherein the above “alkyl” is bonded to sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
In one embodiment, “alkylsulfonyl” is methylsulfonyl or ethylsulfonyl.

  The “alkenylsulfonyl” includes a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl, butenylsulfonyl and the like can be mentioned.

  The “alkynylsulfonyl” includes a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl, butynylsulfonyl and the like can be mentioned.

The “monoalkylcarbonylamino” includes a group in which one hydrogen atom bonded to the nitrogen atom of the amino group is replaced with the above “alkylcarbonyl”. Examples thereof include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like.
In one embodiment, “monoalkylcarbonylamino” is methylcarbonylamino or ethylcarbonylamino.

“Dialkylcarbonylamino” includes a group in which two hydrogen atoms bonded to the nitrogen atom of an amino group are replaced with two of the above “alkylcarbonyl”. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
In one embodiment, “dialkylcarbonylamino” is dimethylcarbonylamino or diethylcarbonylamino.

The “monoalkylsulfonylamino” includes a group in which one hydrogen atom bonded to the nitrogen atom of the amino group is replaced with the above “alkylsulfonyl”. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
In one embodiment, “monoalkylsulfonylamino” is methylsulfonylamino or ethylsulfonylamino.

“Dialkylsulfonylamino” includes a group in which two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “alkylsulfonyl”. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
In one embodiment, “dialkylsulfonylamino” is dimethylsulfonylamino or diethylsulfonylamino.

  The “alkylimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkyl”. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.

  “Alkenylimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkenyl”. Examples thereof include ethylenylimino and propenylimino.

  The “alkynylimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkynyl”. For example, ethynylimino, propynylimino and the like can be mentioned.

  The “alkylcarbonylimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkylcarbonyl”. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.

  The “alkenylcarbonylimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkenylcarbonyl”. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.

  The “alkynylcarbonylimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkynylcarbonyl”. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.

  The “alkyloxyimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkyloxy”. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.

  The “alkenyloxyimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkenyloxy”. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.

  The “alkynyloxyimino” includes a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is replaced with the above “alkynyloxy”. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.

“Alkylcarbonyloxy” includes a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. For example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
In one embodiment, “alkylcarbonyloxy” is methylcarbonyloxy or ethylcarbonyloxy.

  “Alkenylcarbonyloxy” includes a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.

  “Alkynylcarbonyloxy” includes a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.

The “alkyloxycarbonyl” includes a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
In one embodiment, “alkyloxycarbonyl” is methyloxycarbonyl, ethyloxycarbonyl or propyloxycarbonyl.

  “Alkenyloxycarbonyl” includes a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl and the like can be mentioned.

  “Alkynyloxycarbonyl” includes a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl and the like can be mentioned.

The “alkylsulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “alkyl”. Examples thereof include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, tert-butylsulfanyl, isobutylsulfanyl and the like.
The “cyanoalkylsulfanyl” includes a group in which a cyano group is bonded to the above “alkylsulfanyl”. Examples include cyanomethylsulfanyl, cyanoethylsulfanyl, cyanopropylsulfanyl and the like.

  “Alkenylsulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “alkenyl”. For example, ethylenylsulfanyl, propenylsulfanyl, butenylsulfanyl and the like can be mentioned.

  “Alkynylsulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “alkynyl”. Examples include ethynylsulfanyl, propynylsulfanyl, butynylsulfanyl and the like.

  “Alkylsulfinyl” includes a group wherein the above “alkyl” is bonded to a sulfinyl group. For example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like can be mentioned.

  “Alkenylsulfinyl” includes a group in which the above “alkenyl” is bonded to a sulfinyl group. Examples include ethylenylsulfinyl, propenylsulfinyl, butenylsulfinyl and the like.

  “Alkynylsulfinyl” includes a group wherein the above “alkynyl” is bonded to a sulfinyl group. Examples include ethynylsulfinyl, propynylsulfinyl, butynylsulfinyl and the like.

  The “monoalkylcarbamoyl” includes a group in which one hydrogen atom bonded to the nitrogen atom of the carbamoyl group is replaced with the above “alkyl”. For example, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl and the like can be mentioned.

  The “dialkylcarbamoyl” includes a group in which two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with two of the above “alkyl”. Two alkyl groups may be the same or different. For example, dimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamoyl and the like can be mentioned.

  The “monoalkylsulfamoyl” includes a group in which one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group is replaced with the above “alkyl”. Examples thereof include methylsulfamoyl, ethylsulfamoyl, n-propylsulfamoyl, isopropylsulfamoyl and the like.

  The “dialkylsulfamoyl” includes a group in which two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group are replaced with two of the above “alkyl”. Two alkyl groups may be the same or different. Examples thereof include dimethylsulfamoyl, diethylsulfamoyl, N-methyl-N-ethylsulfamoyl and the like.

  “Trialkylsilyl” includes a group in which three of the above “alkyl” are bonded to a silicon atom. The three alkyls may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.

  “Alkylidene” includes a divalent group formed from an alkane by removing two hydrogen atoms from the same carbon atom. For example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene.

The alkenyl part of “alkenylcarbonylamino”, “alkyloxyalkenyloxy”, “alkenylsulfanyl” and “alkenylamino” is the same as the above “alkenyl”.
The alkynyl part of “alkynylcarbonylamino”, “alkyloxyalkynyloxy”, “alkynylsulfanyl” and “alkynylamino” is the same as the above “alkynyl”.
“Hydroxyalkyl”, “hydroxyalkyloxy”, “monoalkylcarbonylamino”, “dialkylcarbonylamino”, “monoalkylamino”, “dialkylamino”, “aminoalkyl”, “alkyloxyalkenyloxy”, “alkyloxy” “Alkynyloxy”, “alkylcarbonyl”, “monoalkylcarbamoyl”, “dialkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “alkyloxyamino”, “alkylsulfanyl”, “monoalkylsulfonylamino”, “dialkylsulfonylamino”, "Alkylsulfonylalkylamino", "alkylsulfonylimino", "alkylsulfinyl", "alkylsulfinylamino", "alkylsulfinylalkylamino", "al Rusulfinylimino, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic alkyl, nonaromatic carbocyclic alkyl, aromatic heterocyclic alkyl, and nonaromatic "Heterocyclic alkyl", "aromatic carbocyclic alkyloxy", "non-aromatic carbocyclic alkyloxy", "aromatic heterocyclic alkyloxy", and "non-aromatic heterocyclic alkyloxy", "aromatic carbocyclic alkyl""Oxycarbonyl","non-aromatic carbocyclic alkyloxycarbonyl", "aromatic heterocyclic alkyloxycarbonyl", and "non-aromatic heterocyclic alkyloxycarbonyl", "aromatic carbocyclic alkyloxyalkyl", "non-aromatic Aromatic carbocyclic alkyloxyalkyl "," aromatic heterocyclic alkyloxyalkyl ", and" non-aromatic heterocyclic alkyl ""Luoxyalkyl","Aromatic carbocyclic alkylamino", "Non-aromatic carbocyclic alkylamino", "Aromatic heterocyclic alkylamino", "Non-aromatic heterocyclic alkylamino", "Aromatic carbocyclic alkylcarbamoyl" , “Non-aromatic carbocyclic alkylcarbamoyl”, “aromatic heterocyclic alkylcarbamoyl” and “nonaromatic heterocyclic alkylcarbamoyl”, and “cycloalkylalkyl” are the same as the above “alkyl”. .

等が挙げられる。
１つの態様として、「芳香族炭素環アルキル」は、ベンジル、フェネチルまたはベンズヒドリルである。 “Aromatic carbocyclic alkyl” includes alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, and the groups shown below

Etc.
In one embodiment, the “aromatic carbocyclic alkyl” is benzyl, phenethyl or benzhydryl.

等が挙げられる。 “Non-aromatic carbocyclic alkyl” includes alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. “Non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with one or more of the above “aromatic carbocyclic groups”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyl” includes alkyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyl” is an “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with one or more of the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl and the groups shown below

Etc.

等が挙げられる。 “Non-aromatic heterocyclic alkyl” includes alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. “Non-aromatic heterocyclic alkyl” is substituted with one or more of the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are "non-aromatic heterocyclic alkyl". For example, tetrahydropyranylmethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, and groups shown below

Etc.

等が挙げられる。 “Aromatic carbocyclic alkyloxy” includes alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, and the groups shown below

Etc.

等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” includes alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. “Non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with one or more of the above “aromatic carbocyclic groups”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, and the groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyloxy” includes alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” is an “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with one or more of the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also includes “oxy”. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, and the groups shown below

Etc.

等が挙げられる。 The “non-aromatic heterocyclic alkyloxy” includes alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. “Non-aromatic heterocyclic alkyloxy” is an “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group” having one or more alkyl moieties. Also included are substituted “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, and the groups shown below

Etc.

等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” includes alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, and the groups shown below

Etc.

等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” includes alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. “Non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with one or more of the above “aromatic carbocyclic groups”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, and groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” includes alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic ring” in which the alkyl moiety is substituted with one or more of the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also includes “alkyloxycarbonyl”. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, and groups shown below

Etc.

等が挙げられる。 The “non-aromatic heterocyclic alkyloxycarbonyl” includes alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In addition, “non-aromatic heterocyclic alkyloxycarbonyl” refers to the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group” having one or more alkyl moieties. Also included are “non-aromatic heterocyclic alkyloxycarbonyl” substituted with For example, tetrahydropyranylmethyloxycarbonyl, morpholinylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl, and the groups shown below

Etc.

等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” includes alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, and the groups shown below

Etc.

等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” includes alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic ring” in which the alkyl moiety to which the non-aromatic carbocyclic ring is bonded is substituted with one or more “aromatic carbocyclic group”. Also includes “alkyloxyalkyl”. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, and the groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” includes alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocycle alkyloxyalkyl” is an “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group” in which the alkyl moiety to which the aromatic heterocycle is bonded is one or more. Also included are substituted “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, and groups shown below

Etc.

等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” includes alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In addition, “non-aromatic heterocyclic alkyloxyalkyl” means that the above-mentioned “aromatic carbocyclic group”, “non-aromatic carbocyclic group” having one or more alkyl moieties to which the non-aromatic heterocyclic ring is bonded and Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, and the groups shown below

Etc.

  The “aromatic carbocyclic alkylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “aromatic carbocyclic alkyl”. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.

  The “non-aromatic carbocyclic alkylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “non-aromatic carbocyclic alkyl”. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.

  The “aromatic heterocyclic alkylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “aromatic heterocyclic alkyl”. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.

The “non-aromatic heterocyclic alkylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
The “aromatic carbocyclic alkylcarbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “aromatic carbocyclic alkyl”. Examples include benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl, benzhydrylcarbamoyl, tritylcarbamoyl, naphthylmethylcarbamoyl, dibenzylcarbamoyl and the like.

  The “non-aromatic carbocyclic alkylcarbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “non-aromatic carbocyclic alkyl”. Examples thereof include cyclopropylmethylcarbamoyl, cyclobutylmethylcarbamoyl, cyclopentylmethylcarbamoyl, cyclohexylmethylcarbamoyl and the like.

  The “aromatic heterocyclic alkylcarbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “aromatic heterocyclic alkyl”. For example, pyridylmethylcarbamoyl, furanylmethylcarbamoyl, imidazolylmethylcarbamoyl, indolylmethylcarbamoyl, benzothiophenylmethylcarbamoyl, oxazolylmethylcarbamoyl, isoxazolylmethylcarbamoyl, thiazolylmethylcarbamoyl, isothiazolylmethylcarbamoyl , Pyrazolylmethylcarbamoyl, isopyrazolylmethylcarbamoyl, pyrrolidinylmethylcarbamoyl, benzoxazolylmethylcarbamoyl and the like.

  The “non-aromatic heterocyclic alkylcarbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “non-aromatic heterocyclic alkyl”. Examples thereof include tetrahydropyranylmethylcarbamoyl, morpholinylethylcarbamoyl, piperidinylmethylcarbamoyl, piperazinylmethylcarbamoyl and the like.

"Aromatic carbocyclic ring", "Aromatic carbocyclic oxy", "Aromatic carbocyclic carbonyl", "Aromatic carbocyclic carbonyloxy", "Aromatic carbocyclic oxycarbonyl", "Aromatic carbocyclic carbonylamino", The “aromatic carbocyclic” moiety of “aromatic carbocyclic amino”, “aromatic carbocyclic sulfanyl” and “aromatic carbocyclic sulfonyl”, “aromatic carbocyclic sulfamoyl” and “aromatic carbocyclic carbamoyl” is also described above. The same as “aromatic carbocyclic group”.
The “aromatic carbocyclic oxy” includes a group in which an “aromatic carbocyclic group” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
The “aromatic carbocyclic carbonyl” includes a group in which an “aromatic carbocyclic group” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
The “aromatic carbocyclic carbonyloxy” includes a group in which an “aromatic carbocyclic group” is bonded to a carbonyloxy group. For example, phenylcarbonyloxy, naphthylcarbonyloxy and the like can be mentioned.
The “aromatic carbocyclic oxycarbonyl” includes a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
The “aromatic carbocyclic carbonylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “aromatic carbocyclic carbonyl”. Examples include benzoylamino and naphthylcarbonylamino.
The “aromatic carbocyclic amino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “aromatic carbocyclic group”. For example, phenylamino, naphthylamino and the like can be mentioned.
The “aromatic carbocyclic sulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “aromatic carbocyclic group”. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
The “aromatic carbocyclic sulfonyl” includes a group in which the above “aromatic carbocyclic group” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
The “aromatic carbocyclic sulfamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group are replaced with the above “aromatic carbocyclic group”. Examples thereof include phenylsulfamoyl and naphthylsulfamoyl.
The “aromatic carbocyclic carbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “aromatic carbocyclic group”. For example, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.

“Non-aromatic carbocyclic ring”, “Non-aromatic carbocyclic oxy”, “Non-aromatic carbocyclic carbonyloxy”, “Non-aromatic carbocyclic carbonyl”, “Non-aromatic carbocyclic oxycarbonyl”, “Non-aromatic” “Carbocyclic carbonylamino”, “non-aromatic carbocyclic amino”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfonyl”, “non-aromatic carbocyclic sulfamoyl” and “non-aromatic carbocyclic carbamoyl” The “non-aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
The “non-aromatic carbocyclic oxy” includes a group in which a “non-aromatic carbocyclic group” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
The “non-aromatic carbocyclic carbonyl” includes a group in which a “non-aromatic carbocyclic group” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic carbonyloxy” includes a group in which a “non-aromatic carbocyclic group” is bonded to a carbonyloxy group. For example, cyclopropylcarbonyloxy, cyclohexylcarbonyloxy, cyclohexenylcarbonyloxy and the like can be mentioned.

The “non-aromatic carbocyclic oxycarbonyl” includes a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic carbonylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “non-aromatic carbocyclic carbonyl”. For example, cyclopropylcarbonylamino, cyclohexylcarbonylamino, cyclohexenylcarbonylamino and the like can be mentioned.
The “non-aromatic carbocyclic amino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “non-aromatic carbocyclic group”. For example, cyclopropylamino, cyclohexylamino, cyclohexenylamino and the like can be mentioned.
The “non-aromatic carbocyclic sulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “non-aromatic carbocyclic group”. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
The “non-aromatic carbocyclic sulfonyl” includes a group in which the “non-aromatic carbocyclic group” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
The “non-aromatic carbocyclic sulfamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group are replaced with the above “non-aromatic carbocyclic group”. Examples include cyclopropylsulfamoyl, cyclohexylsulfamoyl, cyclohexenylsulfamoyl and the like.
The “non-aromatic carbocyclic carbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “non-aromatic carbocyclic group”. Examples include cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like.

"Aromatic heterocycle", "Aromatic heterocycle oxy", "Aromatic heterocycle carbonyl", "Aromatic heterocycle carbonyloxy", "Aromatic heterocycle oxycarbonyl", "Aromatic heterocycle carbonylamino", The “aromatic heterocyclic” part of “aromatic heterocyclic amino”, “aromatic heterocyclic sulfanyl”, “aromatic heterocyclic sulfonyl”, “aromatic heterocyclic sulfamoyl” and “aromatic heterocyclic carbamoyl” is also described above. The same as “aromatic heterocyclic group”.
Examples of the “aromatic heterocycle” in ring B include pyridine, pyrazine, pyrimidine, pyridazine, oxazole and the like.
The “aromatic heterocyclic oxy” includes a group in which the above “aromatic heterocyclic group” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
The “aromatic heterocyclic carbonyl” includes a group in which the above “aromatic heterocyclic group” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
The “aromatic heterocyclic carbonyloxy” includes a group in which the above “aromatic heterocyclic group” is bonded to a carbonyloxy group. For example, pyridylcarbonyloxy, oxazolylcarbonyloxy and the like can be mentioned.
The “aromatic heterocyclic oxycarbonyl” includes a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
The “aromatic heterocyclic carbonylamino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “aromatic heterocyclic carbonyl”. For example, pyridylcarbonylamino, oxazolylcarbonylamino and the like can be mentioned.

The “aromatic heterocyclic amino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “aromatic heterocyclic group”. For example, pyridylamino, oxazolylamino and the like can be mentioned.
The “aromatic heterocyclic sulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “aromatic heterocyclic group”. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
The “aromatic heterocyclic sulfonyl” includes a group in which the above “aromatic heterocyclic group” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
The “aromatic heterocyclic sulfamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group are replaced with the above “aromatic heterocyclic group”. For example, pyridyl sulfamoyl, oxazolyl sulfamoyl, etc. are mentioned.
The “aromatic heterocyclic carbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “aromatic heterocyclic group”. For example, pyridylcarbamoyl, oxazolylcarbamoyl and the like can be mentioned.

“Non-aromatic heterocyclic group”, “non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic carbonyloxy”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic oxycarbonyl” "Aromatic heterocyclic carbonylamino", "Non-aromatic heterocyclic amino", "Non-aromatic heterocyclic sulfanyl", "Non-aromatic heterocyclic sulfonyl", "Non-aromatic heterocyclic sulfamoyl" and "Non-aromatic heterocyclic" The “non-aromatic heterocyclic ring” portion of “carbamoyl” is the same as the above “non-aromatic heterocyclic group”.
The “non-aromatic heterocyclic oxy” includes a group in which the “non-aromatic heterocyclic group” is bonded to an oxygen atom. For example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
The “non-aromatic heterocyclic carbonyl” includes a group in which a “non-aromatic heterocyclic group” is bonded to a carbonyl group. For example, piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic carbonyloxy” includes a group in which the above “non-aromatic heterocyclic group” is bonded to a carbonyloxy group. For example, piperidinylcarbonyloxy, tetrahydrofurylcarbonyloxy and the like can be mentioned.
The “non-aromatic heterocyclic oxycarbonyl” includes a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.

（式中、Ｒはハロゲンまたは置換若しくは非置換のアルキルであり、ｍは１または２の整数である）
であることをを包含する。 The “non-aromatic heterocyclic carbonylamino” includes a group in which the above “non-aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and the like can be mentioned.
The “non-aromatic heterocyclic amino” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the amino group are replaced with the above “non-aromatic heterocyclic group”. For example, piperidinylamino, tetrahydrofurylamino and the like can be mentioned.
The “non-aromatic heterocyclic sulfanyl” includes a group in which a hydrogen atom bonded to a sulfur atom of a sulfanyl group is replaced with the above “non-aromatic heterocyclic ring”. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
The “non-aromatic heterocyclic sulfonyl” includes a group in which the “non-aromatic heterocyclic group” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
The “non-aromatic heterocyclic sulfamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group are replaced with the above “non-aromatic heterocyclic group”. For example, piperidinyl sulfamoyl, tetrahydrofuryl sulfamoyl and the like can be mentioned.
The “non-aromatic heterocyclic carbamoyl” includes a group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group are replaced with the above “non-aromatic heterocyclic group”. For example, piperidinylcarbamoyl, tetrahydrofurylcarbamoyl and the like can be mentioned.
“R ^2a and R ^2b together with the carbon atom to which they are attached may form a substituted cycloalkane”

Wherein R is halogen or substituted or unsubstituted alkyl, and m is an integer of 1 or 2.
It is included.

Examples of the substituent of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, and “substituted or unsubstituted alkynyl” include the following substituents. The carbon atom at any position may be bonded to one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino,
Alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxy Imino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, amine Quinylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group Group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic Heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic Aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy,
Aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic Aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino,
Aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl,
Aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.

The substituent of “substituted or unsubstituted alkyl” is, for example, one or more groups selected from the following substituent group α.
Substituent group α is halogen, hydroxy, alkyloxy, haloalkyloxy, hydroxyalkyloxy, alkyloxyalkyloxy, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, Aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, aromatic carbocyclic carbonyloxy, non-aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic heterocyclic carbonyloxy Carboxy, alkyloxycarbonyl, amino, monoalkylcarbonylamino, dialkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, aromatic carbocyclic carbonyla , Non-aromatic carbocyclic carbonylamino, aromatic heterocyclic carbonylamino, non-aromatic heterocyclic carbonylamino, monoalkylamino, dialkylamino, imino, hydroxyimino, alkyloxyamino, alkylsulfanyl, carbamoyl, monoalkylcarbamoyl, Dialkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkylsulfonyl, monoalkylsulfonylamino, dialkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinyl, alkylsulfinylamino, alkylsulfinyl Alkylamino, alkylsulfinylimino, cyano, nitro, aromatic carbocyclic, non-aromatic Carbocyclic groups, aromatic heterocyclic groups, and non-aromatic heterocyclic groups (the respective aromatic carbocycles, non-aromatic carbocycles, aromatic heterocycles and non-aromatic heterocycles are halogen, alkyl, hydroxy and And optionally substituted with one or more groups selected from alkyloxy.
Substituents for “substituted or unsubstituted alkyl” are, for example, halogen, hydroxy, and the like.

  The substituents of “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyl” and “substituted or unsubstituted alkynyl” are, for example, one or more groups selected from the above substituent group α. Specifically, halogen, hydroxy and the like.

  Examples of the substituent of “substituted or unsubstituted amino” include alkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aromatic carbocyclic carbonyl, nonaromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, nonaromatic heterocyclic 1 or 2 selected from carbonyl, hydroxy, alkyloxy, alkyloxycarbonyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group and non-aromatic heterocyclic group Groups. Specifically, alkyl, alkylcarbonyl and the like.

“Substituted or unsubstituted aromatic carbocycle”, “substituted or unsubstituted nonaromatic carbocycle”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted aromatic heterocycle” and “substituted or Substituents on "aromatic carbocycle", "non-aromatic carbocycle", "cycloalkyl", "aromatic heterocycle" and "non-aromatic heterocycle" in "unsubstituted non-aromatic heterocycle" As, for example, the following substituents are included. One or more atoms at any position on the ring may be bonded to one or more groups selected from the following substituents.

Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, Alkynylcarbonyl, monoalkylamino, dialkylamino,
Alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxy Imino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, amine Quinylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group Group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic Heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl,
Aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic Group heterocyclic alkyloxy,
Aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl , Aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl,
Aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino,
Aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl,
Aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.

In addition, “substituted or unsubstituted non-aromatic carbocycle” and “substituted or unsubstituted non-aromatic heterocycle” may be substituted with “oxo”. In this case, it includes a group in which two hydrogen atoms on the same carbon atom are substituted with oxo as follows.

“Substituted or unsubstituted aromatic carbocycle”, “Substituted or unsubstituted nonaromatic carbocycle”, “Substituted or unsubstituted aromatic heterocycle”, “Substituted or unsubstituted non-substituted aromatic ring” in Ring A and Ring B "Aromatic heterocycle", "Substituted or unsubstituted benzene", "Substituted or unsubstituted pyridine", "Substituted or unsubstituted pyrazine", "Substituted or unsubstituted oxazole", "Substituted or unsubstituted pyrimidine" Or as an example of a substituent of "substituted or unsubstituted pyridazine"
(A) a group selected from the substituent group α (for example, halogen, hydroxy, alkyloxy, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic ring Carbonyl, non-aromatic heterocyclic carbonyl, formyloxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, aromatic carbocyclic carbonyloxy, non-aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic hetero Ring carbonyloxy, carboxy, alkyloxycarbonyl, carbamoyl, amino, cyano, monoalkylamino, dialkylamino and / or alkylsulfanyl, etc.);
(B) an alkyl or unsubstituted alkyl substituted with one or more groups selected from the substituent group α, hydroxyimino and alkyloxyimino;
(C) aminoalkyl substituted with one or more groups selected from substituent group α;
(D) alkenyl or unsubstituted alkenyl substituted with one or more groups selected from substituent group α;
(E) alkynyl or unsubstituted alkynyl substituted with one or more groups selected from substituent group α;

(F) alkyloxy substituted with one or more groups selected from substituent group α;
(G) alkyloxyalkyloxy substituted with one or more groups selected from substituent group α;
(H) alkenyloxy or unsubstituted alkenyloxy substituted with one or more groups selected from substituent group α;
(I) alkyloxyalkenyloxy substituted with one or more groups selected from substituent group α;
(J) alkynyloxy or unsubstituted alkynyloxy substituted with one or more groups selected from substituent group α;
(K) alkyloxyalkynyloxy substituted with one or more groups selected from substituent group α;
(L) an alkylsulfanyl substituted with one or more groups selected from the substituent group α, or an unsubstituted alkylsulfanyl;
(M) an alkenylsulfanyl substituted with one or more groups selected from the substituent group α, or an unsubstituted alkenylsulfanyl;
(N) an alkynylsulfanyl substituted with one or more groups selected from the substituent group α, or an unsubstituted alkynylsulfanyl;
(O) monoalkylamino substituted with one or more groups selected from substituent group α;
(P) a dialkylamino substituted with one or more groups selected from the substituent group α;

(Q) alkenylamino substituted with one or more groups selected from substituent group α;
(R) an alkynylamino substituted with one or more groups selected from substituent group α;
(S) aminooxy substituted with one or more groups selected from substituent group α and alkylidene, or unsubstituted aminooxy;
(T) an alkylcarbonyl substituted with one or more groups selected from substituent group α;
(U) an alkenylcarbonyl substituted with one or more groups selected from substituent group α;
(V) alkynylcarbonyl substituted with one or more groups selected from substituent group α;
(W) an aromatic carbocyclic carbonyl substituted with one or more groups selected from substituent group α;
(X) a non-aromatic carbocyclic carbonyl substituted with one or more groups selected from the substituent group α;
(Y) an aromatic heterocyclic carbonyl substituted with one or more groups selected from the substituent group α;
(Z) a non-aromatic heterocyclic carbonyl substituted with one or more groups selected from the substituent group α;

(Aa) a monoalkylcarbamoyl substituted with one or more groups selected from the substituent group α;
(Ab) a dialkylcarbamoyl substituted with one or more groups selected from the substituent group α;
(Ac) an alkyloxycarbonyl substituted with one or more groups selected from the substituent group α;
(Ad) alkylsulfonyl substituted with one or more groups selected from substituent group α, or unsubstituted alkylsulfonyl;
(Ae) an alkylsulfinyl substituted with one or more groups selected from the substituent group α, or an unsubstituted alkylsulfinyl;
(Af) monoalkylsulfamoyl substituted with one or more groups selected from substituent group α;
(Ag) a dialkylsulfamoyl substituted with one or more groups selected from the substituent group α;
(Ah) an aromatic carbocyclic group substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Ai) a non-aromatic carbocyclic group substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Aj) an aromatic heterocyclic group substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;

(Ak) a non-aromatic heterocyclic group substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Al) an aromatic carbocyclic alkyl or an unsubstituted aromatic carbocyclic alkyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Am) a non-aromatic carbocyclic alkyl or an unsubstituted non-aromatic carbocyclic alkyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(An) an aromatic heterocyclic alkyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic alkyl;
(Ao) a non-aromatic heterocyclic alkyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic alkyl;

(Ap) an aromatic carbocyclic oxy or unsubstituted aromatic carbocyclic oxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Aq) a non-aromatic carbocyclic oxy or an unsubstituted non-aromatic carbocyclic oxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Ar) an aromatic heterocyclic oxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic oxy;
(As) a non-aromatic heterocyclic oxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic oxy;
(At) an aromatic carbocyclic alkyloxy or an unsubstituted carbocyclic alkyloxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Au) a non-aromatic carbocyclic alkyloxy or an unsubstituted non-aromatic carbocyclic alkyloxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Av) an aromatic heterocyclic alkyloxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic alkyloxy;

(Aw) a non-aromatic heterocyclic alkyloxy substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic alkyloxy;
(Ax) an aromatic carbocyclic alkyloxycarbonyl or an unsubstituted aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Ay) a non-aromatic carbocyclic alkyloxycarbonyl or an unsubstituted non-aromatic carbocyclic alkyloxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Az) an aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic alkyloxycarbonyl;
(Ba) a non-aromatic heterocyclic alkyloxycarbonyl or an unsubstituted non-aromatic heterocyclic alkyloxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bb) an aromatic carbocyclic sulfanyl or an unsubstituted aromatic carbocyclic sulfanyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bc) a non-aromatic carbocyclic sulfanyl or an unsubstituted non-aromatic carbocyclic sulfanyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;

(Bd) an aromatic heterocyclic sulfanyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic sulfanyl;
(Be) a non-aromatic heterocyclic sulfanyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic sulfanyl;
(Bf) an aromatic carbocyclic amino or an unsubstituted aromatic carbocyclic amino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bg) a non-aromatic carbocyclic amino or an unsubstituted non-aromatic carbocyclic amino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bh) an aromatic heterocyclic amino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic amino;
(Bi) a non-aromatic heterocyclic amino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic amino;
(Bj) an aromatic carbocyclic alkylamino or an unsubstituted aromatic carbocyclic alkylamino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;

(Bk) a non-aromatic carbocyclic alkylamino or an unsubstituted non-aromatic carbocyclic alkylamino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bl) an aromatic heterocyclic alkylamino or an unsubstituted aromatic heterocyclic alkylamino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bm) a non-aromatic heterocyclic alkylamino substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic alkylamino;
(Bn) an aromatic carbocyclic sulfamoyl or unsubstituted aromatic carbocyclic sulfamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bo) a non-aromatic carbocyclic sulfamoyl or unsubstituted non-aromatic carbocyclic sulfamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bp) an aromatic heterocyclic sulfamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic sulfamoyl;
(Bq) a non-aromatic heterocyclic sulfamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic sulfamoyl;

(Br) an aromatic carbocyclic sulfonyl or an unsubstituted aromatic carbocyclic sulfonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bs) a non-aromatic carbocyclic sulfonyl or an unsubstituted non-aromatic carbocyclic sulfonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bt) an aromatic heterocyclic sulfonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic sulfonyl;
(Bu) a non-aromatic heterocyclic sulfonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic sulfonyl;
(Bv) an aromatic carbocyclic carbamoyl or unsubstituted aromatic carbocyclic carbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Bw) a non-aromatic carbocyclic carbamoyl or unsubstituted non-aromatic carbocyclic carbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;

(Bx) an aromatic heterocyclic carbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic carbamoyl;
(By) a non-aromatic heterocyclic carbamoyl substituted with one or more groups selected from the substituent group α, azido, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic carbamoyl;
(Bz) an aromatic carbocyclic alkylcarbamoyl or an unsubstituted aromatic carbocyclic alkylcarbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Ca) a non-aromatic carbocyclic alkylcarbamoyl or an unsubstituted non-aromatic carbocyclic alkylcarbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Cb) an aromatic heterocyclic alkylcarbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic alkylcarbamoyl;
(Cc) a non-aromatic heterocyclic alkylcarbamoyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic alkylcarbamoyl;
(Cd) an aromatic carbocyclic oxycarbonyl or an unsubstituted aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Ce) a non-aromatic carbocyclic oxycarbonyl or an unsubstituted non-aromatic carbocyclic oxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl;
(Cf) an aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted aromatic heterocyclic oxycarbonyl;
(Cg) a non-aromatic heterocyclic oxycarbonyl substituted with one or more groups selected from the substituent group α, azide, alkyl and haloalkyl, or an unsubstituted non-aromatic heterocyclic oxycarbonyl;
(Ch) alkylenedioxy substituted with halogen or unsubstituted alkylenedioxy;
(Ci) oxo; and (cj) azide and the like.
"Substituted or unsubstituted aromatic carbocycle", "Substituted or unsubstituted nonaromatic carbocycle", "Substituted or unsubstituted benzene", "Substituted or unsubstituted aromatic heterocycle", "Substituted or unsubstituted "Substituted non-aromatic heterocycle", "Substituted or unsubstituted pyridine", "Substituted or unsubstituted pyrazine", "Substituted or unsubstituted oxazole", "Substituted or unsubstituted pyrimidine", or "Substituted or unsubstituted The cyclic group of “substituted pyridazine” may be substituted with one or more groups selected from the above substituents.

“Substituted or unsubstituted aromatic carbocycle”, “Substituted or unsubstituted nonaromatic carbocycle”, “Substituted or unsubstituted benzene”, “Substituted or unsubstituted aromatic heterocycle” in ring A and ring B ”,“ Substituted or unsubstituted non-aromatic heterocycle ”,“ substituted or unsubstituted pyridine ”,“ substituted or unsubstituted pyrazine ”,“ substituted or unsubstituted oxazole ”,“ substituted or unsubstituted pyrimidine ” Or as a substituent of “substituted or unsubstituted pyridazine”, for example,
halogen;
Cyano;
Hydroxy;
Nitro;
Carboxy;
Alkyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkyl;
Alkenyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkenyl;
Alkynyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkynyl;

Alkyloxy substituted with one or more groups selected from substituent group α;
Unsubstituted alkyloxy;
Alkenyloxy substituted with one or more groups selected from substituent group α;
Unsubstituted alkenyloxy;
Alkynyloxy substituted with one or more groups selected from substituent group α;
Unsubstituted alkynyloxy;
Alkylsulfanyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkylsulfanyl;
Alkenylsulfanyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkenylsulfanyl;
Alkynylsulfanyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkynylsulfanyl;
Amino substituted with one or more groups selected from substituent group α;
Unsubstituted amino;
Monoalkylamino substituted with one or more groups selected from substituent group α;
Unsubstituted monoalkylamino;

Dialkylamino substituted with one or more groups selected from substituent group α;
Unsubstituted dialkylamino;
Cycloalkylamino substituted with one or more groups selected from substituent group α;
Unsubstituted cycloalkylamino;
A carbamoyl substituted with one or more groups selected from the substituent group α;
Unsubstituted carbamoyl;
A monoalkylcarbamoyl substituted with one or more groups selected from the substituent group α;
Unsubstituted monoalkylcarbamoyl;
Dialkylcarbamoyl substituted with one or more groups selected from substituent group α;
Unsubstituted dialkylcarbamoyl;
Alkyloxycarbonyl substituted with one or more groups selected from substituent group α;
Unsubstituted alkyloxycarbonyl;

An alkyl substituted with one or more groups selected from substituent group α, an unsubstituted alkyl, and an aromatic carbocyclic group substituted with one or more groups selected from substituent group α;
Unsubstituted aromatic carbocyclic groups;
Alkyl substituted with one or more groups selected from substituent group α, unsubstituted alkyl, and non-aromatic carbocyclic group substituted with one or more groups selected from substituent group α;
Unsubstituted non-aromatic carbocyclic groups;
An alkyl group substituted with one or more groups selected from substituent group α, an unsubstituted alkyl group, and an aromatic heterocyclic group substituted with one or more groups selected from substituent group α;
Unsubstituted aromatic heterocyclic groups;
Alkyl substituted with one or more groups selected from substituent group α, unsubstituted alkyl, and non-aromatic heterocyclic group substituted with one or more groups selected from substituent group α; and unsubstituted non-substituted One or more groups selected from aromatic heterocyclic groups may be mentioned.

In one embodiment, the substituent is halogen, cyano, hydroxy, alkyl, haloalkyl, cycloalkylalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, cyanoalkyloxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkenyloxy, And one or more groups selected from alkynyloxy, alkylsulfanyl, cyanoalkylsulfanyl, amino, monoalkylamino, dialkylamino, cycloalkylamino and cycloalkyl.
In other embodiments, the substituent is one or more groups selected from halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cycloalkylalkyloxy, and alkynyloxy.
In another embodiment, the substituent for ring A includes one or more groups selected from halogen.
In another embodiment, the substituent on ring B includes one or more groups selected from halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy.

In one embodiment, the substituent of “substituted or unsubstituted cycloalkyl” is selected from alkyl substituted with one or more groups selected from substituent group α, unsubstituted alkyl, and substituent group α. One or more groups may be mentioned.
In another embodiment, “substituted or unsubstituted cycloalkyl” is unsubstituted cycloalkyl.

（式中、各記号は前記と同義である）
で示される化合物またはその製薬上許容される塩である。
式（ＩＡ）、（ＩＢ）、（ＩＣ）、（ＩＪ）または（ＩＫ）の１つの態様として、Ｒ^２ａはアルキルまたはハロアルキルオキシである。
式（ＩＤ）、（ＩＥ）、（ＩＪ）または（ＩＫ）の１つの態様として、Ｒ^２ａはハロゲンである。
式（ＩＬ）、（ＩＭ）、（ＩＮ）または（ＩＯ）の１つの態様として、Ｒはハロゲンであり、かつｍは２の整数である。
式（ＩＦ）の１つの態様として、Ｒ^５はハロゲンであり、かつｎは１または２の整数である。
式（ＩＧ）、（ＩＨ）または（ＩＩ）の１つの態様として、Ｒ^２ａはハロゲンである。
式（ＩＨ）の１つの態様として、Ｒ^２ａはアルキルオキシである。 Specific embodiments of the present invention are exemplified below. Embodiments include the following formulas (IA) to (IO):

(Wherein each symbol has the same meaning as above)
Or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (IA), (IB), (IC), (IJ) or (IK), R ^2a is alkyl or haloalkyloxy.
In one embodiment of formula (ID), (IE), (IJ) or (IK), R ^2a is halogen.
In one embodiment of formula (IL), (IM), (IN) or (IO), R is a halogen and m is an integer of 2.
In one embodiment of formula (IF), R ⁵ is halogen and n is an integer of 1 or 2.
In one embodiment of formula (IG), (IH) or (II), R ^2a is halogen.
In one embodiment of formula (IH), R ^2a is alkyloxy.

Specific examples of each symbol in formula (I) are shown below. All combinations of these embodiments are examples of compounds of formula (I).
In formula (I):
X is —O—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is H, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X1 and )
X is —O—, R ^3a is CF ₃ , R ^3b is alkyl, R ^2a is H, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X2 And)
X is —O—, R ^3a is CHF ₂ , R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X3 And)
X is —O—, R ^3a is CHFCH ₃ , R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X4 And)
X is —O—, R ^3a is CF ₂ CH ₃ , R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (below) X5),
X is —O—, R ^3a is a substituted haloalkyl (wherein the substituent is alkyloxy or cycloalkyl), R ^3b is H, R ^2a is halogen, and R ^2b is H And R ¹ is alkyl or haloalkyl (hereinafter referred to as X6),
X is —O—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X7 and )
X is —O—, R ^3a is haloalkyl, R ^3b is H, R ^2a is alkyl, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X8 and )

X is —O—, R ^3a is CHF ₂ , R ^3b is H, R ^2a is CH ₃ , R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X8 And)
X is —O—, R ^3a is CF ₃ , R ^3b is H, R ^2a is CH ₃ , R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter, X10).
X is —O—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is alkyl, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X11 and )
X is —O—, R ^3a is haloalkyl, R ^3b is H, R ^2a is alkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter, X12 And)
X is —O—, R ^3a is CH ₂ F, R ^3b is H, R ^2a is OCH ₃ , R ^2b is H, and R ¹ is alkyl or haloalkyl (below) , X13),
X is —O—, R ^3a is CF ₃ , R ^3b is H, R ^2a is OCH ₃ , R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter, X14),
X is —O—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is alkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X15 And)
X is —O—, R ^3a is haloalkyl, R ^3b is H, R ^2a is haloalkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X16 And)

X is —O—, R ^3a is CH ₂ F, R ^3b is H, R ^2a is OCH ₂ CF ₃ , R ^2b is H, and R ¹ is alkyl or haloalkyl. (Hereinafter referred to as X17),
X is —O—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is haloalkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X18). And)
X is —S—, R ^3a is alkyl, R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X19 and )
X is —S—, R ^3a is CH ₃ or CH ₂ CH ₃ , R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl. Yes (hereinafter referred to as X20)
X is —S—, R ^3a is alkyl, R ^3b is alkyl, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X21 and )
X is —S—, R ^3a is alkyl, R ^3b is H, R ^2a is alkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X22). And)

X is —S—, R ^3a is alkyl, R ^3b is alkyl, R ^2a is alkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X23). And)
X is —S—, R ^3a is alkyl, R ^3b is H, R ^2a is haloalkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X24). And)
X is —S—, R ^3a is alkyl, R ^3b is alkyl, R ^2a is haloalkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X25 And)
X is —S—, R ^3a is haloalkyl, R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X26 and )
X is —S—, R ^3a is CH ₂ F, R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter, X27),
X is —S—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X28 and )
X is —S—, R ^3a is haloalkyl, R ^3b is H, R ^2a is alkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X29). And)

X is —S—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is alkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X30). And)
X is —S—, R ^3a is haloalkyl, R ^3b is H, R ^2a is haloalkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X31). And)
X is —S—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is haloalkyloxy, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter, X32 And)
X is —S—, R ^3a is haloalkyl, R ^3b is H, R ^2a is alkyl, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X33 and )
X is —S—, R ^3a is haloalkyl, R ^3b is alkyl, R ^2a is alkyl, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X34 and )
X is —S—, R ^3a is alkyloxyalkyl, R ^3b is H, R ^2a is halogen, R ^2b is H, and R ¹ is alkyl or haloalkyl (hereinafter, X35),

であり、Ｒ^３ｂがＨであり、ｎが０であり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ３６とする）、
Ｘが−Ｏ−であり、

であり、Ｒ^３ｂがアルキルであり、ｎが０であり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ３７とする）、
Ｘが−Ｏ−であり、

であり、Ｒ^３ｂがＨであり、ｎが１であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ３８とする）、
Ｘが−Ｏ−であり、

であり、Ｒ^３ｂがアルキルであり、ｎが１であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ３９とする）、
Ｘが−Ｏ−であり、

であり、Ｒ^３ｂがＨであり、ｎが２であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４０とする）、
Ｘが−Ｏ−であり、

であり、Ｒ^３ｂがアルキルであり、ｎが２であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４１とする）、
Ｘが−Ｓ−であり、

であり、Ｒ^３ｂがＨであり、ｎが０であり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４２とする）、
Ｘが−Ｓ−であり、

であり、Ｒ^３ｂがアルキルであり、ｎが０であり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４３とする）、
Ｘが−Ｓ−であり、

であり、Ｒ^３ｂがＨであり、ｎが１であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４４とする）、
Ｘが−Ｓ−であり、

であり、Ｒ^３ｂがアルキルであり、ｎが１であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４５とする）、
Ｘが−Ｓ−であり、

であり、Ｒ^３ｂがＨであり、ｎが２であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４６とする）、
Ｘが−Ｓ−であり、

であり、Ｒ^３ｂがアルキルであり、ｎが２であり、Ｒ^５がハロゲンであり、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４７とする）、
Ｘが−Ｓ−または−Ｏ−であり、Ｒ^３ａがＨまたはアルキルであり、Ｒ^３ｂがＨであり、Ｒ^２ａおよびＲ^２ｂが、それらが結合している炭素原子と一緒になって、１または２個のハロゲンで置換されたシクロアルカンを形成してもよく、かつＲ^１がアルキルまたはハロアルキルである（以下、Ｘ４８とする）、
環Ａが置換若しくは非置換のベンゼンであり、かつ環Ｂが置換若しくは非置換のピリジンである（以下、ＡＢ１とする）、
環Ａが置換若しくは非置換のベンゼンであり、かつ環Ｂが置換若しくは非置換のピラジンである（以下、ＡＢ２とする）、
環Ａが置換若しくは非置換のベンゼンであり、かつ環Ｂが置換若しくは非置換のオキサゾールである（以下、ＡＢ３とする）、
環Ａが置換若しくは非置換のベンゼンであり、かつ環Ｂが置換若しくは非置換のピリミジンまたは置換若しくは非置換のピリダジンである（以下、ＡＢ４とする）、
環Ａが置換若しくは非置換のピリジンであり、かつ環Ｂが置換若しくは非置換のピリジン（以下、ＡＢ５とする）、
環Ａが置換若しくは非置換のピリジンであり、かつ環Ｂが置換若しくは非置換のピラジンである（以下、ＡＢ６とする）、
環Ａが置換若しくは非置換のピリジンであり、かつ環Ｂが置換若しくは非置換のオキサゾールである（以下、ＡＢ７とする）、
環Ａがハロゲン（ＦまたはＣｌ等）で置換されたベンゼンであり、かつ環Ｂが、ハロゲン、シアノ、アルキル、アルキルオキシおよびハロアルキルオキシから選択される１または２個の置換基で置換されたピリジンである（以下、ＡＢ８とする）、
環Ａがハロゲン（ＦまたはＣｌ等）で置換されたベンゼンであり、かつ環Ｂが、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、アルキニルオキシおよびシクロアルキルアルキルオキシから選択される１または２個の置換基で置換されたピラジンである（以下、ＡＢ９とする）、
環Ａがハロゲン（ＦまたはＣｌ等）で置換されたベンゼンであり、かつ環Ｂが、アルキルおよびハロアルキルから選択される１または２個の置換基で置換されたオキサゾールである（以下、ＡＢ１０とする）、
環Ａがハロゲン（ＦまたはＣｌ等）で置換されたベンゼンであり、かつ環Ｂが、ハロアルキルオキシから選択される１または２個の置換基で置換されたピリミジン、または、アルキルオキシから選択される１または２個の置換基で置換されたピリダジンである（以下、ＡＢ１１とする）、
環Ａがハロゲンで置換されたピリジンであり、かつ環Ｂが、ハロゲンおよびシアノから選択される１または２個の置換基で置換されたピリジンである（以下、ＡＢ１２とする）、
環Ａがハロゲンで置換されたピリジンであり、かつ環Ｂが、アルキルオキシおよびハロアルキルオキシから選択される１または２個の置換基で置換されたピラジンである（以下、ＡＢ１３とする）。 X is -O-

R ^3b is H, n is 0, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X36).
X is -O-

R ^3b is alkyl, n is 0, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X37).
X is -O-

R ^3b is H, n is 1, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X38).
X is -O-

R ^3b is alkyl, n is 1, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X39).
X is -O-

R ^3b is H, n is 2, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X40).
X is -O-

R ^3b is alkyl, n is 2, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X41).
X is -S-

R ^3b is H, n is 0, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X42).
X is -S-

R ^3b is alkyl, n is 0, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X43).
X is -S-

R ^3b is H, n is 1, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X44).
X is -S-

R ^3b is alkyl, n is 1, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X45).
X is -S-

R ^3b is H, n is 2, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X46).
X is -S-

R ^3b is alkyl, n is 2, R ⁵ is halogen, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X47).
X is —S— or —O—, R ^3a is H or alkyl, R ^3b is H, R ^2a and R ^2b together with the carbon atom to which they are attached are 1 Or a cycloalkane substituted with two halogens, and R ¹ is alkyl or haloalkyl (hereinafter referred to as X48).
Ring A is substituted or unsubstituted benzene, and Ring B is substituted or unsubstituted pyridine (hereinafter referred to as AB1).
Ring A is substituted or unsubstituted benzene, and Ring B is substituted or unsubstituted pyrazine (hereinafter referred to as AB2).
Ring A is substituted or unsubstituted benzene, and Ring B is substituted or unsubstituted oxazole (hereinafter referred to as AB3).
Ring A is substituted or unsubstituted benzene, and Ring B is substituted or unsubstituted pyrimidine or substituted or unsubstituted pyridazine (hereinafter referred to as AB4).
Ring A is a substituted or unsubstituted pyridine, and Ring B is a substituted or unsubstituted pyridine (hereinafter referred to as AB5),
Ring A is substituted or unsubstituted pyridine, and Ring B is substituted or unsubstituted pyrazine (hereinafter referred to as AB6).
Ring A is a substituted or unsubstituted pyridine, and Ring B is a substituted or unsubstituted oxazole (hereinafter referred to as AB7).
Pyridine in which ring A is benzene substituted with halogen (such as F or Cl) and ring B is substituted with 1 or 2 substituents selected from halogen, cyano, alkyl, alkyloxy and haloalkyloxy (Hereinafter referred to as AB8)
Ring A is benzene substituted with halogen (such as F or Cl) and Ring B is 1 or 2 substituents selected from haloalkyl, alkyloxy, haloalkyloxy, alkynyloxy and cycloalkylalkyloxy A substituted pyrazine (hereinafter referred to as AB9);
Ring A is benzene substituted with halogen (such as F or Cl), and Ring B is oxazole substituted with one or two substituents selected from alkyl and haloalkyl (hereinafter referred to as AB10) ),
Ring A is benzene substituted with halogen (such as F or Cl) and Ring B is selected from pyrimidine or alkyloxy substituted with one or two substituents selected from haloalkyloxy Pyridazine substituted with 1 or 2 substituents (hereinafter referred to as AB11),
Ring A is pyridine substituted with halogen, and Ring B is pyridine substituted with 1 or 2 substituents selected from halogen and cyano (hereinafter referred to as AB12).
Ring A is pyridine substituted with halogen, and ring B is pyrazine substituted with one or two substituents selected from alkyloxy and haloalkyloxy (hereinafter referred to as AB13).

^Examples of the combination (X, AB) of “X, R ^3a , R ^3b , R ^2a , R ^2b and R ¹ ” and “Ring A and Ring B” of the compound represented by formula (I) include the following: It is done.
(X1, AB1), (X1, AB2), (X1, AB3), (X1, AB4), (X1, AB5), (X1, AB6), (X1, AB7), (X1, AB8), (X1 , AB9), (X1, AB10), (X1, AB11), (X1, AB12), (X1, AB13), (X2, AB1), (X2, AB2), (X2, AB3), (X2, AB4 ), (X2, AB5), (X2, AB6), (X2, AB7), (X2, AB8), (X2, AB9), (X2, AB10), (X2, AB11), (X2, AB12), (X2, AB13), (X3, AB1), (X3, AB2), (X3, AB3), (X3, AB4), (X3, AB5), (X3, AB6), (X3, AB7), (X3 , AB8), (X3, AB9), (X3, AB10), (X3, AB11), (X3, AB12), (X3, AB13), (X4, AB1), (X4, AB2), (X4, AB3 ), (X4, AB4), (X4, AB5), (X4, AB6), (X4, AB7), (X4, AB8), (X4, AB9), (X4, AB10), (X4, AB11), (X4, AB12), (X4, AB13), (X5, AB1), (X5, AB2), (X5, AB3), (X5, AB4), (X5, AB5), (X5, AB6), (X5 , AB7), (X5, AB8), (X5, AB9), (X5, AB10), (X5, AB11), (X5, AB12), (X5, AB13), (X6, AB1), (X6, AB2 ), (X6, AB3), (X6, AB4), (X6, AB5), (X6, AB6), (X6, AB7), (X6, AB8), (X6, AB9), (X6, AB10), (X6, AB11), (X6, AB12), (X6, AB13), (X7, AB1), (X7, AB2), (X7, AB3), (X7, AB4), (X7, AB5), (X7 , AB6), (X7, AB7), (X7, AB8), (X7, AB9), (X7, AB10), (X7, AB11), (X7, AB12), (X7, AB13), (X8, AB1 ), (X8, AB2), (X8, AB3), (X8, AB4), (X8, AB5), (X8, AB6), (X8, AB7), (X8, AB8), (X8, AB9), (X8, AB10), (X8, AB11), (X8, AB12), (X8, AB13), (X9, AB1), (X9, AB2), (X9, AB3), (X9, A B4), (X9, AB5), (X9, AB6), (X9, AB7), (X9, AB8), (X9, AB9), (X9, AB10), (X9, AB11), (X9, AB12) , (X9, AB13), (X10, AB1), (X10, AB2), (X10, AB3), (X10, AB4), (X10, AB5), (X10, AB6), (X10, AB7), ( (X10, AB8), (X10, AB9), (X10, AB10), (X10, AB11), (X10, AB12), (X10, AB13), (X11, AB1), (X11, AB2), (X11, (AB3), (X11, AB4), (X11, AB5), (X11, AB6), (X11, AB7), (X11, AB8), (X11, AB9), (X11, AB10), (X11, AB11) , (X11, AB12), (X11, AB13), (X12, AB1), (X12, AB2), (X12, AB3), (X12, AB4), (X12, AB5), (X12, AB6), ( (X12, AB7), (X12, AB8), (X12, AB9), (X12, AB10), (X12, AB11), (X12, AB12), (X12, AB13), (X13, AB1), (X13, (AB2), (X13, AB3), (X13, AB4), (X13, AB5), (X13, AB6), (X13, AB7), (X13, AB8), (X13, AB9), (X13, AB10) , (X13, AB11), (X13, AB12), (X13, AB13), (X14, AB1), (X14, AB2), (X14, AB3), (X14, AB4), (X14, AB5), ( (X14, AB6), (X14, AB7), (X14, AB8), (X14, AB9), (X14, AB10), (X14, AB11), (X14, AB12), (X14, AB13), (X15, (AB1), (X15, AB2), (X15, AB3), (X15, AB4), (X15, AB5), (X15, AB6), (X15, AB7), (X15, AB8), (X15, AB9) , (X15, AB10), (X15, AB11), (X15, AB12), (X15, AB13), (X16, AB1), (X16, AB2), (X16, AB3), (X16, AB4), ( (X16, AB5), (X16, AB6), (X16, AB7), (X16, AB8), (X16, AB9), (X16, AB10), (X16, A B11), (X16, AB12), (X16, AB13), (X17, AB1), (X17, AB2), (X17, AB3), (X17, AB4), (X17, AB5), (X17, AB6) , (X17, AB7), (X17, AB8), (X17, AB9), (X17, AB10), (X17, AB11), (X17, AB12), (X17, AB13), (X18, AB1), ( (X18, AB2), (X18, AB3), (X18, AB4), (X18, AB5), (X18, AB6), (X18, AB7), (X18, AB8), (X18, AB9), (X18, (AB10), (X18, AB11), (X18, AB12), (X18, AB13), (X19, AB1), (X19, AB2), (X19, AB3), (X19, AB4), (X19, AB5) , (X19, AB6), (X19, AB7), (X19, AB8), (X19, AB9), (X19, AB10), (X19, AB11), (X19, AB12), (X19, AB13), ( (X20, AB1), (X20, AB2), (X20, AB3), (X20, AB4), (X20, AB5), (X20, AB6), (X20, AB7), (X20, AB8), (X20, (AB9), (X20, AB10), (X20, AB11), (X20, AB12), (X20, AB13), (X21, AB1), (X21, AB2), (X21, AB3), (X21, AB4) , (X21, AB5), (X21, AB6), (X21, AB7), (X21, AB8), (X21, AB9), (X21, AB10), (X21, AB11), (X21, AB12), ( (X21, AB13), (X22, AB1), (X22, AB2), (X22, AB3), (X22, AB4), (X22, AB5), (X22, AB6), (X22, AB7), (X22, (AB8), (X22, AB9), (X22, AB10), (X22, AB11), (X22, AB12), (X22, AB13), (X23, AB1), (X23, AB2), (X23, AB3) , (X23, AB4), (X23, AB5), (X23, AB6), (X23, AB7), (X23, AB8), (X23, AB9), (X23, AB10), (X23, AB11), ( X23, AB12), (X23, AB13), (X24, AB1), (X24, AB2), (X24, AB3), (X24, (AB4), (X24, AB5), (X24, AB6), (X24, AB7), (X24, AB8), (X24, AB9), (X24, AB10), (X24, AB11), (X24, AB12) , (X24, AB13), (X25, AB1), (X25, AB2), (X25, AB3), (X25, AB4), (X25, AB5), (X25, AB6), (X25, AB7), ( (X25, AB8), (X25, AB9), (X25, AB10), (X25, AB11), (X25, AB12), (X25, AB13), (X26, AB1), (X26, AB2), (X26, (AB3), (X26, AB4), (X26, AB5), (X26, AB6), (X26, AB7), (X26, AB8), (X26, AB9), (X26, AB10), (X26, AB11) , (X26, AB12), (X26, AB13), (X27, AB1), (X27, AB2), (X27, AB3), (X27, AB4), (X27, AB5), (X27, AB6), ( (X27, AB7), (X27, AB8), (X27, AB9), (X27, AB10), (X27, AB11), (X27, AB12), (X27, AB13), (X28, AB1), (X28, (AB2), (X28, AB3), (X28, AB4), (X28, AB5), (X28, AB6), (X28, AB7), (X28, AB8), (X28, AB9), (X28, AB10) , (X28, AB11), (X28, AB12), (X28, AB13), (X29, AB1), (X29, AB2), (X29, AB3), (X29, AB4), (X29, AB5), ( (X29, AB6), (X29, AB7), (X29, AB8), (X29, AB9), (X29, AB10), (X29, AB11), (X29, AB12), (X29, AB13), (X30, (AB1), (X30, AB2), (X30, AB3), (X30, AB4), (X30, AB5), (X30, AB6), (X30, AB7), (X30, AB8), (X30, AB9) , (X30, AB10), (X30, AB11), (X30, AB12), (X30, AB13), (X31, AB1), (X31, AB2), (X31, AB3), (X31, AB4), ( X31, AB5), (X31, AB6), (X31, AB7), (X31, AB8), (X31, AB9), (X31, AB 10), (X31, AB11), (X31, AB12), (X31, AB13), (X32, AB1), (X32, AB2), (X32, AB3), (X32, AB4), (X32, AB5) , (X32, AB6), (X32, AB7), (X32, AB8), (X32, AB9), (X32, AB10), (X32, AB11), (X32, AB12), (X32, AB13), ( (X33, AB1), (X33, AB2), (X33, AB3), (X33, AB4), (X33, AB5), (X33, AB6), (X33, AB7), (X33, AB8), (X33, (AB9), (X33, AB10), (X33, AB11), (X33, AB12), (X33, AB13), (X34, AB1), (X34, AB2), (X34, AB3), (X34, AB4) , (X34, AB5), (X34, AB6), (X34, AB7), (X34, AB8), (X34, AB9), (X34, AB10), (X34, AB11), (X34, AB12), ( (X34, AB13), (X35, AB1), (X35, AB2), (X35, AB3), (X35, AB4), (X35, AB5), (X35, AB6), (X35, AB7), (X35, (AB8), (X35, AB9), (X35, AB10), (X35, AB11), (X35, AB12), (X35, AB13), (X36, AB1), (X36, AB2), (X36, AB3) , (X36, AB4), (X36, AB5), (X36, AB6), (X36, AB7), (X36, AB8), (X36, AB9), (X36, AB10), (X36, AB11), ( (X36, AB12), (X36, AB13), (X37, AB1), (X37, AB2), (X37, AB3), (X37, AB4), (X37, AB5), (X37, AB6), (X37, (AB7), (X37, AB8), (X37, AB9), (X37, AB10), (X37, AB11), (X37, AB12), (X37, AB13), (X38, AB1), (X38, AB2) , (X38, AB3), (X38, AB4), (X38, AB5), (X38, AB6), (X38, AB7), (X38, AB8), (X38, AB9), (X38, AB10), ( X38, AB11), (X38, AB12), (X38, AB13), (X39, AB1), (X39, AB2), (X39, (AB3), (X39, AB4), (X39, AB5), (X39, AB6), (X39, AB7), (X39, AB8), (X39, AB9), (X39, AB10), (X39, AB11) , (X39, AB12), (X39, AB13), (X40, AB1), (X40, AB2), (X40, AB3), (X40, AB4), (X40, AB5), (X40, AB6), ( (X40, AB7), (X40, AB8), (X40, AB9), (X40, AB10), (X40, AB11), (X40, AB12), (X40, AB13), (X41, AB1), (X41, (AB2), (X41, AB3), (X41, AB4), (X41, AB5), (X41, AB6), (X41, AB7), (X41, AB8), (X41, AB9), (X41, AB10) , (X41, AB11), (X41, AB12), (X41, AB13), (X42, AB1), (X42, AB2), (X42, AB3), (X42, AB4), (X42, AB5), ( (X42, AB6), (X42, AB7), (X42, AB8), (X42, AB9), (X42, AB10), (X42, AB11), (X42, AB12), (X42, AB13), (X43, (AB1), (X43, AB2), (X43, AB3), (X43, AB4), (X43, AB5), (X43, AB6), (X43, AB7), (X43, AB8), (X43, AB9) , (X43, AB10), (X43, AB11), (X43, AB12), (X43, AB13), (X44, AB1), (X44, AB2), (X44, AB3), (X44, AB4), ( (X44, AB5), (X44, AB6), (X44, AB7), (X44, AB8), (X44, AB9), (X44, AB10), (X44, AB11), (X44, AB12), (X44, (AB13), (X45, AB1), (X45, AB2), (X45, AB3), (X45, AB4), (X45, AB5), (X45, AB6), (X45, AB7), (X45, AB8) , (X45, AB9), (X45, AB10), (X45, AB11), (X45, AB12), (X45, AB13), (X46, AB1), (X46, AB2), (X46, AB3), ( (X46, AB4), (X46, AB5), (X46, AB6), (X46, AB7), (X46, AB8), (X46, AB 9), (X46, AB10), (X46, AB11), (X46, AB12), (X46, AB13), (X47, AB1), (X47, AB2), (X47, AB3), (X47, AB4) , (X47, AB5), (X47, AB6), (X47, AB7), (X47, AB8), (X47, AB9), (X47, AB10), (X47, AB11), (X47, AB12), ( (X47, AB13), (X48, AB1), (X48, AB2), (X48, AB3), (X48, AB4), (X48, AB5), (X48, AB6), (X48, AB7), (X48, AB8), (X48, AB9), (X48, AB10), (X48, AB11), (X48, AB12) or (X48, AB13).

また、式（Ｉ）で示される化合物は、不斉炭素原子を有しており、以下のような光学異性体のいずれをも包含する。

１つの態様として、本発明に係る化合物は以下のものである。

式（Ｉ）の化合物の光学活性体は、光学活性な出発原料を用いる、適切な段階で不斉合成により光学活性な中間体を得る、または適切な段階でそれぞれラセミ体である中間体若しくは目的化合物の光学分割を行う、等の方法により得ることができる。光学分割の方法としては、例えば、光学活性なカラムを用いる光学異性体の分割；酵素反応を利用した速度論的光学分割；キラルな酸またはキラルな塩基を用いた塩形成によるジアステレオマー結晶化による分割；および優先晶析法等が挙げられる。 The compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof. For example, the compound represented by the formula (I) includes the following tautomers.

In addition, the compound represented by the formula (I) has an asymmetric carbon atom and includes any of the following optical isomers.

In one embodiment, the compound according to the present invention is as follows.

The optically active form of the compound of formula (I) is obtained by using an optically active starting material, obtaining an optically active intermediate by asymmetric synthesis at an appropriate stage, or an intermediate or an objective, each of which is a racemate at an appropriate stage. It can be obtained by a method such as optical resolution of the compound. Examples of the optical resolution method include resolution of optical isomers using an optically active column; kinetic optical resolution using an enzymatic reaction; diastereomeric crystallization by salt formation using a chiral acid or chiral base And the preferential crystallization method.

One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. In this method, a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, and inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid, Stone acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Of the salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph. Various solvates and crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound according to the present invention having a group that can be chemically or metabolically decomposed, and becomes a compound according to the present invention that is pharmaceutically active by solvolysis or under physiological conditions in vivo. It is. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted to a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxy group, for example, a compound having a hydroxy group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent. For _{example, CH 3 COO-, C 2 H} 5 COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO -, (m-NaOOCPh) COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH (NH 2 _{) COO-, CH 2 N (CH} 3) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p _{-CH 3 O-PhSO 3 -,} PhSO 3 -, p-CH 3 PhSO 3 - and the like.

The compound represented by the formula (I) may be synthesized using a method shown below together with a synthesis method known to those skilled in the art.
The starting materials are commercially available or may be synthesized according to known methods.
In each of the following syntheses, it may be preferable or necessary to protect sensitive or reactive substituents in each molecule. In this case, protection can be carried out by using a normal protecting group described in Green's Protective Group in Organic Synthesis, John Willy & Sons, 2007, and the like.
The following compounds are formed as a mixture of diastereomers and / or enantiomers, and are subjected to conventional techniques (recrystallization, silica gel chromatography, chiral or achiral high performance liquid chromatography (HPLC), In some cases, it can be obtained as a single enantiomer in the present invention, which can be understood by those skilled in the art.
Moreover, about all the following processes, the order of the process to implement can be changed suitably, and each intermediate body may be isolated and used for the following process. The reaction time, reaction temperature, solvent, reagent, protecting group, etc. are all merely examples, and are not particularly limited as long as the reaction is not hindered.

（式中、Ｐ^１はアルキルであり、Ｐ^２はそれぞれ、アルキル、ベンゾイル、ベンジル、４−メトキシベンジル、２，４−ジメトキシベンジルなどの保護基または水素であり、Ｙはハロゲン（例えば、Ｂｒ、Ｉ等）、ニトロ、またはトリフルオロアセチルアミノ（−ＮＨＣＯＣＦ_３）であり、その他の記号は前記と同義である） General synthesis method A:

(Wherein P ¹ is alkyl, P ² is a protecting group such as alkyl, benzoyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl or hydrogen, and Y is halogen (eg, Br, I and the like), nitro, or trifluoroacetylamino (—NHCOCF ₃ ), and other symbols are as defined above.

The general synthesis method A is a method of synthesizing a compound represented by the formula (Ia) from a compound represented by the formula (A1) through a plurality of steps 1 to 7. ^One skilled in the art can appreciate that the protecting groups P ¹ and P ² are selected depending on the reaction conditions used in the subsequent steps. Starting materials of formula (A1) are described in Chem. Rev. 2010, 110, 3600-3740 and can be synthesized by a method similar to the conditions described.

Step 1:
A compound represented by the formula (A2) can be synthesized by a Mannich reaction between sulfinylimine (A1) and an enolate derived from an ester. Such reactions are described in Chem. Rev. It can be implemented by using the conditions described in 2010, 110, 3600-3740. Preferably, the enolate can be prepared from the corresponding ester, lithium diisopropylamide (LDA), and TiCl (Oi-Pr) ₃ to synthesize the compound of formula (A2) by reacting with (A1) it can. The reaction solvent used in this step is not particularly limited as long as the reaction is not inhibited. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, toluene, and benzene. The reaction temperature is preferably -78 ° C to -30 ° C. The reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 30 minutes to 6 hours.

Step 2:
By deprotecting (A2), the compound represented by the formula (A3) can be synthesized. This deprotection reaction is known to those skilled in the art and is described in Chem. Rev. 2010, 110, 3600-3740. This reaction can be carried out at room temperature to 60 ° C. under acidic conditions such as hydrochloric acid. Examples of the solvent include methanol, 1,4-dioxane, and ethyl acetate. The reaction time is not particularly limited, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

Step 3:
A compound represented by the formula (A4) can be synthesized by reacting (A3) with a reagent such as benzoyl isothiocyanate or benzyl isothiocyanate. Those skilled in the art can obtain a compound of formula (A4) by reacting a reagent such as thiophosgene or thiocarbonyldiimidazole with an isothiocyanate produced from (A3) with a primary or secondary amine. Understandable. The solvent used in this step is not particularly limited as long as the reaction is not inhibited. Examples of the solvent include dichloromethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and toluene. The reaction time is not particularly limited, but is usually 1 hour to 24 hours, preferably 3 hours to 6 hours. The reaction temperature is usually 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature. The reagent used for thiourea production in this step is not particularly limited as long as it can be deprotected in step 6, but a preferred reagent is benzoyl isothiocyanate.

Step 4:
A compound represented by the formula (A5) can be synthesized by reacting a Grignard reagent such as methylmagnesium bromide or ethylmagnesium bromide or an alkyllithium reagent such as methyllithium, butyllithium or phenyllithium with (A4). . By adding these nucleophiles stepwise, a compound represented by the formula (A5) having various substituents R ^3a and R ^3b can be obtained. The solvent used is not particularly limited as long as the reaction is not inhibited. Examples of preferred solvents include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, toluene and benzene. The reaction temperature is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 6 hours. The reaction temperature is generally −100 ° C. to room temperature, preferably −78 ° C. to 0 ° C.

Step 5:
Cyclization of (A5) with reagents such as m-CPBA, hydrogen peroxide, carbodiimide reagents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, and is represented by formula (A6). Compounds can be synthesized. Alternatively, the compound represented by (A6) can also be obtained by reacting (A5) with an alkylating agent and carrying out a cyclization reaction under basic conditions. In the former case, a suitable reagent includes m-CPBA, and the reaction temperature is usually from 0 ° C. to room temperature, preferably room temperature. Preferred solvents include dichloromethane or chloroform. In the latter case, suitable alkylating agents include methyl iodide and suitable bases include sodium hydride, sodium bicarbonate, potassium carbonate.

Step 6:
The compound of formula (Ia) can be synthesized by the following series of reactions:
1) Y = H; P ² deprotection in formula (A6), nitration, protection, reduction, followed by amide coupling reaction with an amine yields a compound of formula (Ia),
2) Y = Br or I; Buchwald-Hartwig reaction of formula (A6) with an amide, followed by deprotection of P ² yields a compound of formula (Ia),
3) Y = trifluoroacetylamino; deprotection of the trifluoroacetylamino group, amide coupling reaction, followed by deprotection of P ² yields a compound of formula (Ia).
Examples of reaction conditions used in 1) to 3) are shown below.
1) Y = H:
The compound represented by the formula (A6) can be deprotected under the conditions described in Green's Protective Groups in Organic Synthesis. When P ² is benzoyl, the deprotection reaction can be performed at room temperature to 80 ° C. using, for example, hydrazine monohydrate or potassium carbonate as a base and using, for example, methanol, ethanol, or the like as a solvent.
Nitration of the deprotected compound can be carried out by methods known to those skilled in the art. For example, a nitrated compound can be obtained by using nitric acid or nitrate ion in a mixed solvent of sulfuric acid and trifluoroacetic acid, or a solvent such as sulfuric acid. The reaction temperature is usually -20 ° C to 0 ° C. The reaction time is usually 1 minute to 1 hour.
The amidine group of the deprotected compound can be protected with a Boc group under the conditions described in Greene's Protective Groups in Organic Synthesis. For example, Boc protection can be performed using Boc ₂ O and a catalytic amount of N, N-dimethyl-4-aminopyridine in a solvent such as dichloromethane or tetrahydrofuran at room temperature to 50 ° C.
Reduction of the nitrated compound can be carried out by methods known to those skilled in the art and the corresponding aniline can be obtained; the following conditions can be used: 1) Method using iron powder in the presence of hydrochloric acid or ammonium chloride 2) A method using palladium carbon in a hydrogen atmosphere. Examples of the solvent include water, methanol, ethanol, ethyl acetate, tetrahydrofuran, and a mixed solvent thereof.

The amide coupling reaction of aniline and amine can be carried out by methods known to those skilled in the art. Suitable coupling conditions are described in Chem. Rev. 2011, 111, 6557-6602, including a) a reaction using a condensing agent; b) a reaction using an acid chloride or an acid fluoride.
Reaction a) includes dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride), O- (7-aza-1H-benzotriazole -1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), 1H- (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), etc. It can carry out using an agent. When using a uronium salt or phosphonium salt such as HATU or PyBOP, the reaction can be carried out in the presence of a base such as triethylamine or diisopropylethylamine. In some cases, this reaction can be promoted by using a catalyst such as 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). The solvent used for the reaction is not particularly limited as long as the reaction is not inhibited. Examples of the solvent include dichloromethane, N, N-dimethylformamide, N-methylpyrrolidone and tetrahydrofuran. The reaction temperature is usually 0 ° C. to 50 ° C., preferably room temperature.
Reaction b) is a commercially available acid chloride or a compound synthesized using a method known to those skilled in the art, and in a solvent such as dichloromethane, tetrahydrofuran or ethyl acetate, triethylamine, diisopropylethylamine, pyridine, N, N-dimethyl-4 -It can be carried out in the presence of a base such as aminopyridine. The reaction temperature is usually 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature. Although reaction time is not specifically limited, Usually, it is 5 minutes-24 hours, Preferably it is 30 minutes-6 hours.

2) Y = Br or I:
The Buchwald-Hartwig reaction between the compound represented by the formula (A6) and the amide derivative can be performed by the method described in Metal-Catalyzed Cross-Coupling Reactions, 2 ^nd Ed. For example, transition metal catalysts such as tris (dibenzylideneacetone) dipalladium, palladium acetate, and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 4,5-bis (diphenylphosphine) Fino) -9,9-dimethylxanthene (Xantphos), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (X-Phos) and other ligands, sodium tert-butoxide, carbonic acid This reaction can be carried out in the presence of a base such as cesium or potassium phosphate. The reaction temperature is usually 40 ° C to 150 ° C, preferably 60 ° C to 100 ° C. By carrying out under microwave irradiation, this reaction may be promoted. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane.
After the Buchwald-Hartwig reaction, deprotection of P ² in the resulting compound can be performed under the conditions described above.

3) Y = trifluoroacetylamino:
Deprotection of the trifluoroacetylamino group in the compound represented by the formula (A6) can be carried out by methods known to those skilled in the art. Appropriate conditions are described in Greene's Protective Groups in Organic Synthesis. For example, a normal method includes a method using potassium carbonate in methanol at room temperature, but is not limited thereto. It followed deprotection of the amide coupling reaction and P ² may be carried out under the same conditions as above.

（式中、各記号は一般合成法Ａと同義である）
一般合成法Ｂは、式（Ａ５）で示される化合物から複数工程を経て、式（Ｉｂ）で示される化合物を合成する方法である。式（Ｂ１）で示される化合物を用い、一般合成法Ａに記載の方法に従って式（Ｉｂ）で示される化合物を合成することができる。 General synthesis method B:

(In the formula, each symbol has the same meaning as in General Synthesis Method A)
General synthesis method B is a method of synthesizing a compound represented by formula (Ib) from a compound represented by formula (A5) through a plurality of steps. Using the compound represented by the formula (B1), the compound represented by the formula (Ib) can be synthesized according to the method described in the general synthesis method A.

Step 1:
The compound represented by the formula (B1) can be synthesized by converting the hydroxy group of the compound represented by the formula (A5) into a leaving group such as Cl, Br, or triflate, followed by cyclization reaction. The reaction conditions are known to those skilled in the art. For example, chlorination and subsequent cyclization may be performed using a reagent such as 1-chloro-N, N, 2-trimethylpropenylamine. Alternatively, trifluoromethanesulfonic anhydride may be used in the presence of a base such as N, N-dimethyl-4-aminopyridine or pyridine. Examples of the solvent include dichloromethane and tetrahydrofuran. The reaction temperature is usually 0 ° C. to room temperature, preferably 0 ° C. Although reaction time is not specifically limited, Usually, it is 0.5 to 3 hours.

（式中、Ｈａｌはハロゲンであり、Ｒ^３ａ‘およびＲ^３ｂ’は各々独立して水素またはアルキルであり、その他の各記号は一般合成法Ａと同義である） General synthesis method C:

(Wherein Hal is halogen, R ^{3a ′} and R ^{3b ′} are each independently hydrogen or alkyl, and the other symbols are as defined in General Synthesis Method A)

General synthesis method C is a method of synthesizing a compound represented by formula (Ic) from a compound represented by formula (A3) through a plurality of steps. The compound represented by the formula (Ic) can be synthesized according to the method described in the general synthesis method A using the compound represented by the formula (C6).
Step 1:
A compound represented by the formula (C1) can be synthesized by a urea formation reaction of the compound represented by the formula (A3). Such a reaction is known to those skilled in the art. Usually, a compound represented by the formula (A3) is treated with a reagent such as triphosgene, 4-nitrophenyl chloroformate, carbonyldiimidazole, and then bis (2,4- This can be done by adding an amine such as dimethoxybenzyl) amine. A preferred combination of these reagents includes 4-nitrophenyl chloroformate and bis (2,4-dimethoxybenzyl) amine. In this case, the reaction can be performed in a solvent such as water, tetrahydrofuran, ethyl acetate, and a mixed solvent thereof in the presence of a base such as sodium hydrogen carbonate. The reaction temperature is usually 0 ° C. to room temperature. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.

Step 2:
A compound represented by formula (C2) can be synthesized by reducing a compound represented by formula (C1). This reaction is known to those skilled in the art and is usually carried out using diisobutylaluminum hydride (DIBAL-H). Examples of the solvent include dichloromethane, tetrahydrofuran and toluene. The reaction temperature is usually less than -60 ° C, preferably less than -70 ° C. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.

Step 3:
A compound represented by the formula (C3) can be synthesized by a Wittig reaction between the compound represented by the formula (C2) and the corresponding phosphonium ylide. Alternatively, Peterson olefination, Horner-Wadsworth-Emmons reaction, Julia coupling, Knoevenagel condensation may be considered. These reactions are known to those skilled in the art. For example, the Wittig reaction can generally be carried out by treating the corresponding alkyl halide with triphenylphosphine followed by a base such as n-butyltylium and adding it to the compound of formula (C3). Examples of the solvent include tetrahydrofuran. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.

Step 4:
A compound represented by the formula (C4) can be synthesized by cyclizing the compound represented by the formula (C3) with iodine. Examples of the solvent include acetonitrile, tetrahydrofuran and dichloromethane. The reaction temperature is usually 0 ° C. to 50 ° C., preferably room temperature. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.

Step 5:
The compound represented by the formula (C5) can be synthesized as follows. 1) halogenate the compound of formula (C4); 2) hydroxylate the compound of formula (C4) and deoxygenate the corresponding alcohol.
Regarding 1), the halogenation of the compound represented by the formula (C4) includes, for example, fluorination, and can be performed using a reagent such as tetrabutylammonium fluoride (TBAF). Examples of the solvent include acetonitrile and tetrahydrofuran. The reaction temperature is usually 0 ° C. to 50 ° C., preferably room temperature. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.
Regarding 2), the hydroxylation of the compound represented by the formula (C4) can be carried out using a reagent such as potassium superoxide (KO ₂ ), silver trifluoroacetate, silver trifluoroborate. Examples of preferred solvents, dimethyl sulfoxide for KO ₂ (DMSO), trifluoroacetic against silver acetate nitromethane - including the DMSO- water to water, trifluoroborate silver. The reaction temperature is not particularly limited, preferably, the KO ₂ room temperature, 60 ° C. to 80 ° C. in silver trifluoroacetate, 60 ° C. to 80 ° C. in trifluoroacetic boric silver. Subsequent deoxygenated halogenation includes, for example, deoxygenated fluorination, such as N, N-diethylaminosulfur trifluoride (DAST), bis (2-methoxyethyl) aminosulfur trifluoride (Deoxofluor ™), etc. It can be carried out using a reagent. Examples of the solvent include dichloromethane, acetonitrile, and tetrahydrofuran. The reaction temperature is usually -78 ° C to room temperature, preferably -78 ° C to 0 ° C. Another condition is described in Synthesis 2002, 2561-2578.

（式中、各記号は一般合成法Ａと同義である） General synthesis method D:

(In the formula, each symbol has the same meaning as in General Synthesis Method A)

  General synthesis method D is a method of synthesizing a compound represented by formula (I) from a compound represented by formula (D1) through a plurality of steps. Using the compound represented by the formula (A5), the compound represented by the formula (I) can be synthesized according to the methods described in General Synthesis Methods A and B. Starting materials of formula (D1) are described in Chem. Rev. It can be synthesized by a method similar to the conditions described in 2010, 110, 3600-3740.

Step 1:
A compound represented by the formula (D2) can be synthesized by adding a compound represented by the formula (D1) to a ketone represented by the formula (R ^3a COR ^3b ). This reaction is described in Chem. Rev. 2010, 110, 3600-3740 can be performed under similar conditions. For example, (D2) can be obtained by adding lithium diisopropylamide followed by a ketone of the formula (R ^3a COR ^3b ) to a ketimine derived from formula (D1). Examples of the solvent include tetrahydrofuran and toluene. The reaction temperature is usually less than -60 ° C, preferably less than -70 ° C. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.

Step 2:
A compound represented by the formula (D3) can be synthesized by reacting (D2) with a Grignard reagent such as methyl magnesium bromide or ethyl magnesium bromide, or an alkyl lithium reagent such as methyl lithium, butyl lithium, or phenyl lithium. it can. The solvent is not particularly limited as long as the progress of the reaction is not inhibited. Examples of preferred solvents include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, toluene, benzene. The reaction temperature is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 6 hours. The reaction temperature is usually -78 ° C to room temperature, preferably -78 ° C to -40 ° C.
Step 3:
The compound represented by the formula (D4) can be synthesized according to the method described in Step 2 of General Synthesis Method A.
Step 4:
According to the method described in Step 3 of General Synthesis Method A, the compound represented by Formula (A5) can be synthesized.

General synthesis method E:

(Wherein P is a protecting group for a hydroxy group such as benzyl, tert-butyldimethylsilyl, R is alkyl or haloalkyl, and other symbols are as defined in General Synthesis Method A)
The general synthesis method E is a method of synthesizing a compound represented by the formula (I) from a compound represented by the formula (E1) through a plurality of steps. Using the compound represented by the formula (E8), the compound represented by the formula (I) can be synthesized according to the methods described in the general synthesis methods A and B.

Step 1:
The compound represented by the formula (E2) undergoes addition reaction of Me ₃ SiCF ₃ , Me ₃ SiCHF ₂ , Me ₃ SiCH ₂ F, etc. in the presence of a catalytic amount of a base (TBAF, cesium fluoride, potassium fluoride, etc.). Can be synthesized. Examples of the solvent include tetrahydrofuran, N, N-dimethylformamide (DMF), acetonitrile, and toluene. The reaction temperature is usually −20 ° C. to room temperature, preferably room temperature. Alternatively, this reaction can also be carried out using an alkyl or haloalkyl cerium reagent prepared from cerium (III) chloride and an alkyl lithium or Grignard reagent, yielding a compound of formula (E2). (E2) may be obtained using alkyl or haloalkyllithium reagents or Grignard reagents without the use of cerium (III) chloride according to methods known to those skilled in the art.

Step 2:
A compound represented by the formula (E3) can be synthesized by epoxidation of the compound represented by the formula (E2). Epoxidation is known to those skilled in the art, and can be performed using an oxidizing agent such as m-CPBA or tert-butyl hydroperoxide in a solvent such as dichloromethane or chloroform. Although reaction time is not specifically limited, Usually, it is 0.5 to 3 hours. The reaction temperature is usually −50 ° C. to room temperature. It is also possible to apply asymmetric epoxidation such as sharpened asymmetric epoxidation to this step using methods known to those skilled in the art, and it may be useful for synthesizing chiral compounds without optical resolution. is there. Suitable conditions are described in Comprehensive Organic Synthesis 1991, 7, 389.

Step 3:
A compound represented by the formula (E4) can be synthesized by ring-opening the compound represented by the formula (E3) using sodium azide in the presence of a Lewis acid such as Ti (OEt) ₄ . Examples of the solvent include solvents such as tetrahydrofuran, toluene, and ethyl ether. Although reaction time is not specifically limited, Usually, it is 1 to 24 hours. The reaction temperature is usually room temperature.

Step 4:
Protection of the compound represented by the formula (E4) can be carried out using benzyl bromide or tert-butyldimethylsilyl chloride to obtain a compound represented by the formula (E5). When protecting with a benzyl group, protection may sometimes be achieved using benzyl bromide in the presence of dibutyltin oxide. Examples of the solvent include toluene, methanol, DMF, and a mixed solvent thereof. The reaction temperature is usually 60 ° C to 100 ° C. For protection with a tert-butyldimethylsilyl group, suitable conditions are described in Greene's Protective Group in Organic Synthesis. For example, protection may be performed using tert-butyldimethylsilyl chloride in the presence of imidazole as a base. Examples of the solvent include tetrahydrofuran, dichloromethane, and DMF. The reaction temperature is usually 0 ° C. to room temperature.

Step 5:
By alkylating the compound represented by the formula (E5), the compound represented by the formula (E6) can be synthesized. This reaction is known to those skilled in the art, and is usually performed in the presence of a base such as sodium hydride, potassium carbonate, or sodium carbonate using an alkylating agent such as alkyl iodide, alkyl bromide, or alkyl triflate. Examples of the solvent include tetrahydrofuran, DMF, toluene, acetone, and acetonitrile. The reaction temperature is usually 0 ° C. to room temperature.

Step 6:
The compound of formula (E7) can be deprotected under conditions similar to those described in Greene's Protective Group in Organic Synthesis. For example, when P is a benzyl group, deprotection can be performed by hydrogenation in the presence of a catalytic amount of palladium on carbon or palladium hydroxide. When P is a tert-butyldimethylsilyl group, deprotection can be performed at 0 ° C. to room temperature in a solvent such as tetrahydrofuran using TBAF.

General synthesis method F:

(Wherein P ¹ is alkyl; P ² is a protecting group for a hydroxy group such as tert-butyldimethylsilyl; P ³ is methanesulfonyl or toluenesulfonyl, and other symbols are as defined in General Synthesis Method A)

  The general synthesis method F is a method of synthesizing a compound represented by the formula (If) from a compound represented by the formula (E1) through a plurality of steps. Using the compound represented by the formula (F9), the compound represented by the formula (I) can be synthesized according to the methods described in General Synthesis Methods A and B.

Step 1:
A compound represented by the formula (F1) can be synthesized by a Reformatsky reaction between the compound represented by the formula (E1) and an α-haloester. This reaction is known to those skilled in the art and is usually performed under the conditions described in Tetrahedron 2004, 42, 9325-9374. For example, a mixture of a compound represented by the formula (F1) and an α-haloester is reacted at room temperature to 100 ° C. in the presence of zinc powder in a solvent such as tetrahydrofuran, acetonitrile, or toluene. Although reaction time is not specifically limited, Usually, it is 1 to 12 hours.

Step 2:
According to the method described in Step 2 of General Synthesis Method C, the compound represented by Formula (F2) can be synthesized.

Step 3:
A compound represented by the formula (F3) can be synthesized by protecting the alcohol represented by the formula (F2). The protecting group can be selected according to the reaction conditions used in the next step. Suitable protecting groups are described in Greene's Protective Group in Organic Synthesis. For example, when a tert-butyldimethylsilyl group is selected, tert-butyldimethylsilyl chloride is used and protected in the presence of a base such as imidazole or sodium hydride in a solvent such as DMF, tetrahydrofuran or acetonitrile at 0 ° C. to room temperature. It can be performed. Although reaction time is not specifically limited, Usually, it is 0.5 to 6 hours. If the yield is low, it may be appropriate to use tert-butyldimethylsilyl triflate instead of the corresponding chloride.

Step 4:
The compound represented by the formula (F4) can be synthesized according to the method described in Step 2 of General Synthesis Method E.

Step 5:
A compound represented by the formula (F5) can be synthesized by deprotecting the compound represented by the formula (F4). Depending on the protecting group of formula (F4), deprotection conditions can be selected according to Greene's Protective Group in Organic Synthesis. If P ² is tert- butyldimethylsilyl group, using TBAF, it can be carried out in tetrahydrofuran, DMF, in a solvent such as acetonitrile, the deprotection at 0 ° C. ~ room temperature. Although reaction time is not specifically limited, Usually, it is 0.5 to 6 hours.

Step 6:
The compound represented by the formula (F6) can be synthesized according to the method described in Step 3 of General Synthesis Method E.

Step 7:
The terminal alcohol of the compound represented by the formula (F6) can be converted into a corresponding leaving group such as methanesulfonate and toluenesulfonate in this step. This reaction is known to those skilled in the art, and is usually performed according to the method described in Green's Protective Group in Organic Synthesis. For example, using toluenesulfonyl chloride, in the presence of a base such as N, N-dimethylamino-4-pyridine, pyridine, or triethylamine, protection with a toluenesulfonyl group in a solvent such as dichloromethane, tetrahydrofuran, or acetonitrile at 0 ° C. to room temperature. It can be carried out. Although reaction time is not specifically limited, Usually, it is 0.5 to 6 hours.

Step 8:
By cyclization of the compound represented by the formula (F7), the compound represented by the formula (F8) can be synthesized. This reaction can be carried out using a base such as potassium carbonate or sodium carbonate in a solvent such as methanol, ethanol or acetone at room temperature. Although reaction time is not specifically limited, Usually, it is 1 to 6 hours.

Step 9:
The compound represented by the formula (F9) can be synthesized according to the method described in Step 4 of General Synthesis Method E.

Since the pharmaceutical composition of the present invention has a BACE1 inhibitory action, it is effective for treatment and / or prevention of diseases induced by amyloid β protein production, secretion or deposition, symptom improvement and progression prevention. Examples of such diseases include Alzheimer's disease, Alzheimer type dementia, Alzheimer type senile dementia, mild cognitive impairment (MCI), Alzheimer's disease prodromal Alzheimer's disease (eg MCI due to Alzheimer's disease) ), Down syndrome, memory impairment, prion disease (Kreuzfeld-Jakob disease), Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy, other degenerative dementia, mixed dementia (eg, Alzheimer's disease and vascular dementia) Dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy body Alzheimer's disease, age-related macular degeneration, Parkinson's disease And amyloid angiopathy.
Furthermore, the pharmaceutical composition of the present invention is also effective in preventing progression in asymptomatic (preclinical Alzheimer's disease) patients at risk for Alzheimer-type dementia.
“A patient asymptomatic at risk for Alzheimer dementia” is normal, cognitively and functionally, but has potential early-onset signs or additional signs of Alzheimer's disease. There is evidence of age-related changes (eg, mild white matter lesions on MRI, etc.) and / or evidence of amyloid deposition as indicated by low cerebrospinal fluid Aβ _1-42 levels The administration subject seen is included. For example, “a patient asymptomatic at risk for Alzheimer dementia” is a clinical dementia assessment method (CDR) or a clinical dementia assessment method-Japan version (CDR-J ) And / or a functional assessment stage (FAST) is stage 1 or 2.

The compound according to the present invention has not only BACE1 inhibitory activity but also usefulness as a medicine, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and low clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
h) High brain transferability.
i) High oral absorption.
j) Long half-life.
k) High non-protein binding rate.
l) Ames test is negative.
m) High selectivity to BACE1 over BACE2.
Since the pharmaceutical composition of the present invention has high inhibitory activity against BACE1 and / or high selectivity with respect to other enzymes such as BACE2, it can be a pharmaceutical with reduced side effects. Furthermore, since it has a high inhibitory effect on amyloid β production in cell systems, and particularly a high inhibitory effect on amyloid β production in the brain, it can be an excellent pharmaceutical product. Furthermore, it can become a pharmaceutical with a wider safety margin with respect to a side effect by setting it as the optically active substance which has appropriate stereochemistry.

When the pharmaceutical composition of the present invention is administered, it can be administered orally or parenterally. Compositions for oral administration include oral solid preparations (eg tablets, powders, granules, capsules, pills, films, etc.), oral liquid preparations (suspensions, emulsions, elixirs, syrups, limonades, spirits, etc.) , Fragrances, extracts, decoctions, tinctures, etc.) and can be administered according to commonly used methods. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets. Powders and granules may be dry syrup. The capsule may be a soft capsule, a microcapsule or a sustained release capsule.
The composition for parenteral administration is a commonly used parenteral administration form such as transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration. Can be preferably administered. In the case of parenteral administration, injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, mouthwashes, enemas, ointments , Plaster, jelly, cream, patch, patch, external powder, suppository, etc.) and any commonly used dosage form can be preferably administered. The injection may be an emulsion such as O / W, W / O, O / W / O, and W / O / W type.
Since the pharmaceutical composition of the present invention has high oral absorbability, it can be preferably administered as an oral preparation.
If necessary, various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form and an effective amount of the compound according to the present invention are mixed to form a pharmaceutical composition. Can do. Furthermore, it is good also as a pharmaceutical composition for a pediatric patient, an elderly patient, a serious patient, or a surgery by changing suitably the effective amount of the compound based on this invention, dosage form, and / or various pharmaceutical additives. The pharmaceutical composition for pediatric use can be preferably administered to patients under 12 or 15 years of age. In addition, pediatric pharmaceutical compositions can be administered to patients within 27 days of birth, 28 days to 23 months of age, 2-11 years old, 12-16 years old or 18 years old. The pharmaceutical composition for the elderly can be preferably administered to patients over 65 years old.

The dosage of the pharmaceutical composition of the present invention is desirably set in consideration of the age and weight of the patient, the type and degree of disease, the administration route, and the like. The oral dose to an adult is usually in the range of 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, the dose varies greatly depending on the administration route, but is usually within a range of 0.005 to 10 mg / kg / day, and preferably within a range of 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
The compound according to the present invention is a therapeutic agent for other Alzheimer's disease such as acetylcholinesterase inhibitor, Alzheimer type dementia (hereinafter referred to as concomitant drug) for the purpose of enhancing the action of the compound or reducing the dose of the compound. Can be used in combination. At this time, the administration time of the compound according to the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, or may be administered after a certain period of time. Furthermore, the compound according to the present invention and the concomitant drug may be administered as two different compositions each containing an active ingredient, or may be administered as a single composition containing both active ingredients.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound according to the present invention and the concomitant drug can be appropriately selected in consideration of the administration subject, administration route, target disease, symptom, combination and the like. For example, when the subject of administration is a human, the concomitant drug can be used within a range of 0.01 to 100 parts by weight per 1 part by weight of the compound according to the present invention.
Examples of the concomitant drug include donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine, vinpocetine and the like.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
Moreover, the abbreviation used in an Example represents the following meaning.
Ac Acetyl Et Ethyl Boc tert-Butoxycarbonyl Bn Benzyl Bz Benzoyl Me Methyl Ph Phenyl t-Bu tert-Butyl TBS tert-Butyldimethylsilyl TMS Trimethylsilyl AIBN Azobisisobutyronitrile DAST Trifluoride N, N-Diethylaminosulfur DIBAL Hydrogen Diisobutylaluminum DIPEA N, N-diisopropylethylamine DMF N, N-dimethylformamide DMAP 4-dimethylaminopyridine DMSO dimethyl sulfoxide EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide HATU 1- [bis (dimethylamino) Methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate LH MDS lithium hexamethyldisilazide m-CPBA metachloroperbenzoic acid TFA trifluoroacetic acid THF tetrahydrofuran TBAF tetrabutylammonium fluoride WSCD 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

¹ H-NMR spectra were displayed using a Bruker Advance 400 MHz spectrometer, and chemical shifts were displayed from tetramethylsilane or residual solvent peaks (CDCl ₃ = 7.26 ppm, DMSO-d ₆ = 2.50 ppm).
Analytical LC / MS (ESI positive or negative, retention time (RT)) data was measured using Shimadzu UFLC or Waters UPLC under the following conditions.
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min Column oven: 50 ° C.
UV detection wavelength: 254 nm
Mobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1% formic acid-containing acetonitrile solution Gradient: Solvent [B] 10% -100% linear gradient was performed in 3 minutes, and solvent [B] 100% was maintained for 1 minute.

Synthesis of Compound I-5

Process 1
A stirred suspension of zinc (1.40 g, 21.4 mmol) in THF (80 ml) was heated to reflux. To the suspension was added a solution of compound 1-1 (8.46 g, 19.4 mmol) in THF (20 ml) and ethyl 2-bromo-2-fluoroacetate (3.95 g, 21.4 mmol) in THF (10 ml). added. After stirring at the same temperature for 3 hours, the reaction solution was treated with a saturated aqueous NH ₄ Cl solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc at 25%. The collected fractions were concentrated under reduced pressure to obtain compound 1-2 (5.76 g, 10.6 mmol, 55%) as a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.84-0.89 (m, 6H), 0.94-0.98 (m, 9H), 1.24 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H), 1.96 (s, 3H), 4.26 (m, 2H), 5.16 (s, 1H), 5.34 (d, J = 46.4 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H).
Process 2
To a solution of compound 1-2 (5.76 g, 10.6 mmol) and AcOH (1.22 ml, 21.3 mmol) in THF (30 ml) was added KF (1.24 g, 21.3 mmol). DMF (30 ml) was added and stirred at room temperature. After stirring at the same temperature for 2.5 hours, the reaction solution was treated with a saturated aqueous NaHCO ₃ solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 30% to 50%. The collected fractions were concentrated under reduced pressure to give compound 1-3 (4.01 g, 9.38 mmol, 88%) as a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H), 1.97 (s, 3H), 4.27 (m, 2H), 5.14 (s, 1H), 5.35 (d, J = 46.4 Hz, 1H), 7.29 (dd, J = 10.8, 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.9 Hz, 1H).

Process 3
To a solution of compound 1-3 (3.94 g, 9.22 mmol) in CH ₂ Cl ₂ (40 ml) was added 1.02 mol / L DIBAL (27.1 ml, 27.7 mmol) at −78 ° C. The mixture was stirred at the same temperature for 15 minutes, then treated with a saturated aqueous Rochelle salt solution, and stirred for 2.5 hours. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 1-4 as a yellow amorphous and used in the next step without purification.
To a toluene (85 ml) solution of methyltriphenylphosphonium bromide (8.23 g, 23.0 mmol), a 1.00 mol / L t-BuOK THF solution (21.2 ml, 21.2 mmol) was added at room temperature. After stirring at the same temperature for 1 hour, a toluene (30 ml) solution of compound 1-4 was added at 0 ° C. After stirring at room temperature for 90 minutes, the reaction solution was treated with a saturated aqueous NH ₄ Cl solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 10% to 50%. The collected fractions were concentrated under reduced pressure to obtain compound 1-5 (1.57 g, 4.12 mmol, 45%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (s, 9H), 1.85 (t, J = 1.8 Hz, 3H), 5.11 (s, 1H), 5.17-5.32 (m, 2H), 5.34 ( d, J = 1.1 Hz, 1H), 5.91-6.04 (m, 1H), 7.29 (dd, J = 10.7, 8.5 Hz, 1H), 7.43 (dd, J = 3.0, 8.5 Hz, 1H).
Process 4
To a solution of compound 1-5 (1.57 g, 4.12 mmol) in MeOH (16 ml) was added 4 mol / L HCl dioxane solution (1.54 ml, 6.18 mmol) at room temperature. After stirring at the same temperature for 30 minutes, the reaction solution was treated with an aqueous NaHCO ₃ solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO _{4 ,} filtered and concentrated to give compound 1-6, which was used in the next step without purification.
To a solution of 1-6 in CH ₂ Cl ₂ (11 ml), benzoyl isothiocyanate (0.848 ml, 2.58 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated, the resulting residue was applied to a silica gel column, and hexane / EtOAc was eluted at 0% to 25%. The collected fractions were concentrated under reduced pressure to obtain compound 1-7 (1.81 g, 4.12 mmol, quantitative) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.12 (d, J = 0.9 Hz, 3H), 5.43-5.61 (m, 3H), 5.90-6.03 (m, 1H), 7.19 (dd, J = 10.6 , 8.5 Hz, 1H), 7.40 (dd, J = 8.5, 3.0 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.85 (d, J = 7.7 Hz, 2H), 8.83 (s, 1H), 11.53 (s, 1H).

Process 5
To a solution of iodine (2.09 g, 8.24 mmol) in MeCN (40 ml), a solution of compound 1-7 (1.81 g, 4.12 mmol) in MeCN (14 ml) was added at 0 ° C. After stirring at the same temperature for 20 minutes, the reaction solution was treated with an aqueous solution of NaHCO ₃ and Na ₂ S ₂ O ₃ . The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 35%. The collected fractions were concentrated under reduced pressure to obtain compound 1-8 (2.18 g, 3.85 mmol, 94%) as a yellow amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90 (s, 3H), 3.29 (dd, J = 10.4, 5.0 Hz, 1H), 3.58 (t, J = 10.4 Hz, 1H), 3.94-3.79 ( m, 1H), 5.75 (d, J = 47.3 Hz, 1H), 7.52-7.32 (m, 6H), 8.16 (d, J = 6.9 Hz, 2H).
Step 6
To a solution of compound 1-8 (1.52 g, 2.68 mmol) in DMSO (1 ml) and H ₂ O (0.1 ml), AgBF ₄ (1.05 g, 5.37 mmol) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was treated with an aqueous NaHCO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc was eluted from 0% to 50%. The collected fractions were concentrated under reduced pressure to give compound 1-9 (684 mg, 1.50 mmol, 56%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.88 (s, 3H), 3.74-3.94 (m, 2H), 4.14 (dd, J = 7.3, 2.8 Hz, 1H), 5.67 (d, J = 47.2 Hz, 1H), 7.31-7.51 (m, 6H), 8.18 (d, J = 7.3 Hz, 2H).

Step 7
To a solution of compound 1-9 (325 mg, 0.712 mmol) in DMF (4 ml) was added imidazole (194 mg, 2.85 mmol) and TBSCl (215 mg, 1.42 mmol) at 0 ° C. After stirring at room temperature for 20 minutes, the reaction was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain compound 1-10 (384 mg, 0.673 mmol, 95%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.11 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.87 (s, 3H), 3.64-3.69 (m, 1H), 3.72-3.79 (m, 1H), 4.03-4.09 (m, 1H), 5.60 (dd, J = 46.9, 1.3 Hz, 1H), 7.50-7.30 (m, 5H), 8.20 (d, J = 7.3 Hz, 2H).
Process 8
To a solution of compound 1-10 (384 mg, 0.673 mmol) in THF (4 ml), Boc ₂ O (0.234 ml, 1.01 mmol) and DMAP (32.9 mg, 0.269 mmol) were added at room temperature. After stirring at the same temperature for 20 minutes, the mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain compound 1-11 (451 mg, 0.672 mmol, quantitative) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.39 (s, 9H), 1.62 (d, J = 2.4 Hz, 3H), 3.71-3.76 (m, 1H), 3.89 (dt, J = 30.3, 7.7 Hz, 1H), 4.06 (dd, J = 9.8, 7.7 Hz, 1H), 5.33 (dd, J = 47.4, 1.6 Hz , 1H), 7.19 (t, J = 9.2 Hz, 1H), 7.33-7.40 (m, 3H), 7.48 (t, J = 7.3 Hz, 1H), 7.76 (d, J = 7.3 Hz, 2H).

Step 9
To a solution of compound 1-11 (451 mg, 0.672 mmol) in THF (2 ml), MeOH (2 ml) and H ₂ O (2 ml) was added K ₂ CO ₃ (279 mg, 2.02 mmol) at room temperature. After stirring at 50 ° C. for 2 hours, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain compound 1-12 (346 mg, 0.611 mmol, 91%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.50 (s, 9H), 1.79 (s, 3H), 3.49- 3.70 (m, 2H), 3.99 (t, J = 9.0 Hz, 1H), 5.53 (d, J = 47.2 Hz, 1H), 7.30 (t, J = 9.4 Hz, 1H), 7.45-7.41 (m, 1H ).
Step 10
To a solution of compound 1-12 (346 mg, 0.611 mmol) in THF (4 ml) was added Boc ₂ O (0.213 ml, 0.916 mmol) and DMAP (29.8 mg, 0.244 mmol) at room temperature. After stirring at the same temperature for 30 minutes, the mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 1-13 (370 mg, 0.555 mmol, 91%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.11 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.42 (s, 18H), 1.82 (d, J = 1.9 Hz, 3H), 3.73-3.79 (m, 1H), 3.97-4.15 (m, 2H), 5.45 (d, J = 47.7 Hz, 1H), 7.25-7.31 (m, 1H), 7.39 (dd, J = 8.4, (3.0 Hz, 1H).

Step 11
To a THF (8 ml) solution of compound 1-13 (400 mg, 0.600 mmol), AcOH (0.0510 ml, 0.900 mmol) and TBAF (1.00 mol / L THF solution, 1.80 ml, 1.80 mmol) were added at room temperature. Added in. After stirring at the same temperature for 1 hour, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 10% to 50%. The collected fractions were concentrated under reduced pressure to obtain Compound 1-14 (323 mg, 0.585 mmol, 98%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (s, 9H), 1.84 (s, 3H), 3.84-3.95 (m, 1H), 4.04-4.19 (m, 2H), 5.51 (d, J = 47.4 Hz, 1H), 7.27-7.42 (m, 2H).
Step 12
To a solution of compound 1-14 (323 mg, 0.585 mmol) in CH ₂ Cl ₂ (10 ml) was added DAST (0.257 ml, 1.75 mmol) at −78 ° C. After stirring at room temperature for 40 minutes, the reaction was treated with aqueous NaHCO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 5-15 (310 mg, 0.559 mmol, 96%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (s, 18H), 1.85 (d, J = 2.1 Hz, 3H), 4.28-4.61 (m, 2H), 4.90 (dt, J = 46.6, 8.4 Hz, 1H), 5.50 (dd, J = 47.1, 1.8 Hz, 1H), 7.30 (t, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 3.1 Hz, 1H).

Step 13
A degassed mixture of Pd ₂ (dba) ₃ (11.6 mg, 0.0130 mmol) and xanthophos (21.9 mg, 0.0380 mmol) in dioxane (1 ml) was stirred at room temperature for 1 hour. To the mixture was added dioxane (3 ml), compound 1-15 (70.0 mg, 0.126 mmol), 5- (fluoromethoxy) pyrazine-2-carboxamide (25.9 mg, 0.152 mmol) and cesium carbonate (49.4 mg). 0.152 mmol) was added. After stirring at 90 ° C. for 6 hours, 5- (fluoromethoxy) pyrazine-2-carboxamide (25.9 mg, 0.152 mmol) and cesium carbonate (49.4 mg, 0.152 mmol) were added to the reaction solution. After further stirring for 11 hours, the reaction solution was treated with an aqueous citric acid solution and filtered. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 35%. The collected fractions were concentrated under reduced pressure to give compound 1-16 (55.0 mg, 0.0850 mmol, 68%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 18H), 1.89 (s, 3H), 3.99-4.11 (m, 1H), 4.37-4.53 (m, 1H), 4.85 (dt, J = 47.0, 8.8 Hz, 1H), 5.49 (d, J = 48.4 Hz, 1H), 6.16 (d, J = 50.9 Hz, 2H), 7.52 (t, J = 9.3 Hz, 1H), 8.31 (s, 1H ), 8.39 (dd, J = 9.3, 3.0 Hz, 1H), 9.09 (s, 1H), 10.01 (s, 1H).
Step 14
A solution of compound 1-16 (55.0 mg, 0.0850 mmol) in formic acid (0.982 ml) was stirred at room temperature for 22 hours. The reaction was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give compound I-5 (24.0 mg, 0.0540 mmol, 63%) as a tan solid.

工程１
化合物２−１（２．００ｇ、８．２９ｍｍｏｌ）のＴＨＦ（２０ｍｌ）溶液に、ＬＨＭＤＳ（１．００ｍｍｏｌ／Ｌ ＴＨＦ溶液、１６．６ｍＬ、１６．６ｍｍｏｌ）を−７８℃で加えた。４０分間攪拌した後、１，１，１−トリフルオロプロパン−２−オン（１．４８ｍｌ、１６．６ｍｍｏｌ）のＴＨＦ（５ｍｌ）溶液を加え、同温で２０分間攪拌した。反応液をＮＨ_４Ｃｌ水溶液で処理した。水層をＡｃＯＥｔで抽出し、有機層をＮａ_２ＳＯ_４で乾燥し、ろ過および濃縮した。粗生成物をシリカゲルカラムに付し、ヘキサン／ＥｔＯＡｃを０％から２０％で溶出した。集めたフラクションを減圧濃縮し、化合物２−２（１．７９ｇ、５．０７ｍｍｏｌ、６１％）を黄色固体として得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (s, 3H), 1.39 (s, 9H), 3.45 (d, J = 12.7 Hz, 1H), 3.80 (d, J = 12.7 Hz, 1H), 6.31 (s, 1H), 7.15 (dd, J = 11.4, 8.3 Hz, 1H), 7.24 (t, J = 8.3 Hz, 1H), 7.55-7.44 (m, 2H).
工程２
化合物２−２（８９６ｍｇ、２．５４ｍｍｏｌ）のＭｅＯＨ（１２ｍｌ）溶液に、４ｍｏｌ／Ｌ ＨＣｌ水溶液（６．３４ｍｌ、１２．７ｍｍｏｌ）を室温で加えた。同温度で１時間攪拌した後、反応液をＮａＨＣＯ_３水溶液で処理し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＨ_２Ｏおよび食塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥し_、ろ過および濃縮した。粗生成物をシリカゲルカラムに付し、ヘキサン／ＥｔＯＡｃを２０％で溶出した。集めたフラクションを減圧濃縮し、化合物２−３（６０３ｍｇ、２．４１ｍｍｏｌ、９５％）を白色固体として得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.50 (s, 3H), 3.17 (d, J = 17.8 Hz, 1H), 3.53 (d, J = 17.8 Hz, 1H), 5.06 (s, 1H), 7.18 (t, J = 9.8 Hz, 1H), 7.26-7.31 (m, 1H), 7.63-7.56 (m, 1H), 7.86 (t, J = 7.5 Hz, 1H). Synthesis of Compound I-7

Process 1
LHMDS (1.00 mmol / L THF solution, 16.6 mL, 16.6 mmol) was added to a solution of compound 2-1 (2.00 g, 8.29 mmol) in THF (20 ml) at −78 ° C. After stirring for 40 minutes, a solution of 1,1,1-trifluoropropan-2-one (1.48 ml, 16.6 mmol) in THF (5 ml) was added and stirred at the same temperature for 20 minutes. The reaction was treated with aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to obtain compound 2-2 (1.79 g, 5.07 mmol, 61%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.04 (s, 3H), 1.39 (s, 9H), 3.45 (d, J = 12.7 Hz, 1H), 3.80 (d, J = 12.7 Hz, 1H) , 6.31 (s, 1H), 7.15 (dd, J = 11.4, 8.3 Hz, 1H), 7.24 (t, J = 8.3 Hz, 1H), 7.55-7.44 (m, 2H).
Process 2
To a solution of compound 2-2 (896 mg, 2.54 mmol) in MeOH (12 ml) was added 4 mol / L aqueous HCl (6.34 ml, 12.7 mmol) at room temperature. After stirring at the same temperature for 1 hour, the reaction solution was treated with an aqueous NaHCO ₃ solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO _{4 ,} filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc at 20%. The collected fractions were concentrated under reduced pressure to obtain compound 2-3 (603 mg, 2.41 mmol, 95%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50 (s, 3H), 3.17 (d, J = 17.8 Hz, 1H), 3.53 (d, J = 17.8 Hz, 1H), 5.06 (s, 1H) , 7.18 (t, J = 9.8 Hz, 1H), 7.26-7.31 (m, 1H), 7.63-7.56 (m, 1H), 7.86 (t, J = 7.5 Hz, 1H).

Process 3
To a solution of compound 2-3 (500 mg, 2.00 mmol) in toluene (5 ml) was added tetraethyl orthotitanate (0.836 ml, 4.00 mmol) and (S) -2-methylpropane-2-sulfinamide (363 mg, 3 ml 0.000 mmol) was added. After stirring at 80 ° C. for 15 minutes, MeCN (10 ml) and H ₂ O (0.25 mL) were added to the reaction mixture at room temperature, and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and eluted with hexane / EtOAc at 30%. The collected fractions were concentrated under reduced pressure to give compound 2-4 (588 mg, 1.66 mmol, 83%) as a white solid.
¹ H-NMR (400 MHz, CDCl3) δ: 1.33 (s, 3H), 1.37 (s, 9H), 3.35 (d, J = 13.0 Hz, 1H), 3.95 (d, J = 13.0 Hz, 1H), 5.89 (s, 1H), 7.07-7.25 (m, 2H), 7.54-7.40 (m, 2H).
Process 4
To a solution of compound 2-4 (550 mg, 1.56 mmol) in DMF (5 ml) was added imidazole (318 mg, 4.67 mmol), TMSCl (338 mg, 3.11 mmol) and DMAP (95.0 mg, 0.778 mmol) at room temperature. added. After stirring at the same temperature for 40 minutes, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to give compound 2-5 (406 mg, 0.954 mmol, 61%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: -0.14 (s, 9H), 1.30 (s, 9H), 1.42 (s, 3H), 3.61 (d, J = 13.2 Hz, 1H), 3.99 (d , J = 13.2 Hz, 1H), 7.07 (dd, J = 8.4, 10.7 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.43-7.35 (m, 1H), 7.46-7.53 (m, 1H).

Process 5
To a THF (3 ml) solution of compound 2-5 (200 mg, 0.470 mmol), MeLi (1.13 mmol / L ethyl ether solution, 1.25 mL, 1.41 mmol) was added at −78 ° C. After stirring at 0 ° C. for 30 minutes, the reaction solution was treated with an aqueous NH ₄ Cl solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 2-6 (18.0 mg, 0.0408 mmol, 8.7%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.01 (s, 9H), 1.06 (s, 3H), 1.28 (s, 9H), 1.69 (s, 3H), 2.30 (d, J = 15.1 Hz, 1H), 2.53 (d, J = 15.1 Hz, 1H), 5.54 (s, 1H), 6.96-7.03 (m, 1H), 7.24-7.17 (m, 2H), 8.14 (t, J = 8.0 Hz, 1H ).
Step 6
To a solution of compound 2-6 (86.0 mg, 0.195 mmol) in MeOH (1 ml) was added 4 mol / L HCl dioxane solution (0.292 ml, 1.17 mmol) at room temperature. After stirring at the same temperature for 17 hours, the reaction solution was treated with an aqueous NaHCO ₃ solution, and the aqueous layer was extracted with CHCl ₃ . The combined organic layers were dried over Na ₂ SO _{4 ,} filtered and concentrated to give compound 2-7, which was used in the next step without purification.
To a solution of 2-7 in CH ₂ Cl ₂ (1 ml) was added benzoyl isothiocyanate (0.0400 ml, 0.292 mmol) at 0 ° C. After stirring at room temperature for 2.5 hours, the reaction solution was concentrated. The resulting residue was applied to a silica gel column and eluted with hexane / EtOAc from 0% to 25% The collected fractions were concentrated in vacuo to give 2-8 (72.0 mg, 0.168 mmol, 86%) as a yellow oil. Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.31 (s, 3H), 2.25 (s, 3H), 2.66 (d, J = 15.2 Hz, 1H), 2.98 (d, J = 15.2 Hz, 1H) , 7.02-7.09 (m, 1H), 7.16 (t, J = 7.1 Hz, 1H), 7.27-7.33 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.86 (d, J = 7.7 Hz, 2H), 8.83 (s, 1H), 11.65 (s, 1H).

Step 7
To a solution of compound 2-8 (72.0 mg, 0.168 mmol) in MeCN (1 ml) was added WSCD.HCl (64.4 mg, 0.336 mmol) at room temperature. After stirring at the same temperature for 20 hours, the reaction solution was concentrated. The resulting residue was applied to a silica gel column and eluted with hexane / EtOAc from 0% to 20%. The collected fractions were concentrated under reduced pressure to give compound 2-9 (55.0 mg, 0.139 mmol, 83%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.11 (s, 3H), 1.82 (s, 3H), 2.43 (d, J = 14.3 Hz, 1H), 3.06 (d, J = 14.3 Hz, 1H) , 7.10-7.21 (m, 2H), 7.32-7.47 (m, 4H), 7.52 (t, J = 7.3 Hz, 1H), 8.28 (d, J = 7.3 Hz, 2H), 11.94 (s, 1H).
Process 8
To a solution of compound 2-9 (55.0 mg, 0.139 mmol) in MeOH (1 ml) was added K ₂ CO ₃ (57.8 mg, 0.418 mmol) at room temperature. After stirring at 50 ° C. for 4 hours, the reaction solution was treated with H ₂ O, and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give compound 2-10, which was used in the next step without purification.
To a solution of 2-10 TFA (1 ml), sulfuric acid (0.245 ml, 4.60 mmol) was added at -20 ° C. After stirring at 0 ° C. for 5 minutes, the reaction was added to HNO ₃ (0.00935 ml, 0.209 mmol) at −20 ° C. After stirring at 0 ° C. for 15 minutes, the reaction solution was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt, and the organic layer was dried over Na ₂ SO ₄ . The filtrate was concentrated under reduced pressure to give compound 2-11 as a yellow oil, which was used in the next step without purification.
To a solution of 2-11 in THF (1 ml), Boc ₂ O (0.0970 ml, 0.419 mmol) and DMAP (6.82 mg, 0.0560 mmol) were added at room temperature. After stirring at the same temperature for 1 hour, the mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to give compound 2-12 (70.0 mg, 0.131 mmol, 94%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.09 (s, 3H), 1.53 (s, 18H), 1.66 (s, 3H), 2.19 (d, J = 14.8 Hz, 1H), 2.90 (d, J = 14.8 Hz, 1H), 7.28-7.24 (m, 1H), 8.19-8.24 (m, 1H), 8.59 (dd, J = 6.9, 2.9 Hz, 1H).

Step 9
A suspension of 2-12 (70.0 mg, 0.131 mmol) and 10% Pd / C (7.05 mg) in MeOH (3 ml) was stirred at room temperature under a hydrogen atmosphere. After stirring at the same temperature for 1.5 hours, the mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give compound 2-13 (57.0 mg, 0.113 mmol, 86%) as a white solid that was used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.14 (s, 3H), 1.52 (s, 18H), 1.61 (s, 3H), 2.04 (d, J = 14.2 Hz, 1H), 2.93 (d, J = 14.2 Hz, 1H), 3.51 (s, 2H), 6.55-6.50 (m, 1H), 6.89-6.81 (m, 2H).
Step 10
To a solution of 2-13 (57.0 mg, 0.113 mmol) in DMF (1 ml), 5-cyanopicolinic acid monohydrate (18.7 mg, 0.113 mmol), HATU (51.4 mg, 0.135 mmol) and DIPEA (0.0390 ml, 0.226 mmol) was added at room temperature. After stirring at the same temperature for 1 hour, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain compound 2-14 (70.0 mg, 0.110 mmol, 98%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.11 (s, 3H), 1.54 (s, 18H), 1.67 (s, 3H), 2.12 (d, J = 14.3 Hz, 1H), 2.94 (d, J = 14.3 Hz, 1H), 7.13 (dd, J = 11.5, 9.0 Hz, 1H), 7.53 (dd, J = 7.0, 2.6 Hz, 1H), 8.21 (dd, J = 8.2, 1.8 Hz, 1H), 8.32-8.27 (m, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.80 (s, 1H), 9.91 (s, 1H).
Step 11
A solution of compound 2-14 (70.0 mg, 0.110 mmol) in formic acid (0.972 ml) was stirred at room temperature for 19 hours. The reaction was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give compound 1-7 (40.0 mg, 0.0920 mmol, 83%) as a white solid.

Synthesis of Compound I-8

Process 1
To a solution of compound 3-1 (373 mg, 1.24 mmol) in MeOH (4 ml) was added 4 mol / L HCl dioxane solution (0.464 ml, 1.86 mmol) at room temperature. After stirring at the same temperature for 30 minutes, the reaction solution was treated with an aqueous NaHCO ₃ solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 3-2 as a brown oil, which was used in the next step without purification.
To a solution of compound 3-2 in CH ₂ Cl ₂ (3 ml), benzoyl isothiocyanate (0.255 ml, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, the reaction solution was concentrated. The resulting residue was applied to a silica gel column and eluted with hexane / EtOAc from 0% to 25%. The collected fractions were concentrated under reduced pressure to obtain Compound 3-3 (397 mg, 1.10 mmol, 89%) as a white amorphous.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.13 (s, 3H), 5.48 (d, J = 10.6 Hz, 1H), 5.60-5.76 (m, 2H), 5.82-5.96 (m, 1H), 7.00 -7.07 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.27-7.33 (m, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.85 (d, J = 7.7 Hz, 2H), 8.82 (s, 1H), 11.50 (s, 1H).
Process 2
To a solution of iodine (559 mg, 2.20 mmol) in MeCN (30 ml), a solution of compound 3-3 (397 mg, 1.10 mmol) in MeCN (10 ml) was added at 0 ° C. After stirring at the same temperature for 20 minutes, the reaction solution was treated with an aqueous solution of NaHCO ₃ and Na ₂ S ₂ O _{3 .} The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to obtain compound 3-4 (489 mg, 1.01 mmol, 91%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90 (s, 3H), 3.14-3.28 (m, 2H), 3.50 (t, J = 9.3 Hz, 1H), 5.70 (d, J = 47.3 Hz, 1H), 7.12-7.23 (m, 2H), 7.31-7.48 (m, 4H), 7.53 (t, J = 7.3 Hz, 1H), 8.21 (d, J = 7.3 Hz, 2H).

Process 3
To a solution of compound 3-4 (489 mg, 1.01 mmol) in toluene (5 ml) was added Bu ₃ SnH (0.320 ml, 1.21 mmol) and AIBN (8.26 mg, 0.0500 mmol) at room temperature. After stirring at 80 ° C. for 100 minutes, the reaction solution was concentrated. The resulting residue was applied to an amino silica gel column and eluted with hexane / EtOAc from 0% to 20%. The collected fractions were concentrated under reduced pressure to obtain Compound 3-5 (336 mg, 0.932 mmol, 93%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40 (d, J = 6.7 Hz, 3H), 1.88 (s, 3H), 3.13 (dq, J = 31.4, 6.7 Hz, 1H), 5.25 (d, J = 47.2 Hz, 1H), 7.11 (dd, J = 12.3, 8.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.33-7.46 (m, 4H), 7.51 (t, J = 7.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 2H), 12.13 (br s, 1H).
Process 4
To a solution of compound 3-5 (336 mg, 0.932 mmol) in EtOH (3 ml) was added hydrazine monohydrate (0.226 ml, 4.66 mmol) at room temperature. After stirring at the same temperature for 14 hours, the reaction solution was concentrated. The resulting residue was applied to an amino silica gel column and eluted with hexane / EtOAc from 10% to 50%. The collected fractions were concentrated under reduced pressure to give compound 3-6 (195 mg, 0.761 mmol, 82%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (d, J = 6.8 Hz, 3H), 3.08-2.94 (m, 1H), 5.09 (d, J = 47.4 Hz, 1H), 6.99-7.07 ( m, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.23-7.31 (m, 2H).
Process 5
To a TFA (2 ml) solution of compound 3-6, sulfuric acid (0.507 ml, 9.51 mmol) was added at −20 ° C. After stirring for 5 minutes at 0 ° C., the reaction was added to HNO ₃ (0.0510 ml, 1.14 mmol) at −20 ° C. After stirring at 0 ° C. for 20 minutes, the reaction solution was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt, and the organic layer was dried over Na ₂ SO ₄ . The filtrate was concentrated under reduced pressure to give compound 3-7 as a yellow oil, which was used in the next step without purification.
To a solution of compound 3-7 in THF (2 ml), Boc ₂ O (0.529 ml, 2.28 mmol) and DMAP (37.1 mg, 0.304 mmol) were added at room temperature. After stirring at the same temperature for 50 minutes, the mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 40%. The collected fractions were concentrated under reduced pressure to obtain Compound 3-8 (381 mg, 0.760 mmol, quantitative) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (d, J = 6.8 Hz, 3H), 1.55 (s, 18H), 1.82 (s, 3H), 3.09 (dq, J = 29.6, 6.8 Hz, 1H), 5.12 (d, J = 46.7 Hz, 1H), 7.23 (dd, J = 10.9, 9.1 Hz, 1H), 8.23-8.18 (m, 1H), 8.52 (dd, J = 6.6, 2.8 Hz, 1H ).

Step 6
To a solution of compound 3-8 (381 mg, 0.760 mmol) in EtOH (4 ml), THF (2 ml) and H ₂ O (2 ml), NH ₄ Cl (488 mg, 9.12 mmol) and iron powder (339 mg, 6.08 mmol). ) Was added at room temperature. After stirring at 60 ° C. for 90 minutes, the mixture was treated with H ₂ O and filtered through Celite (registered trademark). The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 40%. The collected fractions were concentrated under reduced pressure to give compound 3-9 (247 mg, 0.524 mmol, 69%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (d, J = 7.0 Hz, 3H), 1.54 (s, 18H), 1.80 (t, J = 2.0 Hz, 3H), 3.19 (dq, J = 29.6, 7.0 Hz, 1H), 3.57 (s, 2H), 5.05 (d, J = 48.2 Hz, 1H), 6.55-6.51 (m, 1H), 6.88-6.80 (m, 2H).
Step 7
To a solution of compound 3-9 (60.0 mg, 0.127 mmol) in DMF (1 ml), 5-methoxypyrazine-2-carboxylic acid (20.6 mg, 0.134 mmol), HATU (58.1 mg, 0.153 mmol) And DIPEA (0.0440 ml, 0.254 mmol) were added at room temperature. After stirring at the same temperature for 20 minutes, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 3-10 (70.0 mg, 0.115 mmol, 91%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (d, J = 7.0 Hz, 3H), 1.58 (s, 18H), 1.86 (s, 3H), 3.17 (dq, J = 30.5, 7.0 Hz, 1H), 4.06 (s, 3H), 5.09 (d, J = 46.8 Hz, 1H), 7.10 (dd, J = 9.3, 11.7 Hz, 1H), 7.51 (d, J = 6.7 Hz, 1H), 8.06 ( s, 1H), 8.44-8.39 (m, 1H), 9.01 (s, 1H), 9.69 (s, 1H).
Process 8
A solution of compound 3-10 (70.0 mg, 0.115 mmol) in formic acid (0.972 ml) was stirred at room temperature for 19 hours. The reaction was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt, the organic layer was dried over _Na 2 SO _4, filtered and concentrated to give Compound I-8 (35.0mg, 0.0860mmol, 75%) as a white solid.

Synthesis of Compound I-13

Process 1
HCl-dioxane (4M, 15.1 ml, 60.4 mmol) was added to a solution of compound 4-1 (15.0 g, 43.2 mmol) in methanol (150 ml). After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 4-2 (10.5 g, quantitative), which was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 0.83, MS calculated 244.10 (M + H ⁺ ), found 244.30.
Process 2
To a solution of compound 4-2 (10.5 g, 43.2 mmol) and NaHCO ₃ (12.7 g, 151 mmol) in AcOEt (100 ml) and H ₂ O (50 ml) was added 4-nitrophenyl chloroformate (8.71 g, 43 0.2 mmol) was added at 0 ° C. After stirring at 0 ° C. for 1 hour, bis (2,4-dimethoxybenzyl) amine (13.7 g, 43.2 mmol) was added. After further stirring at 0 ° C. for 1 hour, the reaction solution was quenched with H ₂ O, and the aqueous layer was extracted with AcOEt. The organic layer was washed twice with aqueous K ₂ CO ₃ and H ₂ O to remove 4-nitrophenol. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 4-3 (25.3 g, 43.1 mmol, 100%, containing a small amount of 4-nitrophenol).
¹ H-NMR (CDCl ₃ ) δ: 0.97 (t, J = 7.2 Hz, 3H), 1.95 (s, 3H), 3.80 (s, 6H), 3.81 (s, 6H), 3.87 (dq, J = 10.6 , 7.2 Hz, 1H), 4.01 (dq, J = 10.6, 7.2 Hz, 1H), 4.33 (d, J = 16.2 Hz, 2H), 4.42 (d, J = 16.2 Hz, 2H), 5.58 (d, J = 47.8 Hz, 1H), 6.07 (s, 1H), 6.42-6.49 (m, 4H), 7.00 (m, 1H), 7.08 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.24 (m, 1H), 7.36 (m, 1H).

Process 3
To a solution of compound 4-3 (25.3 g, 43.2 mmol, containing a small amount of 4-nitrophenol) in CH ₂ Cl ₂ (125 ml) was added DIBAL (1.02 mol / L toluene solution, 127 ml, 130 mmol) to −65. Added at ° C. After stirring at −65 ° C. for 1 hour, the reaction was quenched with a solution of AcOEt and Rochelle salt (98 g, 346 mmol) in H ₂ O. After further stirring at room temperature for 2 hours, the aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 4-4 (19.5 g, 35.9 mmol, 83%, 3 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.67 (s, 3H), 3.80 (s, 6H), 3.81 (s, 6H), 4.36 (d, J = 15.9 Hz, 2H), 4.43 (d, J = 15.9 Hz, 2H), 5.76 (d, J = 46.9 Hz, 1H), 5.77 (s, 1H), 6.43-6.51 (m, 4H), 7.00-7.20 (m, 4H), 7.22-7.35 (m, 2H) , 9.51 (d, J = 10.0 Hz, 1H).
Process 4
To a THF (129 ml) solution of ethyltriphenylphosphonium bromide (28.2 g, 76.0 mmol), KHMDS (0.5 mol / L toluene solution, 143 ml, 71.3 mmol) was added at 0 ° C. After KHMDS was added dropwise, a solution of compound 4-4 (12.9 g, 23.8 mmol) in THF (80 ml) was quickly added to the reaction solution. After stirring at 0 ° C. for 30 minutes, the temperature was raised to 50 ° C. After stirring for an additional hour, the reaction was cooled to 0 ° C. and quenched with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compounds 4-5 and 4-6 as a mixture (12.4 g, 22.4 mmol, 94%, compound 4-5: compound 4-6 = 1.5: 1). .
Compound 4-5:
¹ H-NMR (CDCl ₃ ) δ: 1.54 (m, 3H), 1.87 (s, 3H), 3.78 (s, 6H), 3.81 (s, 6H), 4.31-4.47 (m, 4H), 5.31 (m , 1H), 5.58-5.83 (m, 3H), 6.42-6.48 (m, 4H), 6.97 (m, 1H), 7.07 (m, 1H), 7.10-7.17 (m, 2H), 7.19 (m, 1H ), 7.37 (m, 1H).
Compound 4-6:
¹ H-NMR (CDCl ₃ ) δ: 1.57 (m, 3H), 1.82 (s, 3H), 3.78 (s, 6H), 3.81 (s, 6H), 4.37 (m, 4H), 5.30 (m, 1H ), 5.45 (dd, J = 47.3, 6.8 Hz, 1H), 5.60 (s, 1H), 5.71 (m, 1H), 6.40-6.49 (m, 4H), 6.98 (dd, J = 12.5, 8.2 Hz, 1H), 7.08 (m, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.21 (m, 1H), 7.38 (dd, J = 8.2, 8.0 Hz, 1H).

Process 5
To a solution of iodine (11.4 g, 44.7 mmol) in acetonitrile (500 ml), compounds 4-5 and 4-6 (12.4 g, 22.4 mmol) in acetonitrile (125 ml) were added at 0 ° C. After stirring at 0 ° C. for 1.5 hours, the reaction was quenched with aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ . Acetonitrile was distilled off under reduced pressure, and the aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 4-7 (8.81 g, 13.0 mmol, 58%), and compound 4-6 (3.17 g, 5.72 mmol, 26%) was recovered.
¹ H-NMR (CDCl ₃ ) δ: 1.63 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H), 3.63 (dd, J = 28.6, 9.2 Hz, 1H), 3.75 (s, 6H), 3.82 (s, 6H), 4.12 (m, 1H), 4.49 (d, J = 15.9 Hz, 2H), 4.65 (d, J = 15.9 Hz, 2H), 5.37 (d, J = 48.8 Hz, 1H), 6.41-6.50 (m, 4H), 7.00 (dd, J = 11.9, 8.3 Hz, 1H), 7.06 (dd, J = 7.4, 7.4 Hz, 1H), 7.16-7.28 (m, 3H), 7.42 (dd, J = 8.3, 7.4 Hz, 1H).
Step 6
To a solution of 18-crown-6 (5.45 g, 20.6 mmol) and KO ₂ (1.47 g, 20.6 mmol) in DMSO (40 ml) was added compound 4-7 (3.51 g, 5.16 mmol) in DMSO ( 25 ml) solution was added at room temperature. After stirring for 25 minutes, the reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ . The aqueous layer was extracted with AcOEt, and the organic layer was dried over Na ₂ SO ₄ . This reaction was repeated 3 times (300 mg, 2.0 g and 3.0 g of 4-7 were used in each step). The combined organic layers obtained in each step were concentrated, and the residue was purified by silica gel chromatography. Compound 4-8 (2.05 g, 3.59 mmol, 28%, C7 position was 7.6: 1) Diastereomer mixture) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.3 Hz, 3H), 1.66 (s, 3H), 3.35 (dd, J = 30.4, 7.8 Hz, 1H), 3.75 (s, 6H), 3.81 (s, 6H), 3.85 (m, 1H), 4.45 (d, J = 15.9 Hz, 2H), 4.61 (d, J = 15.9 Hz, 2H), 5.38 (d, J = 48.6 Hz, 1H), 6.41-6.50 (m, 4H), 6.98 (dd, J = 12.0, 8.2 Hz, 1H), 7.05 (dd, J = 7.7, 7.3 Hz, 1H), 7.17-7.28 (m, 3H), 7.42 (dd, J = 8.2, 7.7 Hz, 1H).

Step 7
To a solution of compound 4-8 (1.42 g, 2.49 mmol) and nonafluorobutanesulfonyl fluoride (1.61 ml, 8.96 mmol) in toluene (28 ml) was added DBU (1.34 ml, 8.96 mmol) at room temperature. added. After stirring at room temperature for 12 hours, the reaction was quenched with saturated aqueous NH ₄ Cl, water and 2 mol / L aqueous HCl. The aqueous layer was extracted with AcOEt, and the organic layer was washed with 2 mol / L NaOH aqueous solution. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain a mixture of compound 4-9 and its exo olefin (1.0 g, compound 4-9: exo olefin = 1: 1, inseparable mixture).
LC / MS (Shimadzu): RT 1.98, MS calculated 573.26 (M + H ⁺ ), found 573.25.
Process 8
To a mixture of compound 4-9 and exoolefin (1.0 g, compound 4-9: exoolefin = 1: 1, inseparable mixture) and anisole (1.34 ml, 12.2 mmol), TFA (6 .73 ml, 87.0 mmol) was added at room temperature. After stirring at 80 ° C. for 13.5 hours, the reaction was cooled to 0 ° C. and quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 4-10 (251.8 mg, 925 μmol, 37%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, J = 24.1, 6.4 Hz, 3H), 1.77 (s, 3H), 3.89 (ddd, J = 30.2, 12.9, 7.8 Hz, 1H), 4.88 (ddq , J = 49.0, 7.8, 6.4 Hz, 1H), 5.25 (d, J = 47.2 Hz, 1H), 7.10 (dd, J = 12.3, 8.2 Hz, 1H), 7.24 (m, 1H), 7.32-7.45 ( m, 2H).

Step 9
H ₂ SO ₄ (0.6 ml) was added to a solution of compound 4-10 (251.8 mg, 925 μmol) in TFA (2.4 ml) at −20 ° C. After stirring at 0 ° C. for 5 minutes, the reaction was cooled to −20 ° C. and HNO ₃ (62 μl, 1.39 mmol) was added. After further stirring at 0 ° C. for 30 minutes, the reaction solution was quenched with K ₂ CO ₃ aqueous solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 4-11 (240.1 mg, 757 μmol, 82%).
¹ H-NMR (CDCl ₃ ) δ: 1.39 (dd, J = 24.2, 6.4 Hz, 3H), 1.65 (s, 3H), 3.67 (ddd, J = 30.9, 13.2, 7.4 Hz, 1H), 4.42 (brs , 2H), 4.86 (ddq, J = 48.8, 7.4, 6.4 Hz, 1H), 5.15 (d, J = 47.7 Hz, 1H), 7.23 (m, 1H), 8.22 (m, 1H), 8.45 (m, 1H).
Step 10
To a solution of compound 4-11 (240.1 mg, 757 μmol) and DMAP (18.5 mg, 151 μmol) in CH ₂ Cl ₂ (2.4 ml) was added Boc ₂ O (439 μl, 1.89 mmol) at room temperature. After stirring at room temperature for 35 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 4-12. The residue was triturated with AcOEt / hexane to give compound 4-12 (244.6 mg, 473 μmol, 62%). The stereochemistry at the C7 position in compound 4-12 was determined by X-ray crystallography.
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, J = 24.1, 6.5 Hz, 3H), 1.52 (s, 18H), 1.72 (s, 3H), 3.80 (ddd, J = 29.9, 12.9, 7.2 Hz , 1H), 4.91 (ddq, J = 48.1, 7.2, 6.5 Hz, 1H), 5.19 (d, J = 47.2 Hz, 1H), 7.28 (m, 1H), 8.26 (m, 1H), 8.57 (m, 1H).

Step 11
To a solution of compound 4-12 (241.2 mg, 466 μmol) in THF (3 ml) and MeOH (1.5 ml) was added Pd / C (24.8 mg) at room temperature. After stirring at room temperature for 2 hours under H ₂ atmosphere, the reaction solution was filtered through Celite (registered trademark) and washed with AcOEt. The filtrate was concentrated and the residue was purified by silica gel chromatography to give compound 4-13 (214.2 mg, 439 μmol, 94%).
¹ H-NMR (CDCl ₃ ) δ: 1.39 (dd, J = 24.1, 6.4 Hz, 3H), 1.52 (s, 18H), 1.68 (s, 3H), 3.58 (brs, 2H), 3.91 (ddd, J = 30.0, 13.4, 7.4 Hz, 1H), 4.88 (ddq, J = 48.8, 7.4, 6.4 Hz, 1H), 5.16 (d, J = 47.7 Hz, 1H), 6.56 (m, 1H), 6.82-6.91 ( m, 2H).
Step 12
To a solution of compound 4-13 (70.0 mg, 144 μmol), 5-cyanopicolinic acid monohydrate (28.6 mg, 172 μmol) and diisopropylethylamine (50 μl, 287 μmol) in DMF (1 ml), HATU (65.5 mg, 172 μmol) was added at room temperature. After stirring at room temperature for 1.5 hours, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt and the organic layer was washed with H ₂ O. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 4-14 (90.0 mg, quantitative).
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, J = 24.0, 6.4 Hz, 3H), 1.56 (s, 18H), 1.75 (s, 3H), 3.90 (ddd, J = 30.6, 13.2, 7.4 Hz , 1H), 4.89 (ddq, J = 48.8, 7.4, 6.4 Hz, 1H), 5.18 (d, J = 47.3 Hz, 1H), 7.15 (m, 1H), 7.60 (m, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.40 (m, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.80 (s, 1H), 9.99 (s, 1H).
Step 13
Compound 4-14 (90.0 mg, 144 μmol) was dissolved in formic acid (1 ml) and stirred at room temperature for 16 hours. The reaction was quenched with aqueous K ₂ CO _{3 and the} aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was triturated with AcOEt / hexane to obtain Compound I-13 (48.8 mg, 117 μmol, 81%, 2 steps).

Synthesis of Compound I-16

Process 1
To a solution of iodine (1.05 g, 4.15 mmol) in acetonitrile (45 ml), a solution of compound 4-6 (1.15 g, 2.07 mmol) in acetonitrile (15 ml) was added at 0 ° C. After stirring at 0 ° C. for 3 days, the reaction was quenched with saturated aqueous NaHCO ₃ and Na ₂ S ₂ O ₃ aqueous was added. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 5-1 (1.20 g, 1.76 mmol, 85%).
¹ H-NMR (CDCl ₃ ) δ: 1.65 (s, 3H), 1.74 (d, J = 6.8 Hz, 3H), 3.61 (dd, J = 27.5, 10.0 Hz, 1H), 3.74 (s, 6H), 3.81 (s, 6H), 4.10 (m, 1H), 4.45 (d, J = 16.1 Hz, 2H), 4.61 (d, J = 16.1 Hz, 2H), 5.66 (d, J = 48.3 Hz, 1H), 6.41-6.49 (m, 4H), 7.03 (m, 1H), 7.06 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.22 (m, 1H), 7.41 (m, 1H).
Process 2
To a solution of 18-crown-6 (1.62 g, 6.11 mmol) and KO ₂ (435 mg, 6.11 mmol) in DMSO (25 ml), compound 5-1 (1.04 g, 1.53 mmol) in DMSO (15 ml) The solution was added at room temperature. After stirring for 30 minutes, the reaction was quenched at 0 ° C. with saturated aqueous Na ₂ S ₂ O ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 5-2 (291 mg, 510 μmol, 33%).
¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.3 Hz, 3H), 1.62 (s, 3H), 2.25 (brs, 1H), 3.34 (dd, J = 30.9, 8.0 Hz, 1H), 3.76 (s, 6H), 3.81 (s, 6H), 3.83 (m, 1H), 4.49 (d, J = 15.9 Hz, 2H), 4.67 (d, J = 15.9 Hz, 2H), 5.14 (d, J = 48.8 Hz, 1H), 6.42-6.51 (m, 4H), 6.98 (m, 1H), 7.03 (m, 1H), 7.17-7.29 (m, 3H), 7.37 (m, 1H).

Process 3
To a solution of compound 5-2 (290 mg, 508 μmol) in CH ₂ Cl ₂ (6 ml), DAST (537 μl, 4.06 mmol) was added at −65 ° C. After stirring at room temperature for 22.5 hours, the reaction was quenched at 0 ° C. with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain a mixture of compound 5-3 and its endoolefin compound (212 mg, compound 5-3: endoolefin compound = 2.5: 1, inseparable mixture). The yield of compound 5-3 calculated from the ¹ H NMR ratio was 53%.
¹ H-NMR (CDCl ₃ ) δ: 1.17 (dd, J = 25.5, 6.1 Hz, 3H), 1.66 (s, 3H), 3.53 (m, 1H), 3.75 (s, 6H), 3.81 (s, 6H ), 4.38-4.75 (m, 5H), 5.30 (d, J = 48.3 Hz, 1H), 6.40-6.50 (m, 4H), 7.00 (m, 1H), 7.06 (m, 1H), 7.15-7.29 ( m, 3H), 7.41 (m, 1H).
Process 4
To a mixture of compound 5-3 and exoolefin (5-3 net weight: 172 mg, 300 μmol) and anisole (316 μl, 2.89 mmol), TFA (1.59 ml, 20.7 mmol) was added at room temperature. After stirring at 80 ° C. for 17 hours, the reaction was cooled to 0 ° C. and quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 5-4 (103 mg, quantitative).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (dd, J = 25.3, 6.0 Hz, 3H), 1.85 (s, 3H), 3.84 (m, 1H), 4.86 (m, 1H), 5.44 (d, J = 46.4 Hz, 1H), 7.12 (m, 1H), 7.26 (m, 1H), 7.33-7.43 (m, 2H).

Process 5
To a solution of compound 5-4 (103 mg, 300 μmol) in TFA (1.2 ml) was added H ₂ SO ₄ (0.3 ml) at −20 ° C. After stirring at 0 ° C. for 5 minutes, the reaction solution was cooled to −20 ° C. and HNO ₃ (25 μl, 567 μmol) was added. After stirring for 30 minutes at 0 ° C., the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 5-5 (86.3 mg, 272 μmol, 91%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, J = 25.5, 6.1 Hz, 3H), 1.67 (s, 3H), 3.53 (m, 1H), 4.29 (brs, 2H), 4.81 (m, 1H ), 5.30 (d, J = 47.2 Hz, 1H), 7.23 (m, 1H), 8.21 (m, 1H), 8.44 (m, 1H).
Step 6
To a solution of compound 5-5 (86.3 mg, 272 μmol) and DMAP (16.6 mg, 135 μmol) in CH ₂ Cl ₂ (2 ml) was added Boc ₂ O (158 μl, 680 μmol) at room temperature. After stirring at room temperature for 50 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 5-6 (129 mg, 248 μmol, 91%).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (dd, J = 25.5, 6.1 Hz, 3H), 1.53 (s, 18H), 1.74 (s, 3H), 3.65 (ddd, J = 27.4, 8.3, 4.8 Hz , 1H), 4.87 (ddq, J = 46.7, 8.3, 6.1 Hz, 1H), 5.35 (d, J = 46.9 Hz, 1H), 7.27 (m, 1H), 8.26 (m, 1H), 8.52 (m, 1H).

Step 7
To a solution of compound 5-6 (129 mg, 248 μmol) in THF (2 ml) and MeOH (1 ml) was added Pd / C (26.4 mg) at room temperature. After stirring at room temperature for 7.5 hours under H ₂ atmosphere, the reaction solution was filtered through Celite (registered trademark) and washed with AcOEt. The filtrate was concentrated and the residue was purified by silica gel chromatography to give compound 5-7 (104 mg, 214 μmol, 86%).
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, J = 25.4, 6.1 Hz, 3H), 1.53 (s, 18H), 1.70 (s, 3H), 3.56 (brs, 2H), 3.80 (m, 1H ), 4.84 (m, 1H), 5.33 (d, J = 47.3 Hz, 1H), 6.56 (m, 1H), 6.83 (m, 1H), 6.86 (m, 1H).
Process 8
To a solution of compound 5-7 (44.2 mg, 90.7 μmol), 5- (fluoromethoxy) pyrazine-2-carboxylic acid (18.7 mg, 109 μmol) and diisopropylethylamine (32 μl, 181 μmol) in DMF (1 ml) was added HATU. (41.4 mg, 109 μmol) was added at room temperature. After stirring at room temperature for 50 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 5-8 (51.6 mg, 80.4 μmol, 89%).
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, J = 25.3, 6.1 Hz, 3H), 1.54 (s, 18H), 1.76 (s, 3H), 3.78 (m, 1H), 4.85 (m, 1H ), 5.36 (d, J = 47.2 Hz, 1H), 6.15 (dd, J = 51.1, 14.8 Hz, 2H), 7.14 (m, 1H), 7.47 (m, 1H), 8.20 (s, 1H), 8.35 (m, 1H), 9.08 (s, 1H), 9.62 (s, 1H).
Step 9
Compound 5-8 (51.6 mg, 80.4 μmol) was dissolved in formic acid (0.75 ml) and stirred at room temperature for 18.5 hours. The reaction was quenched at 0 ° C. with aqueous K ₂ CO _{3 and the} aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was triturated with AcOEt / hexane to give compound I-16 (31.0 mg, 70.2 μmol, 87%).

Synthesis of Compound I-28

Process 1
To a stirred solution of diisopropylamine (37.7 mL, 0.265 mol) in THF (260 mL), n-butyllithium (2.65 mol / L hexane solution, 100 mL, 0.265 mol) was added dropwise at −78 ° C. After stirring at 0 ° C. for 25 minutes, a solution of ethyl propionate (30.4 mL, 0.265 mol) followed by chlorotriisopropoxytitanium (IV) (84.0 mL, 0.353 mol) in THF (70 mL) was −78. It was dripped at ° C. After stirring for 30 minutes, a solution of compound 6-1 (21.3 g, 0.088 mol) in THF (70 mL) was added dropwise at −78 ° C. The reaction was stirred at -78 ° C for 30 minutes. The reaction was quenched with saturated ammonium chloride solution. The resulting mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 3: 1 to 1: 1) to give compound 6-2 (24.8 g, 82%). Obtained as a tan oil. This material was obtained as a mixture of diastereomers.
¹ H NMR (400 MHz, CDCl ₃ ) (Main isomer) 1.14 (d, J = 7.0 Hz, 3H), 1.28 (s, 9H), 1.95 (s, 3H), 3.14 (q, J = 7.0 Hz, 1H), 3.98-4.04 (m, 1H), 4.89 (s, 1H), 7.01-7.43 (m, 5H).
Process 2
Under a nitrogen atmosphere, a stirred solution of compound 6-2 (8.33 g, 24.3 mmol) in THF (80 mL) was added to lithium borohydride (1.06 g, 48.5 mmol) and methanol (1.97 mL, 48.5 mmol). Was added at 0 ° C. After stirring at room temperature for 45 minutes, the reaction was quenched with acetic acid at 0 ° C. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
Dess-Martin periodinane (15.4 g, 36.4 mmol) was added to a stirred solution of the crude product in dichloromethane (70 mL) at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature for 1.5 hours, the reaction was quenched with a saturated solution of sodium bicarbonate. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 1: 1 to 1: 2) to give compound 6-3 (1.04 g, 14%). Obtained as a colorless gum. This product contained a small amount of other diastereomers.
¹ H NMR (400 MHz, CDCl ₃ ) 1.06 (d, J = 7.5 Hz, 3H), 1.20 (s, 9H), 1.84 (s, 3H), 3.36 (q, J = 7.5 Hz, 1H), 4.99 ( s, 1H), 7.02-7.45 (m, 4H), 9.76 (s, 1H).

Process 3
Under a nitrogen atmosphere, a stirred solution of compound 6-3 (1.04 g, 3.47 mmol) in THF (20 mL) was added to trimethyl (trifluoromethyl) silane (1.05 mL, 6.95 mmol) and TBAF (1 mol / L THF solution). , 0.243 mL, 0.243 mmol) was added at 0 ° C. After stirring at 0 ° C. for 1 hour, the reaction was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
Hydrochloric acid (4 mol / L dioxane solution, 1.30 mL, 5.20 mmol) was added to a stirred solution of the crude product in methanol (15 mL) at 0 ° C. After stirring at room temperature for 20 hours, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
To a stirred solution of the crude product in dichloromethane (15 mL), benzoyl isothiocyanate (0.559 mL, 4.16 mmol) was added at 0 ° C. After stirring at room temperature for 2.5 hours, the mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate 3: 1) to give compound 6-4 (620 mg, 42%) as a yellow amorphous. This material was obtained as a mixture of diastereomers.
MS: m / z = 395.10 [M + H] ^< +>.
Process 4
A suspension of compound 6-4 (620 mg, 1.45 mmol) and WSCD.HCl (555 mg, 2.89 mmol) in acetonitrile (12 mL) was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate 85:15) to give compound 6-5 (258 mg, 45%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) 1.30 (d, J = 6.9 Hz, 3H), 1.79 (s, 3H), 2.96 (q, J = 6.9 Hz, 1H), 4.35-4.39 (m, 1H), 7.13-7.55 (m, 7H), 8.27 (d, J = 8.0 Hz, 2H), 11.6 (s, 1H).

Process 5
A suspension of compound 6-5 (258 mg, 0.654 mmol) and potassium carbonate (271 mg, 1.96 mmol) in methanol (5 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
To a stirred solution of the crude product in TFA (1.1 mL) was added sulfuric acid (0.28 mL, 5.25 mmol) followed by nitric acid (0.044 mL, 0.982 mmol) at −20 ° C. After stirring at -20 ° C to -10 ° C for 75 minutes, the reaction was quenched with saturated potassium carbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 2: 1 to 1: 1) to give compound 6-6 (149 mg, 68%) as a colorless amorphous product. Got as.
¹ H NMR (400 MHz, CDCl ₃ ) 1.19 (d, J = 7.0 Hz, 3H), 2.74 (q, J = 7.0 Hz, 1H), 3.99-4.04 (m, 1H), 7.22 (t, J = 9.9 Hz, 1H), 8.17-8.21 (m, 1H), 8.35 (dd, J = 6.7, 2.8 Hz, 1H).
Step 6
Compound 6-6 (85.7 mg, 0.256 mmol), iron powder (114 mg, 2.05 mmol), and ammonium chloride (164 mg, 3.07 mmol) in ethanol (0.8 mL) / THF (0.4 mL) / water The (0.4 mL) suspension was stirred at 60 ° C. for 2.5 hours. The mixture was cooled to room temperature and filtered through Celite (registered trademark). The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
To a stirred solution of the crude product and aqueous hydrochloric acid (2 mol / L, 0.081 mL, 0.161 mmol) in methanol (1 mL) was added 5-cyanopicolinic acid monohydrate (29.5 mg, 0.177 mmol) and WSCD · HCl. (37.1 mg, 0.161 mmol) was added at room temperature. After stirring for 1 hour at room temperature, the reaction was quenched with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (amino silica gel, hexane: ethyl acetate gradient from 1: 1 to 0: 1) to give compound I-28 (58.1 mg, 74%). Was obtained as an off-white solid.

Synthesis of Compound I-33

Process 1
A solution of compound 7-1 (6.2 g, 18.1 mmol) (intermediate of I-28) and hydrochloric acid (4 mol / L dioxane solution, 6.77 mL, 27.1 mmol) in methanol (45 mL) was added at room temperature to 75. Stir for minutes. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
A solution of the crude product and Boc ₂ O (5.79 mL, 27.1 mmol) in THF (40 mL) was stirred at room temperature for 16 hours, followed by heating to 50 ° C. for 24 hours. Cool to room temperature and concentrate under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate 9: 1) to give compound 7-2 (5.7 g, 93%) as a tan oil. This material was obtained as a mixture of diastereomers.
¹ H NMR (400 MHz, CDCl ₃ ) (Main isomer) 0.96 (d, J = 7.0 Hz, 3H), 1.23 (t, J = 6.4 Hz), 1.40 (s, 9H), 1.91 (s, 3H) , 3.01 (q, J = 7.0 Hz, 1H), 4.10-4.16 (m, 3H), 5.95 (1H, brs), 6.97-7.31 (m, 5H).
Process 2
To a stirred solution of compound 7-2 (5.12 g, 15.1 mmol) in THF (25 mL) and methanol (25 mL) was added sodium borohydride (2.85 g, 75.0 mmol) slowly at 0 ° C. After stirring at 0 ° C. for 2 hours, sodium borohydride (2.85 g, 75.0 mmol) was slowly added at 0 ° C. The resulting mixture was stirred at room temperature for 16.5 hours. The reaction was quenched with aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
Dess-Martin periodinane (9.54 g, 22.5 mmol) was added at 0 ° C. to a stirred solution of the crude product in dichloromethane (50 mL) under a nitrogen atmosphere. After stirring at room temperature for 4.5, the reaction was quenched with a saturated solution of sodium bicarbonate and sodium thiosulfate. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 1: 1 to 1: 2) to give compound 7-3 (2.15 g, 49%). Obtained as a colorless gum. This material was obtained as a mixture of diastereomers.
¹ H NMR (400 MHz, CDCl ₃ ) (Main isomer) 1.02 (d, J = 6.9 Hz, 3H), 1.97 (s, 3H), 3.15-3.20 (m, 1H), 5.16 (s, 1H), 7.00-7.33 (5H, m), 9.71 (s, 1H).

Process 3
A solution of compound 7-3 (2.15 g, 7.28 mmol) and Hunig's base (6.36 mL, 36.4 mmol) in THF (10 mL) was stirred and refluxed for 25.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 87:13 to 85:15) to give compound 7-4 (1.81 g, 84%) as a colorless gum. . This material was obtained as a mixture of diastereomers.
¹ H NMR (400 MHz, CDCl ₃ ) (Main isomer) 1.12 (d, J = 6.9 Hz, 3H), 1.76 (s, 3H), 3.09-3.14 (m, 1H), 5.17 (s, 1H), 7.02-7.33 (5H, m), 9.57 (s, 1H).
Process 4
To a stirred solution of compound 7-4 (1.81 g, 6.13 mmol) in DMF (18 mL) was added difluoromethyltrimethylsilane (3.35 mL, 24.5 mmol) and cesium fluoride (279 mg, 1.84 mmol) at 0 ° C. added. After stirring at room temperature for 4.5 days, TBAF (1 mol / L THF solution, 6.13 mL, 6.13 mmol) was added at 0 ° C. The resulting mixture was stirred at 0 ° C. for 1 hour and water was added. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was filtered through silica gel using hexane and ethyl acetate (1: 1). The filtrate was concentrated under reduced pressure to give a crude product that was used in the next reaction without further purification.
To a stirred solution of the crude product in dichloromethane (15 mL) was added TFA (1.73 mL, 22.5 mmol) at 0 ° C. After stirring at room temperature for 2.5 hours, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
To a stirred solution of the crude product in dichloromethane (15 mL), benzoyl isothiocyanate (0.724 mL, 5.39 mmol) was added at 0 ° C. After stirring at room temperature for 100 minutes, the solvent was distilled off under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate 3: 1) to give compound 7-5 (749 mg, 41%) as an orange amorphous. This material was obtained as a mixture of diastereomers.
MS: m / z = 411.15 [M + H] ^< +>.

Process 5
A suspension of compound 7-5 (749 mg, 1.83 mmol) and WSCD.HCl (700 mg, 3.65 mmol) in acetonitrile (7 mL) was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate 5: 1-3: 1 to 2: 1 gradient) to give compound 7-6 (248 mg, 36% ) Was obtained as a yellow amorphous. This material was obtained as a mixture of diastereomers.
MS: m / z = 377.15 [M + H] ^< +>.
Step 6
A solution of compound 7-6 (248 mg, 0.659 mmol), Boc ₂ O (0.214 mL, 0.988 mmol) and DMAP (16.1 mg, 0.132 mmol) in THF (3 mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 91: 9 to 84:16) to give compound 7-7 (140 mg, 45%) as a colorless gum. Obtained as a substance.
¹ H NMR (400 MHz, CDCl ₃ ) 1.19 (d, J = 7.0 Hz, 3H), 1.41 (s, 9H), 1.54 (s, 3H), 2.67 (q, J = 7.0 Hz, 1H), 4.00- 4.05 (m, 1H), 5.82 (ddt, J = 55.1, 6.5, 2.6 Hz, 1H), 7.06 (dd, J = 12.5, 7.9 Hz, 1H), 7.14 (t, J = 7.6 Hz), 7.46 (dd , J = 15.4, 7.9 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H).

Step 7
A suspension of compound 7-7 (140 mg, 0.294 mmol) and potassium carbonate (122 mg, 0.881 mmol) in methanol (2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
A solution of the crude product and TFA (0.226 mL, 2.93 mmol) in dichloromethane (2 mL) was stirred at room temperature for 6.5 hours. The reaction was quenched with saturated potassium carbonate solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product, which was used for the next reaction without further purification.
To a stirred solution of the crude product in TFA (1 mL) was added sulfuric acid (0.12 mL, 2.25 mmol) followed by nitric acid (0.020 mL, 0.441 mmol) at −25 ° C. After stirring at −25 ° C. to −15 ° C. for 1.5 hours, the reaction was quenched with saturated potassium carbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (amino silica gel, hexane: ethyl acetate gradient 2: 1 to 1: 1) to give compound 7-8 (82.6 mg, 89%). Was obtained as a colorless amorphous.
¹ H NMR (400 MHz, CDCl ₃ ) 1.14 (d, J = 7.0 Hz, 3H), 1.54 (s, 3H), 2.64 (q, J = 7.0 Hz, 1H), 3.74-3.79 (m, 1H), 5.76 (ddt, J = 55.3, 6.3, 1.9 Hz, 1H), 7.21 (t, J = 9.9 Hz, 1H), 8.16-8.20 (m, 1H), 8.35 (dd, J = 6.8, 2.6 Hz, 1H) .
Process 8
Compound 7-8 (82.6 mg, 0.260 mmol), iron powder (116 mg, 2.08 mmol), and ammonium chloride (167 mg, 3.12 mmol) in ethanol (0.8 mL), THF (0.4 mL), and The water (0.4 mL) suspension was stirred at 60 ° C. for 100 minutes. The mixture was cooled to room temperature and filtered through Celite (registered trademark). The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain a crude product (77.7 mg), which was used in the next reaction without further purification.
To a stirred solution of the crude product (18.8 mg) and aqueous hydrochloric acid (2 mol / L, 0.033 mL, 0.065 mmol) in methanol (1 mL) was added 5- (fluoromethoxy) pyrazine-2-carboxylic acid (12.4 mg, 0.072 mmol) and WSCD.HCl (15.1 mg, 0.079 mmol) were added at room temperature. After stirring for 1 hour at room temperature, the reaction was quenched with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (amino silica gel, hexane: ethyl acetate gradient from 1: 1 to 0: 1) to give compound I-33 (25.0 mg, 87%). Was obtained as an off-white solid.

Synthesis of Compound 1-34

Process 1
To a THF (45 ml) solution of compound 8-1 (4.59 g, 23.63 mmol), a 1.04 mol / L toluene solution (56.8 ml, 59.1 mmol) of DIBAL was added at 0 ° C. After stirring for 2 hours at the same temperature, the mixture was treated with a saturated aqueous Rochelle salt solution and stirred for 1.5 hours. The aqueous layer was extracted with AcOEt, and the combined organic layers were washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude compound was dissolved in CH ₂ Cl ₂ (30 mL) and Dess-Martin periodinane (11.94 g, 28.2 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the mixture was treated with saturated NaHCO ₃ aqueous solution and stirred for 0.5 hour. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 40%. The collected fractions were concentrated under reduced pressure to give compound 8-2 (3.67 g, 22.35 mmol, 95%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.56 (s, 3H), 6.22 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 12.0, 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.32 (m, 1H), 7.37 (m, 1H), 10.18 (d, J = 8.0 Hz, 1H).
Process 2
To a solution of compound 8-2 (2.01 g, 12.25 mmol) and (trifluoromethyl) trimethylsilane (2.61 g, 2.72 mmol) in THF (30 ml) was added TBAF in a 1.00 mol / L THF solution (0. 123 ml, 0.123 mmol) was added at -10 ° C. After stirring at 0 ° C. for 1 hour, a 1.00 mol / L THF solution (1.23 ml, 1.23 mmol) of TBAF was added and stirred at room temperature for 1 hour. The reaction solution was diluted with H ₂ O, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with H ₂ O and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 8-3 (2.81 g, 12.00 mmol, 98%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.19 (d, J = 8.0 Hz, 1H), 2.20 (s, 3H), 4.86 (m, 1H), 5.67 (d, J = 8.0 Hz, 1H) , 7.06 (dd, J = 8.0, 4.0 Hz, 1H), 7.12 (m, 1H), 7.25 (m, 1H), 7.29 (m, 1H).

Process 3
M-CPBA (6.74 g, 27.3 mmol) was added at 0 ° C. to a solution of compound 8-3 (3.2 g, 13.66 mmol) in CH ₂ Cl ₂ (40 ml). The mixture was stirred at room temperature for 2 hours, treated with 2 mol / L NaOH (20.5 ml), and stirred for 0.5 hour. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.72 (s, 3H), 2.72 (d, J = 8.0 Hz, 1H), 3.20 (d, J = 8.0 Hz, 1H), 4.15 (m, 1H) , 7.05 (m, 1H), 7.14 (m, 1H), 7.31 (m, 1H), 7.37 (m, 1H).
Process 4
To a solution of compound 8-4 (3.42 g, 13.67 mmol) and Ti (OEt) ₄ (18.71 g, 82 mmol) in DMF (30 ml) was added NaN ₃ (3.55 mg, 54.7 mmol) at room temperature. . After stirring at the same temperature for 20 hours, the mixture was treated with a saturated aqueous citric acid solution and stirred for 1 hour. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 20% to 60%. The collected fractions were concentrated under reduced pressure to give compound 8-5 (3.03 g, 11.26 mmol, 82%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.93 (s, 3H), 2.85 (d, J = 8.0 Hz, 1H), 3.19 (d, J = 4.0 Hz, 1H), 3.75 (m, 1H) , 4.47 (d, J = 8.0 Hz, 1H), 7.11 (m, 1H), 7.22 (m, 1H), 7.37 (m, 1H), 7.58 (m, 1H).

Process 5
To a solution of compound 8-5 (3.03 g, 11.25 mmol) in toluene (30 ml) and MeOH (30 ml) was added dibutyltin oxide (3.36 g, 13.51 mmol) at room temperature. After stirring at 110 ° C. for 3 hours, the reaction solution was concentrated. Dehydrated toluene (30 ml) was added to the residue and the mixture was concentrated and dried under reduced pressure. The residue was dissolved in toluene (30 ml) and tetrabutylammonium bromide (0.726 g, 2.251 mmol) and benzyl bromide (3.34 ml, 28.1 mmol) were added at room temperature. After stirring at 110 ° C. for 20 hours, the reaction mixture was diluted with H ₂ O and extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / ethyl acetate was eluted at 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 8-6 (3.1 g, 8.09 mmol, 72%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.93 (s, 3H), 3.29 (d, J = 12.0 Hz, 1H), 3.47 (q, J = 8.0 Hz, 1H), 4.43 (d, J = 8.0 Hz, 1H), 4.75 (m, 2H), 7.09 (m, 1H), 7.20 (m, 1H), 7.32-7.41 (m, 6H), 7.56 (m, 1H).
Step 6
To a suspension of NaH (939 mg, 23.48 mmol) in THF (40 ml), compound 8-6 (3.0 g, 7.83 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, MeI (2.45 ml, 39.1 mmol) was added and stirred at room temperature for 30 minutes. The reaction was treated with saturated aqueous NH ₄ Cl and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 8-7 (3.03 g, 7.63 mmol, 97%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91 (s, 3H), 3.54 (s, 3H), 3.61 (s, 1H), 4.08 (s, 1H), 4.72 (s, 2H), 7.07 ( m, 1H), 7.15 (m, 1H), 7.29-7.41 (m, 6H), 7.51 (m, 1H).

Step 7
A suspension of compound 8-7 (3.0 g, 7.55 mmol) and 10% Pd / C (600 mg) in MeOH (40 ml) was stirred at room temperature under a hydrogen atmosphere. After stirring at the same temperature for 24 hours, the mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give compound 8-8 (2.13 g, 7.57 mmol, 100%) as a white solid that was used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.65 (s, 3H), 3.17 (s, 1H), 3.61 (s, 3H), 3.65 (m, 1H), 3.99 (s, 1H), 7.07 ( m, 1H), 7.20 (m, 1H), 7.31 (m, 1H), 7.56 (m, 1H).
Process 8
To a stirred solution of compound 8-8 (2.13 g, 7.57 mmol) in CH ₂ Cl ₂ (30 mL) was added benzoyl isothiocyanate (1.22 mL, 6.82 mmol) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated, the resulting residue was applied to a silica gel column, and hexane / ethyl acetate was eluted at 0% to 50%. The collected fractions were concentrated under reduced pressure to obtain Compound 8-9 (3.03 g, 6.82 mmol, 90%) as a yellow amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.32 (s, 3H), 3.48 (s, 1H), 3.56 (s, 3H), 3.95 (m, 1H), 7.09 (m, 1H), 7.18 ( m, 1H), 7.32 (m, 1H), 7.41 (m, 1H), 7.52 (m, 2H), 7.63 (m, 1H), 7.87 (m, 2H), 8.88 (m, 1H), 11.66 (m , 1H).

Step 9
To a stirred solution of compound 8-9 (3.03 g, 6.84 mmol) in acetonitrile (30 mL) was added EDC (3.93 g, 20.52 mmol) at room temperature. After stirring at the same temperature for 20 hours, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was used in the next reaction without further purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.87 (s, 3H), 3.71 (s, 3H), 4.23 (s, 1H), 4.31 (m, 1H), 7.15 (m, 1H), 7.23 ( m, 1H), 7.35-7.55 (m, 5H), 8.28 (m, 2H), 11.64 (m, 1H).
Step 10
To a stirred solution of compound 8-10 (2.81 g, 6.85 mmol) in THF (40 mL) was added Boc ₂ O (2.385 mL, 10.27 mmol) and DMAP (251 mg, 2.05 mmol) at room temperature under a nitrogen atmosphere. added. After stirring for 1 hour, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude compound was dissolved in methanol (40 mL) and K ₂ CO ₃ (2.50 g, 18.1 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / ethyl acetate was eluted at 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain the Boc-protected compound. The compound was dissolved in CH ₂ Cl ₂ (15 mL) and TFA (4 ml) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction was quenched with 20% aqueous Na ₂ CO ₃ and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 8-11 (1.16 g, 3.79 mmol, 55%) as a white amorphous and used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.69 (s, 3H), 3.66 (s, 3H), 3.99 (m, 1H), 4.16 (s, 1H), 7.07 (dd, J = 12.0. 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.30 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H).

Step 11
To a solution of compound 8-11 (1.14 g, 3.72 mmol) in TFA (4.9 ml), sulfuric acid (1.25 ml, 23.5 mmol) was added at −10 ° C. After stirring at −10 ° C. for 5 minutes, HNO ₃ (0.36 ml, 5.58 mmol) was added to the reaction solution at −10 ° C. After stirring at −10 ° C. for 30 minutes, the reaction solution was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over MgSO ₄ , filtered and concentrated. The filtrate was concentrated under reduced pressure to give compound 8-12 (1.23 g, 3.50 mmol, 94%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.67 (s, 3H), 3.67 (s, 3H), 3.93 (m, 1H), 4.13 (m, 1H), 7.07 (m, 1H), 8.21 ( m, 1H), 8.39 (m, 1H).
Step 12
To a solution of compound 8-12 (1.2 g, 3.42 mmol) and DMAP (125 mg, 1.027 mmol) in THF (10 ml) was added Boc ₂ O (2.38 ml, 10.3 mmol) at room temperature. After stirring at the same temperature for 2 hours, the mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain Compound 8-13 (1.73 g, 3.14 mmol, 92%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.53 (s, 18H), 1.57 (s, 3H), 3.64 (s, 3H), 4.02 (m, 1H), 4.15 (s, 1H), 7.27 ( m, 1H), 8.25 (m, 1H), 8.50 (m, 1H).

Step 13
A suspension of compound 8-13 (1.73 g, 3.14 mmol) and 10% Pd / C (300 mg) in MeOH (8 ml) and THF (6 ml) was stirred at room temperature under a hydrogen atmosphere. After stirring at the same temperature for 2 hours, the mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give compound 8-14 (1.63 g, 3.13 mmol, 99%) as a white amorphous and used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52 (s, 18H), 1.57 (s, 3H), 3.59 (s, 3H), 4.13 (m, 1H), 4.14 (m, 1H), 6.55 ( m, 1H), 6.83 (m, 1H), 6.87 (m, 1H).
Step 14
To a solution of compound 8-14 (201 mg, 0.385 mmol) in CH ₂ Cl ₂ (2 ml), 5-cyanopicolinic acid monohydrate (70.4 mg, 0.424 mmol), HATU (161 mg, 0.424 mmol) and DIPEA (0.101 ml, 0.578 mmol) was added at room temperature. After stirring at the same temperature for 18 hours, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc was eluted from 0% to 50%. The collected fractions were concentrated under reduced pressure to obtain Compound 8-15 (245 mg, 0.376 mmol, 98%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56 (s, 18H), 1.75 (s, 3H), 3.63 (s, 3H), 4.11 (m, 1H), 4.16 (m, 1H), 7.16 ( dd, J = 12.0. 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 4.0 Hz, 1H), 8.22 (dd, J = 8.0, 4.0 Hz, 1H), 8.39 (m, 1H), 8.43 (d , J = 8.0 Hz, 1H), 8.79 (m, 1H), 9.98 (s, 1H).
Step 15
To a solution of compound 8-15 (44 mg, 0.073 mmol) in CH ₂ Cl ₂ (1.5 ml), TFA (0.5 ml) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction was quenched with 20% aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layers were combined and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was purified by Supercritical Fluid Chromatography (SFC) (ChiralPak® IB; 5-40% ethyl alcohol with 0.1% diethylamine) to give compound I-34 (58 mg, 0 128 mmol, 34%) was obtained as a white solid.

Synthesis of Compound I-35

Process 1
To a suspension of zinc (1.20 g, 18.27 mmol) in THF (10 ml), a solution of ethyl bromodifluoroacetate (5.19 g, 25.6 mmol) in THF (10 ml) and compound 9-1 (1.2 g, 7 .31 mmol) in THF (10 ml) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was treated with a saturated aqueous NH ₄ Cl solution, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 40%. The collected fractions were concentrated under reduced pressure to give compound 9-2 (1.91 g, 6.63 mmol, 91%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (t, J = 8.0 Hz, 3H) 2.15 (s, 3H), 2.21 (d, J = 4.0 Hz, 1H), 4.38 (q, J = 8.0 Hz, 2H), 4.98 (m, 1H), 5.67 (d, J = 8.0 Hz, 1H), 7.04 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.28 (m, 1H).
Process 2
To a solution of compound 9-2 (2.09 g, 7.24 mmol) in MeOH (80 ml) was added NaBH ₄ (822 mg, 21.7 mmol) at 0 ° C. After stirring at the same temperature for 0.5 hour, the mixture was treated with a saturated aqueous NH ₄ Cl solution and stirred for 0.5 hour. The aqueous layer was extracted with AcOEt, and the combined organic layers were washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 40%. The collected fractions were concentrated under reduced pressure to give compound 9-3 (1.70 g, 6.91 mmol, 95%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 (s, 3H), 2.32 (t, J = 8.0 Hz, 1H), 2.39 (d, J = 8.0 Hz, 1H), 3.92 (m, 1H) , 4.02 (m, 1H), 4.88 (m, 1H), 5.72 (d, J = 12.0 Hz, 1H), 7.04 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.25 (m, 1H), 7.27 (m, 1H).

Process 3
To a solution of compound 9-3 (1.71 g, 6.94 mmol) in CH ₂ Cl ₂ (30 ml) was added TBSCl (2.09 g, 13.89 mmol) and imidazole (0.946 g, 13.89 mmol) at room temperature. . After stirring at the same temperature for 0.5 hour, the mixture was treated with water and stirred for 0.5 hour. The aqueous layer was extracted with AcOEt, and the combined organic layers were washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to give compound 9-4 (1.95 g, 5.42 mmol, 78%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.10 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 2.13 (s, 3H), 2.31 (d, J = 4.0 Hz, 1H), 3.87 (m, 1H), 3.99 (m, 1H), 4.88 (m, 1H), 5.70 (d, J = 12.0 Hz, 1H), 7.04 (dd, J = 12.0, 8.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.26 (m, 1H).
Process 4
M-CPBA (2.67 g, 10.8 mmol) was added at 0 ° C. to a solution of compound 9-4 (1.95 g, 5.42 mmol) in CH ₂ Cl ₂ (30 ml). The mixture was stirred at room temperature for 2 hours, treated with 2 mol / L NaOH (20.5 ml), and stirred for 0.5 hour. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 9-5 (1.92 g, 5.10 mmol, 94%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.11 (s, 6H), 0.90 (s, 9H), 1.71 (s, 3H), 2.61 (d, J = 8.0 Hz, 1H), 3.28 (d, J = 8.0 Hz, 1H), 3.94 (m, 1H), 4.03 (m, 1H), 4.10 (m, 1H), 7.03 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.27 ( m, 1H), 7.38 (m, 1H).

Process 5
To a THF (25 ml) solution of compound 9-5 (1.92 g, 5.10 mmol), a 1.00 mol / L THF solution (5.61 ml, 5.61 mmol) of TBAF was added at 0 ° C. After stirring at the same temperature for 2 hours, the mixture was treated with a saturated aqueous NaHCO ₃ solution and stirred for 0.5 hours. The aqueous layer was extracted with AcOEt, and the combined organic layers were washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 10% to 50%. The collected fractions were concentrated under reduced pressure to give compound 9-6 (1.31 g, 5.00 mmol, 98%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.72 (s, 3H), 2.09 (t, J = 4.0 Hz, 1H) 2.63 (d, J = 4.0 Hz, 1H), 3.31 (d, J = 8.0 Hz, 1H), 3.97-4.18 (m, 3H), 7.05 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.29 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H ).
Step 6
To a solution of 9-6 (1.31 g, 5.00 mmol) and Ti (OEt) ₄ (6.85 g, 30.0 mmol) in DMF (12 ml) was added NaN ₃ (1.30 g, 20.0 mmol) at room temperature. It was. After stirring at the same temperature for 20 hours, the mixture was treated with a saturated aqueous citric acid solution and stirred for 1 hour. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 20% to 60%. The collected fractions were concentrated under reduced pressure to give compound 9-7 (1.38 g, 4.52 mmol, 90%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.93 (s, 3H), 2.70 (br, 1H), 3.22 (d, J = 8.0 Hz, 1H), 3.38 (br, 1H), 3.67 (m, 1H), 3.77 (m, 1H), 3.90 (m, 1H), 4.50 (s, 1H), 7.10 (dd, J = 12.0, 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.35 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H).

Step 7
To a solution of compound 9-7 (1.38 g, 4.52 mmol) and p-toluenesulfonyl chloride (0.95 g, 4.97 mmol) in CH ₂ Cl ₂ (26 ml) was added DMAP (1.11 g, 9.04 mmol). Added at 0 ° C. After stirring at the same temperature for 2 hours, the mixture was treated with a saturated aqueous NaHCO ₃ solution and stirred for 0.5 hours. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with 0.1 mol / L aqueous HCl and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 9-8 (1.92 g, 4.18 mmol, 92%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90 (s, 3H), 2.46 (s, 3H), 2.83 (d, J = 8.0 Hz, 1H), 3.05 (d, J = 8.0 Hz, 1H) , 3.61 (s, 1H), 4.20 (m, 1H), 4.28 (m, 1H), 4.42 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 12.0, 8.0 Hz, 1H), 7.20 ( t, J = 8.0 Hz, 1H), 7.34 (m, 4H), 7.54 (m, 1H), 7.72 (m, 2H).
Process 8
Compound 9-8 (1.92g, 4.18mmol) in MeOH (30 ml) solution _{of, K 2 CO 3 (1.16g,} 8.36mmol) was added at room temperature. After stirring at the same temperature for 20 hours, the mixture was treated with water and stirred for 0.5 hours. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 9-9 (1.10 g, 3.84 mmol, 92%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92 (s, 3H), 3.72 (m, 1H), 3.78 (m, 1H), 4.04 (m, 1H), 4.28 (m, 1H), 4.74 ( m, 1H), 7.09 (dd, J = 12.0, 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.33 (m, 1H), 7.67 (m, 1H).

Step 9
A suspension of compound 9-9 (1.05 g, 3.66 mmol) in MeOH (25 ml) and 10% Pd / C (200 mg) was stirred at room temperature under a hydrogen atmosphere. After stirring at the same temperature for 24 hours, the mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give compound 9-10 (0.9 g, 3.47 mmol, 95%) as a white solid that was used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.70 (s, 3H), 3.67 (dd, J = 8.0, 4.0 Hz, 1H), 4.04 (m, 1H), 4.25 (m, 1H), 4.54 ( m, 1H), 7.09 (dd, J = 12.0, 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.33 (m, 1H), 7.55 (m, 1H).
Step 10
To a stirred solution of compound 9-10 (750 mg, 2.87 mmol) in CH ₂ Cl ₂ (15 mL) was added benzoyl isothiocyanate (0.579 mL, 4.31 mmol) at 0 ° C. After stirring at room temperature for 6 hours, the reaction solution was concentrated, the resulting residue was applied to a silica gel column, and hexane / ethyl acetate was eluted at 0% to 35%. The collected fractions were concentrated under reduced pressure to obtain Compound 9-11 (1.07 g, 2.51 mmol, 87%) as a colorless amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.28 (s, 3H), 3.96 (m, 1H), 4.14 (m, 1H), 4.46 (m, 1H), 4.80 (m, 1H), 7.06 ( dd, J = 12.0, 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.29 (m, 1H), 7.52 (m, 3H), 7.62 (t, J = 8.0 Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 8.86 (s, 1H), 11.81 (s, 1H).

Step 11
To a stirred solution of compound 9-11 (1.156 g, 2.72 mmol) in acetonitrile (15 mL) was added EDC (1.04 g, 5.45 mmol) at room temperature. After stirring at the same temperature for 20 hours, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / ethyl acetate was eluted from 0% to 40%. The collected fractions were concentrated under reduced pressure to give compound 9-12 (853 mg, 2.19 mmol, 80%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.86 (s, 3H), 4.13-4.33 (m, 3H), 4.87 (s, 1H), 7.15 (m, 1H), 7.18 (m, 1H), 7.30 (m, 1H), 7.38 (m, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 2H), 11.62 (s, 1H).
Step 12
To a stirred solution of compound 9-12 (853 mg, 2.19 mmol) in THF (10 mL) was added Boc ₂ O (0.761 mL, 3.28 mmol) and DMAP (80 mg, 0.656 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude compound was dissolved in methanol (15 mL) and K ₂ CO ₃ (904 mg, 6.54 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / ethyl acetate was eluted at 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain the Boc-protected compound. The compound was dissolved in CH ₂ Cl ₂ (5 mL) and TFA (1.5 ml) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction was quenched with 20% aqueous Na ₂ CO ₃ and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 9-13 (538 mg, 1.88 mmol, 86%) as a white amorphous and used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.65 (s, 3H), 4.00-4.23 (m, 3H), 4.70 (s, 1H), 7.06 (dd, J = 12.0, 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.28 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H).

Step 13
To a solution of compound 9-13 (538 mg, 1.88 mmol) in TFA (2.2 ml) was added sulfuric acid (0.65 ml, 12.2 mmol) at −10 ° C. After stirring at −10 ° C. for 5 minutes, HNO ₃ (0.18 ml, 2.82 mmol) was added to the reaction solution at −10 ° C. After stirring at −10 ° C. for 30 minutes, the reaction solution was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt and the organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was purified by supercritical fluid chromatography (SFC) (ChiralPak® IC; 0-65% methyl alcohol (containing 0.1% diethylamine)) to give compound 9-14 (300 mg, 0 .91 mmol, 48%) was obtained as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.66 (s, 3H), 4.04 (m, 1H), 4.05-4.24 (m, 2H), 4.68 (s, 1H), 7.23 (m, 1H), 8.21 (m, 1H), 8.34 (m, 1H).
Step 14
A suspension of compound 9-14 (71 mg, 0.21 mmol) and 10% Pd / C (20 mg) in MeOH (2 ml) was stirred at room temperature under a hydrogen atmosphere. After stirring at the same temperature for 2 hours, the mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give compound 9-15 (63 mg, 0.21 mmol, 98%) as a white amorphous and used in the next step without purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.61 (s, 3H), 4.02-4.33 (m, 3H), 4.69 (s, 1H), 6.52 (m, 1H), 6.64 (m, 1H), 6.84 (m, 1H).
Step 15
Compound 9-15 (63 mg, 0.21 mmol) in _CH 2 _Cl 2 (2ml) solution of 5-cyano-picolinate monohydrate (38.2mg, 0.23mmol), EDC ( 48mg, 0.25mmol) and 2 mmol / L HCl (aq, 0.11 ml, 0.209 mmol) was added at room temperature. After stirring at the same temperature for 1 hour, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and eluted with hexane / EtOAc from 30% to 70%. The collected fractions were concentrated under reduced pressure to give compound I-35 (66 mg, 0.153 mmol, 73%) as a white solid.

Synthesis of Compound I-63

Step 1: Synthesis of Compound 10-4 To a solution of 3,3-difluorocyclobutanecarboxylic acid (Compound 10-1, 3.00 g, 22.0 mmol) in DMF (30 ml) was added Cs ₂ CO ₃ (14.4 g, 44. 1 mmol) and BnBr (2.62 ml, 22.0 mmol) were added at room temperature. After stirring at 50 ° C. for 20 minutes, the mixture was treated with H ₂ O and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 10-2 as a yellow oil, which was used in the next step without purification.
To a solution of diisopropylamine (2.91 ml, 20.5 mmol) in THF (25 ml), 1.6 mol / L n-BuLi (12.2 ml, 19.5 mmol) was added at -78 ° C. After stirring at the same temperature for 30 minutes, a solution of compound 10-2 (3.30 g, 14.6 mmol) in THF (10 ml) was added, which was stirred for 1 hour, followed by Ti (OiPr) ₃ Cl (4.89 ml). 20.5 mmol) in THF (10 ml) was added. After stirring at the same temperature for 10 minutes, a solution of 10-3 (2.35 g, 9.74 mmol) in THF (10 ml) was added. Stir at the same temperature for 1 hour and treat with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and eluted with hexane / EtOAc at 30%. The collected fractions were concentrated under reduced pressure to give compound 10-4 (1.24 g, 2.65 mmol, 27%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (s, 9H), 1.94 (s, 3H), 2.87-3.33 (m, 4H), 4.79 (s, 2H), 5.15 (s, 1H), 6.94-7.01 (m, 1H), 7.03-7.08 (m, 1H), 7.09-7.14 (m, 2H), 7.22-7.39 (m, 5H).

Step 2: Synthesis of Compound 10-6 To a solution of Compound 10-4 (1.24 g, 2.65 mmol) in MeOH (8 ml) was added HCl in 4 mol / L dioxane (0.995 ml, 3.98 mmol) at room temperature. It was. After stirring at the same temperature for 1 hour, the reaction solution was treated with an aqueous NaHCO ₃ solution, and the aqueous layer was extracted with CHCl ₃ . The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 10-5 as a brown oil, which was used in the next step without purification.
To a solution of compound 10-5 in MeOH (10 ml) was added Boc ₂ O (1.85 ml, 7.96 mmol) at room temperature. After stirring at 60 ° C. for 16 hours, the reaction solution was concentrated. The resulting residue was applied to a silica gel column and eluted with hexane / EtOAc from 0% to 10%. The collected fractions were concentrated under reduced pressure to give 10-6 (914 mg, 1.97 mmol, 74%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (s, 9H), 1.94 (s, 3H), 2.88-3.32 (m, 4H), 4.79 (s, 2H), 5.15 (s, 1H), 6.94-7.01 (m, 1H), 7.03-7.08 (m, 1H), 7.10-7.14 (m, 2H), 7.39-7.22 (m, 5H).

Step 3: Synthesis of Compound 10-7 In a THF (9 ml) solution of Compound 10-6 (914 mg, 1.97 mmol), LiBH _{4 in} a 3 mol / L THF solution (1.97 ml, 5.92 mmol) and MeOH (0. 240 ml, 5.92 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, it was treated with H ₂ O and AcOH. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and eluted with hexane / EtOAc at 20%. The collected fractions were concentrated under reduced pressure to give compound 10-7 (693 mg, 1.93 mmol, 98%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.38 (s, 9H), 1.99 (d, J = 2.5 Hz, 3H), 2.04-2.19 (m, 1H), 2.46-2.60 (m, 1H), 2.78 (q, J = 14.4 Hz, 1H), 2.92 (q, J = 14.4 Hz, 1H), 3.60 (d, J = 10.5 Hz, 1H), 3.77 (d, J = 10.5 Hz, 1H), 6.51 ( s, 1H), 6.99-7.06 (m, 1H), 7.11-7.16 (m, 1H), 7.30-7.23 (m, 1H), 7.35 (t, J = 7.3 Hz, 1H).

Step 4: Synthesis of Compound 10-8 10-7 (693mg, 1.93mmol) in _CH 2 _Cl 2 (7ml) solution, DMP a (2.13 g, 5.01 mmol) was added at room temperature. After stirring at the same temperature for 16 hours, the mixture was treated with an aqueous NaHCO ₃ solution and an aqueous NaHSO ₃ solution. The aqueous layer was extracted with CHCl ₃ and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and eluted with hexane / EtOAc at 20%. The collected fractions were concentrated under reduced pressure to give compound 10-8 (356 mg, 0.996 mmol, 52%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.38 (s, 9H), 1.88 (d, J = 1.6 Hz, 3H), 2.79-3.01 (m, 4H), 5.11 (s, 1H), 7.03- 7.11 (m, 1H), 7.13-7.20 (m, 1H), 7.34-7.22 (m, 2H), 9.57 (s, 1H).

Step 5: Synthesis of Compound 10-9 To a toluene (8 ml) solution of methyltriphenylphosphonium bromide (890 mg, 2.49 mmol), a 1.00 mol / L THF solution (2.29 ml, 2.29 mmol) of t-BuOK was added. Added at room temperature. After stirring at the same temperature for 1 hour, a toluene (4 ml) solution of compound 10-8 (356 mg, 0.996 mmol) was added at 10 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction was treated with saturated aqueous NH ₄ Cl and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to give compound 10-9 (304 mg, 0.855 mmol, 86%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (s, 9H), 1.90 (d, J = 2.4 Hz, 3H), 2.41-2.59 (m, 2H), 2.82-3.01 (m, 2H), 4.99 (s, 1H), 5.23 (d, J = 17.2 Hz, 1H), 5.35 (d, J = 10.5 Hz, 1H), 5.76 (dd, J = 17.2, 10.5 Hz, 1H), 7.02 (dd, J = 13.1, 8.2 Hz, 1H), 7.11 (t, J = 7.1 Hz, 1H), 7.29-7.19 (m, 2H).

Step 6: Synthesis of Compound 10-11 A 4 mol / L HCl (dioxane solution, 2.14 ml, 8.55 mmol) solution of Compound 10-9 (304 mg, 0.855 mmol) was stirred at room temperature for 30 minutes. The reaction was treated with aqueous NaHCO _{3 and the} aqueous layer was extracted with AcOEt. The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give compound 10-10 as a brown oil, which was used in the next step without purification.
In _CH 2 _Cl 2 (2ml) solution of compound 10-10, benzoyl isothiocyanate (0.176ml, 1.28mmol) was added at room temperature. After stirring at the same temperature for 15 hours, the reaction solution was concentrated. The resulting residue was applied to a silica gel column and eluted with hexane / EtOAc from 0% to 20%. The collected fractions were concentrated under reduced pressure to obtain compound 10-11 (347 mg, 0.829 mmol, 97%) as a white amorphous.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.56 (s, 9H), 2.16 (d, J = 2.3 Hz, 3H), 2.56-2.73 (m, 2H), 2.85-3.01 (m, 2H), 5.42 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 10.5 Hz, 1H), 5.89 (dd, J = 17.3, 10.5 Hz, 1H), 7.02-7.08 (m, 1H), 7.14-7.19 ( m, 1H), 7.21-7.34 (m, 2H), 7.52 (t, J = 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 8.85 (s, 1H), 11.55 (s, 1H).

Step 7: Synthesis of Compound 10-12 To a solution of iodine (421 mg, 1.66 mmol) in MeCN (9 ml), a solution of compound 10-11 (347 mg, 0.829 mmol) in MeCN (5 ml) was added at 0 ° C. After stirring at the same temperature for 2 hours, the reaction solution was treated with NaHCO ₃ and Na ₂ S ₂ O ₃ aqueous solution. The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc was eluted from 0% to 15%. The collected fractions were concentrated under reduced pressure to obtain compound 10-12 (343 mg, 0.630 mmol, 76%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.83 (s, 3H), 2.74-2.99 (m, 3H), 3.29 (t, J = 11.1 Hz, 1H), 3.36-3.47 (m, 2H), 3.74 (dd, J = 10.0, 2.5 Hz, 1H), 7.12 (dd, J = 12.7, 8.2 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.29-7.41 (m, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 2H).

Step 8: Synthesis of Compound 10-13 To a solution of Compound 10-12 (343 mg, 0.630 mmol) in toluene (5 ml), Bu ₃ SnH (0.251 ml, 0.945 mmol) and AIBN (10.4 mg, 0.0630 mmol). ) Was added at room temperature. After stirring at 80 ° C. for 1 hour, the reaction solution was concentrated. The resulting residue was applied to an amino silica gel column and eluted with hexane / EtOAc from 0% to 20%. The collected fractions were concentrated under reduced pressure to give compound 10-13 (212 mg, 0.507 mmol, 80%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (d, J = 6.9 Hz, 3H), 1.85 (s, 3H), 2.81 (q, J = 12.5 Hz, 1H), 2.88-3.01 (m, 1H), 3.23 (q, J = 6.9 Hz, 1H), 3.35 (q, J = 12.5 Hz, 1H), 7.10 (dd, J = 12.5, 8.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.32-7.38 (m, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 2H), 12.02 ( br s, 1H).

Step 9: Synthesis of Compound 10-14 To a solution of 1-5 (212 mg, 0.507 mmol) in MeOH (1 ml) and THF (1 ml) was added hydrazine monohydrate (0.246 ml, 5.07 mmol) at room temperature. It was. After stirring at the same temperature for 13 hours, the reaction solution was concentrated. The resulting residue was applied to an amino silica gel column and eluted with hexane / EtOAc from 10% to 50%. The collected fractions were concentrated under reduced pressure to obtain Compound 10-14 (150 mg, 0.477 mmol, 94%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (d, J = 6.8 Hz, 3H), 1.72 (s, 3H), 2.67-2.81 (m, 3H), 3.20 (q, J = 6.8 Hz, 1H), 3.27-3.42 (m, 1H), 7.02 (dd, J = 12.7, 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.22-7.28 (m, 1H), 7.32 (t , J = 8.0 Hz, 1H).

Step 10: Synthesis of Compound 10-16 To a TFA (1.3 ml) solution of 1-6, sulfuric acid (0.318 ml, 5.96 mmol) was added at -20 ° C. After stirring at 0 ° C. for 5 minutes, HNO ₃ (0.0320 ml, 0.716 mmol) was added to the reaction solution at −20 ° C. After stirring at 0 ° C. for 20 minutes, the reaction solution was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt, and the organic layer was dried over Na ₂ SO ₄ . The filtrate was concentrated under reduced pressure to give 1-15 as a yellow oil which was used in the next step without purification.
To a solution of compound 10-15 in THF (2 ml), Boc ₂ O (0.331 ml, 1.43 mmol) and DMAP (23.3 mg, 0.190 mmol) were added at room temperature. After stirring at the same temperature for 30 minutes, the mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 20%. The collected fractions were concentrated under reduced pressure to give 10-16 (252 mg, 0.450 mmol, 95%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (d, J = 6.9 Hz, 3H), 1.55 (s, 18H), 1.85 (d, J = 1.6 Hz, 3H), 2.71-2.94 (m, 3H), 3.21 (q, J = 15.7 Hz, 1H), 3.33 (q, J = 6.9 Hz, 1H), 7.20 (dd, J = 11.2, 9.0 Hz, 1H), 8.22-8.15 (m, 1H), 8.57 (dd, J = 6.8, 2.8 Hz, 1H).

Step 11: Synthesis of Compound 10-17 To a solution of Compound 10-16 (252 mg, 0.450 mmol) in EtOH (2 ml), THF (1 ml) and H ₂ O (1 ml), NH ₄ Cl (289 mg, 5.40 mmol). And Fe (201 mg, 3.60 mmol) were added at room temperature. After stirring at 60 ° C. for 1 hour, the mixture was treated with H ₂ O and filtered through Celite (registered trademark). The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to obtain Compound 10-17 (177 mg, 0.334 mmol, 74%) as a white amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (d, J = 7.0 Hz, 3H), 1.54 (s, 18H), 1.86 (d, J = 2.5 Hz, 3H), 2.63-2.87 (m, 3H), 3.28-3.47 (m, 2H), 3.61 (s, 2H), 6.56-6.50 (m, 1H), 6.82 (dd, J = 12.5, 8.5 Hz, 1H), 7.03 (dd, J = 7.0, (2.8 Hz, 1H).

Step 10: Synthesis of Compound 10-18 To a solution of Compound 10-17 (50.0 mg, 0.0940 mmol) in DMF (1 ml) was added 5-fluoropicolinic acid (13.3 mg, 0.0940 mmol), HATU (43.1 mg). 0.113 mmol) and DIPEA (0.0330 ml, 0.189 mmol) were added at room temperature. After stirring at the same temperature for 30 minutes, the reaction solution was treated with H ₂ O. The aqueous layer was extracted with AcOEt and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was applied to a silica gel column and hexane / EtOAc eluted from 0% to 30%. The collected fractions were concentrated under reduced pressure to give compound 10-18 (58.0 mg, 0.0890 mmol, 94%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (d, J = 7.0 Hz, 3H), 1.60 (s, 18H), 1.92 (s, 3H), 2.70-2.93 (m, 3H), 3.33- 3.49 (m, 2H), 7.08 (dd, J = 12.2, 8.8 Hz, 1H), 7.58 (td, J = 8.8, 2.8 Hz, 1H), 7.72 (dd, J = 7.1, 2.8 Hz, 1H), 8.44 -8.31 (m, 3H), 10.03 (s, 1H).

Step 11: Compound I-63 of compound 10-18 (58.0mg, 0.0890mmol) in _CH 2 _Cl 2 (0.7ml) solution of, TFA and (0.226 mL, 2.93 mmol) was added at room temperature . After stirring at the same temperature for 17 hours, the reaction solution was treated with an aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt, the organic layer was dried over _Na 2 SO _4, to obtain filtered and concentrated to give compound I-63 (34.0mg, 0.0750mmol, 85%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.27 (d, J = 7.0 Hz, 3H), 1.74 (s, 3H), 2.67-2.85 (m, 3H), 3.24-3.42 (m, 2H), 7.06 (dd, J = 11.9, 8.7 Hz, 1H), 7.44 (dd, J = 7.0, 2.6 Hz, 1H), 7.59 (td, J = 8.7, 2.6 Hz, 1H), 7.93-7.87 (m, 1H) , 8.33 (dd, J = 8.7, 4.6 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 9.76 (s, 1H).

Synthesis of Compound I-40

Process 1
HCl-dioxane (4M, 16.3 ml, 65.0 mmol) was added to a solution of compound 11-1 (16.1 g, 46.5 mmol) in methanol (160 ml) at room temperature. After stirring at room temperature for 1.5 hours, the reaction was concentrated and quenched with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 11-2 (12.8 g, quantitative). The obtained compound 11-2 was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 0.80, MS calculated 244.11 (M + H ⁺ ), found 244.00.

Process 2
To a solution of compound 11-2 (12.8 g, 46.5 mmol) in methanol (55 ml), Boc ₂ O (32.4 ml, 140 mmol) was added at room temperature. After stirring at 60 ° C. for 4 hours, the reaction solution was concentrated. The residue was purified by silica gel chromatography to obtain compound 11-3 (21.35 g, quantitative, containing Boc ₂ O, compound 3: Boc ₂ O = 1: 0.8).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (brs, 3H), 1.39 (brs, 9H), 1.96 (brs, 3H), 4.06 (brs, 2H), 5.34 (d, J = 47.2 Hz, 1H), 5.70 (brs, 1H), 7.04 (m, 1H), 7.11 (m, 1H), 7.25-7.35 (m, 2H).

Process 3
To a solution of compound 11-3 (11.4 g, 24.7 mmol, containing Boc ₂ O) in CH ₂ Cl ₂ (110 ml) was added DIBAL (1.02 M toluene solution, 107 ml, 109 mmol) at −65 ° C. After stirring at −65 ° C. for 50 minutes, the reaction was quenched with AcOEt and Rochelle salt (93 g, 331 mmol) in H ₂ O. After stirring at room temperature for 1.5 hours, the aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 11-4 (7.87 g, quantitative). The obtained compound 11-4 was used in the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 1.39 (s, 9H), 1.74 (s, 3H), 5.07 (s, 1H), 5.53 (d, J = 46.8 Hz, 1H), 7.08 (m, 1H), 7.16 (m, 1H), 7.30 (m, 1H), 7.37 (m, 1H), 9.55 (d, J = 9.0 Hz, 1H).

Process 4
To a solution of compound 11-4 (7.87 g, 24.7 mmol) and 2-bromo-2,2-difluoroethyl acetate (15.0 g, 74.1 mmol) in THF (150 ml) was added zinc (4.84 g, 74. 1 mmol) was added at room temperature. After stirring at 70 ° C. for 1.5 hours, the reaction was cooled to 0 ° C. and quenched with saturated aqueous NH ₄ Cl. The resulting mixture was filtered through Celite (registered trademark) and washed with AcOEt. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 11-5 (1.40 g, 4.01 mmol, 16%, 4 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.34 (t, J = 7.2 Hz, 3H), 1.78 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 4.40 (ddd, J = 28.5, 13.7 , 6.3 Hz, 1H), 5.49 (d, J = 47.4 Hz, 1H), 5.83 (s, 1H), 7.15 (m, 1H), 7.28 (m, 1H), 7.42 (m, 1H), 7.51 (m , 1H).

Process 5
Compound 11-5 (1.40g, 4.01mmol) in THF (28 ml) solution _of, LiBH 4 _{(175mg, 8.02mmol)} was added at room temperature. After stirring at room temperature for 45 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 11-6 (740 mg, 2.41 mmol, 60%).
¹ H-NMR (CDCl ₃ ) δ: 1.79 (s, 3H), 1.97 (t, J = 7.1 Hz, 1H), 3.84-4.11 (m, 2H), 4.28 (ddd, J = 30.0, 13.2, 6.4 Hz , 1H), 5.47 (d, J = 46.9 Hz, 1H), 5.69 (s, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H), 7.50 (m, 1H) .

Step 6
To a solution of compound 11-6 (850 mg, 2.77 mmol), PPh ₃ (2.90 g, 11.1 mmol) and imidazole (753 mg, 11.1 mmol) in THF (17 ml), iodine (2.81 g, 11.1 mmol) Was added at room temperature. After stirring at 80 ° C. for 16 hours, the reaction was cooled to 0 ° C. and quenched with aqueous Na ₂ S ₂ O ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 11-7 (1.07 g, 2.57 mmol, 93%).
¹ H-NMR (CDCl ₃ ) δ: 1.79 (s, 3H), 3.56-3.74 (m, 2H), 4.29 (dt, J = 29.5, 7.6 Hz, 1H), 5.41 (d, J = 47.2 Hz, 1H ), 5.72 (s, 1H), 7.16 (m, 1H), 7.29 (m, 1H), 7.43 (m, 1H), 7.50 (m, 1H).

Step 7
To a solution of compound 11-7 (1.07 g, 2.57 mmol) and Boc ₂ O (1.19 ml, 5.13 mmol) in CH ₂ Cl ₂ (20 ml) was added DMAP (157 mg, 1.28 mmol) at room temperature. . After stirring at room temperature for 45 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 11-8 (1.33 g, 2.57 mmol, 100%).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (s, 9H), 1.97 (s, 3H), 3.56-3.74 (m, 2H), 4.31 (dt, J = 30.6, 7.6 Hz, 1H), 5.32 (d , J = 46.9 Hz, 1H), 7.14 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H), 7.48 (m, 1H).

Process 8
To a solution of compound 11-8 (1.33 g, 2.57 mmol) and n-Bu ₃ SnH (1.64 ml, 6.16 mmol) in toluene (26 ml) was added AIBN (63.2 mg, 385 μmol) at room temperature. After stirring at 80 ° C. for 1 hour, the reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give compound 11-9 (717.1 mg, 1.83 mmol, 71%).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (s, 9H), 1.75 (t, J = 19.8 Hz, 3H), 1.97 (s, 3H), 4.05 (ddd, J = 30.7, 10.4, 4.8 Hz, 1H ), 5.27 (d, J = 46.9 Hz, 1H), 7.13 (m, 1H), 7.25 (m, 1H), 7.39 (m, 1H), 7.48 (m, 1H).

Step 9
To a solution of compound 11-9 (717.1 mg, 1.83 mmol) in EtOH (12 ml) and H ₂ O (6 ml) was added Ba (OH) ₂ .8H ₂ O (1.73 g, 5.50 mmol) at room temperature. It was. After stirring at room temperature for 1.5 hours, the reaction solution was quenched with an aqueous citric acid solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was washed with AcOEt and hexane, and the insoluble material was filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography to give compound 11-10 (630.1 mg, 1.73 mmol, 94%).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (s, 9H), 1.61 (t, J = 19.3 Hz, 3H), 2.02 (s, 3H), 2.67 (dd, J = 9.3, 3.8 Hz, 1H), 3.62 (brs, 1H), 5.14 (d, J = 44.5 Hz, 1H), 6.27 (brs, 1H), 7.05 (m, 1H), 7.16 (m, 1H), 7.29 (m, 1H), 7.39 (m , 1H).

Step 10
To a solution of compound 11-10 (630.1 mg, 1.73 mmol) in MeOH (6 ml) was added HCl-dioxane (4M, 1.73 ml, 6.90 mmol) at room temperature. After stirring at 50 ° C. for 2.5 hours, the reaction was concentrated and quenched with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The obtained compound 11-11 was used in the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 1.64 (td, J = 19.6, 1.5 Hz, 3H), 1.76 (s, 3H), 3.46 (dt, J = 29.9, 9.5 Hz, 1H), 5.19 (d, J = 45.7 Hz, 1H), 7.09 (m, 1H), 7.23 (m, 1H), 7.35 (m, 1H), 7.57 (m, 1H).

Step 11
To a solution of compound 11-11 in CH ₂ Cl ₂ (3 ml), BzNCS (348 μl, 2.59 mmol) was added at room temperature. After stirring at room temperature for 2.5 hours, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 11-12 (630.9 mg, 1.47 mmol, 85%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.69 (t, J = 19.2 Hz, 3H), 2.31 (s, 3H), 2.74 (dd, J = 9.9, 2.9 Hz, 1H), 3.85 (m, 1H), 5.41 (d, J = 44.4 Hz, 1H), 7.08 (m, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.47 (m, 1H), 7.52 (m, 2H), 7.63 (m , 1H), 7.87 (m, 2H), 8.91 (s, 1H), 11.80 (s, 1H).

Step 12
Compounds 11-12 (630.9mg, 1.47mmol) in _CH 3 CN (12ml) solution of was added WSCD hydrochloride (565 mg, 2.95 mmol) at room temperature. After stirring at 50 ° C. for 1.5 hours, the reaction was cooled to room temperature and quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 11-13 (564.0 mg, 1.43 mmol, 97%).
¹ H-NMR (CDCl ₃ ) δ: 1.83 (td, J = 19.7, 1.9 Hz, 3H), 1.89 (s, 3H), 4.11 (ddd, J = 29.1, 10.0, 5.0 Hz, 1H), 5.52 (d , J = 47.2 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.48 (m, 4H), 7.53 (m, 1H), 8.27 (m, 2H), 11.80 (s, 1H).

Step 13
Compounds 11-13 (554.0mg, 1.40mmol) in MeOH (22 ml) solution _{of, K 2 CO 3 (1.17g,} 8.43mmol) was added at room temperature. After stirring at 80 ° C. for 3 hours, the reaction was cooled to room temperature and quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 11-14 (374.5 mg, 1.29 mmol, 92%).
¹ H-NMR (CDCl ₃ ) δ: 1.66 (s, 3H), 1.71 (t, J = 19.7 Hz, 3H), 3.83 (ddd, J = 30.0, 10.8, 4.4 Hz, 1H), 4.29 (brs, 2H ), 5.35 (d, J = 48.2 Hz, 1H), 7.05 (m, 1H), 7.17 (m, 1H), 7.29 (m, 1H), 7.44 (m, 1H).

Step 14
To a solution of compound 11-14 (360.0 mg, 1.24 mmol) in TFA (4 ml) was added H ₂ SO ₄ (1 ml) at −20 ° C. After stirring at 0 ° C. for 5 minutes, the reaction was cooled to −20 ° C. and HNO ₃ (83 μl, 1.86 mmol) was added. After stirring at 0 ° C. for 15 minutes, the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 11-15 (530 mg, quantitative).
¹ H-NMR (CDCl ₃ ) δ: 1.77 (t, J = 19.7 Hz, 3H), 1.87 (s, 3H), 4.05 (m, 1H), 5.46 (d, J = 46.6 Hz, 1H), 7.34 ( m, 1H), 8.27-8.36 (m, 2H).

Step 15
To a solution of compound 11-15 (530 mg, quantitative) and Boc ₂ O (864 μl, 3.72 mmol) in CH ₂ Cl ₂ (7 ml) was added DMAP (182 mg, 1.49 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 11-16 (603.8 mg, 1.13 mmol, 91%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (s, 18H), 1.73 (s, 3H), 1.74 (m, 3H), 3.88 (ddd, J = 28.9, 10.3, 4.3 Hz, 1H), 5.39 (d , J = 47.4 Hz, 1H), 7.29 (m, 1H), 8.27 (m, 1H), 8.51 (m, 1H).

Step 16
To a solution of compound 11-16 (603.8 mg, 1.13 mmol) in THF (8 ml) and MeOH (4 ml) was added Pd / C (60.0 mg) at room temperature. After stirring at room temperature for 3.5 hours under H ₂ atmosphere, the reaction solution was filtered through Celite (registered trademark), and the residue was washed with AcOEt. The filtrate was concentrated and the residue was purified by silica gel chromatography to give compound 11-17. The resulting compound 11-17 was further purified by pulverization in AcOEt / hexane to obtain compound 11-17 (482.9 mg, 955 μmol, 85%).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (s, 18H), 1.69 (s, 3H), 1.72 (t, J = 19.6 Hz, 3H), 3.56 (brs, 2H), 4.02 (m, 1H), 5.37 (d, J = 47.8 Hz, 1H), 6.57 (m, 1H), 6.81 (m, 1H), 6.87 (m, 1H).

Step 17
To a solution of compound 11-17 (70.0 mg, 138 μmol), 5-cyanopicolinic acid monohydrate (27.6 mg, 166 μmol) and diisopropylethylamine (48 μl, 277 μmol) in DMF (2 ml), HATU (63.2 mg, 166 μmol) was added at room temperature. After stirring at room temperature for 50 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 11-18 (91.6 mg, quantitative).
¹ H-NMR (CDCl ₃ ) δ: 1.56 (s, 18H), 1.73 (t, J = 19.7 Hz, 3H), 1.76 (s, 3H), 4.01 (ddd, J = 29.6, 10.2, 4.4 Hz, 1H ), 5.40 (d, J = 47.6 Hz, 1H), 7.16 (m, 1H), 7.53 (m, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.37 (m, 1H), 8.43 (d , J = 8.2 Hz, 1H), 8.80 (s, 1H), 9.96 (s, 1H).

Step 18
Compound 11-18 (91.6 mg) was dissolved in formic acid (1 ml, 26.1 mmol) at room temperature. After stirring at room temperature for 8 hours, the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by trituration in AcOEt / hexane to give pure compound I-40 (52.2 mg, 120 μmol, 87%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.67 (s, 3H), 1.72 (t, J = 19.7 Hz, 3H), 3.88 (ddd, J = 29.9, 10.8, 4.4 Hz, 1H), 4.33 (brs, 2H ), 5.38 (d, J = 48.1 Hz, 1H), 7.12 (m, 1H), 7.55 (m, 1H), 8.02 (m, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.43 (d , J = 8.3 Hz, 1H), 8.90 (s, 1H), 9.87 (s, 1H).

Synthesis of Compound I-82

Process 1
To a solution of compound 12-1 (1.50 g, 4.88 mmol) and imidazole (798 mg, 11.7 mmol) in DMF (15 ml) was added TBSCl (883 mg, 5.86 mmol) at room temperature. After stirring at room temperature for 45 minutes, the reaction was quenched with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 12-2. The obtained compound 12-2 was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 2.59, MS calculated 422.18 (M + H ⁺ ), found 422.00.

Process 2
To a solution of compound 12-2 and Boc ₂ O (6.57 ml, 28.3 mmol) in CH ₂ Cl ₂ (20 ml) was added DMAP (238 mg, 1.95 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction solution was concentrated. The residue was purified by silica gel chromatography to obtain compound 12-3 (2.60 g, quantitative).
¹ H-NMR (CDCl ₃ ) δ: -0.04 (s, 3H), -0.02 (s, 3H), 0.69 (s, 9H), 1.52 (s, 9H), 1.98 (m, 3H), 3.76 (m , 1H), 3.94 (ddd, J = 24.1, 11.8, 6.0 Hz, 1H), 4.34 (m, 1H), 5.38 (d, J = 46.9 Hz, 1H), 7.09 (m, 1H), 7.23 (m, 1H), 7.36 (m, 1H), 7.48 (m, 1H).

Process 3
To a solution of compound 12-3 (2.60 g) in MeOH (25 ml) was added K ₂ CO ₃ (2.70 g, 19.5 mmol) at room temperature. After stirring at room temperature for 45 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 12-4. The obtained compound 12-4 was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 2.94, MS calculated 496.25 (M + H ⁺ ), found 496.25.

Process 4
To a solution of compound 12-4 in CH ₂ Cl ₂ (50 ml), TFA (5 ml, 64.9 mmol) was added at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched with a saturated aqueous solution of NaHCO ₃ and K ₂ CO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 12-5 (1.53 g, 3.87 mmol, 79%, 4 steps).
¹ H-NMR (CDCl ₃ ) δ: -0.05 (s, 3H), -0.02 (s, 3H), 0.74 (s, 9H), 1.74 (s, 3H), 3.61-3.77 (m, 2H), 3.91 (ddd, J = 23.5, 11.5, 7.7 Hz, 1H), 5.29 (d, J = 45.8 Hz, 1H), 7.06 (m, 1H), 7.20 (m, 1H), 7.32 (m, 1H), 7.59 ( m, 1H).

Process 5
To a solution of compound 12-5 (1.53 g, 3.87 mmol) in CH ₂ Cl ₂ (6 ml) was added BzNCS (780 μl, 5.80 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction solution was concentrated. The residue was purified by silica gel chromatography to obtain compound 12-6 (2.07 g, containing compound 12-7).
¹ H-NMR (CDCl ₃ ) δ: 0.01 (s, 3H), 0.04 (s, 3H), 0.81 (s, 9H), 2.35 (brs, 3H), 3.22 (dd, J = 11.0, 2.5 Hz, 1H ), 3.76 (td, J = 11.8, 5.5 Hz, 1H), 3.96-4.15 (m, 2H), 5.38 (d, J = 44.2 Hz, 1H), 7.06 (m, 1H), 7.16 (m, 1H) , 7.31 (m, 1H), 7.48 (m, 1H), 7.52 (m, 2H), 7.63 (m, 1H), 7.86 (m, 2H), 8.89 (s, 1H), 11.92 (s, 1H).

Step 6
In _CH 3 CN (21ml) solution of compound 12-6 (2.07 g), was added WSCD hydrochloride (1.42 g, 7.41 mmol) at room temperature. After stirring at 50 ° C. for 1.5 hours, the reaction was cooled to room temperature and quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 12-7. The obtained compound 12-7 was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 3.06, MS calculated 525.22 (M + H ⁺ ), found 525.20.

Step 7
TBAF (1M THF solution, 7.41 ml, 7.41 mmol) was added to a solution of compound 12-7 in THF (20 ml) at room temperature. After stirring at room temperature for 10 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 12-8 (1.55 g, 3.78 mmol, 98%, 3 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.90 (s, 3H), 3.96 (ddd, J = 15.7, 13.3, 7.9 Hz, 1H), 4.14 (m, 1H), 4.35 (ddd, J = 29.5, 12.9, 6.4 Hz, 1H), 5.62 (d, J = 46.9 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.48 (m, 4H), 7.53 (m, 1H), 8.24 ( m, 2H), 11.77 (brs, 1H).

Process 8
Compound 12-8 (500 mg, 1.22 mmol) in _CH 2 _Cl 2 (10ml) was added Dess - Martin periodinane (1.03 g, 2.44 mmol) was added at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched with a saturated aqueous solution of NaHCO ₃ and Na ₂ S ₂ O ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over _Na 2 SO _4, to give compound 12-9 and concentrated. The obtained compound 12-9 was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 1.86, MS calculated 427.13 (M + H ⁺ ), found 427.10.

Step 9
To a suspension of methyltriphenylphosphonium bromide (1.39 g, 3.90 mmol) in THF (8 ml) was added KHMDS (0.5 M toluene solution, 7.31 ml, 3.65 mmol) at 0 ° C. After stirring at 0 ° C. for 20 minutes, a solution of compound 12-9 in THF (8 ml) was added. After stirring at room temperature for 3 hours, the reaction was quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 12-10 (255.3 mg, 628 μmol, 52%).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (s, 3H), 4.18 (ddd, J = 28.9, 9.3, 6.0 Hz, 1H), 5.54 (d, J = 47.2 Hz, 1H), 5.64 (d, J = 11.0 Hz, 1H), 5.87 (m, 1H), 6.08 (m, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.48 (m, 4H), 7.52 (m, 1H) , 8.27 (m, 2H), 11.78 (brs, 1H).

Step 10
To a solution of compound 12-10 (225.3 mg, 554 μmol) and Boc ₂ O (257 μl, 1.11 mmol) in CH ₂ Cl ₂ (4.6 ml) was added DMAP (13.6 mg, 111 μmol) at room temperature. After stirring at room temperature for 40 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to obtain compound 12-11 (289.6 mg, quantitative).
¹ H-NMR (CDCl ₃ ) δ: 1.38 (m, 3H), 1.48 (s, 9H), 4.05 (ddd, J = 28.6, 9.9, 6.3 Hz, 1H), 5.31 (d, J = 47.8 Hz, 1H ), 5.60 (d, J = 11.0 Hz, 1H), 5.77 (m, 1H), 5.99 (m, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.31 (m, 1H), 7.40 -7.47 (m, 3H), 7.55 (m, 1H), 7.76 (m, 2H).

Step 11
In a test tube, 1-methyl-1-nitrosourea (571 mg, 2.77 mmol) was added at 0 ° C. to a mixture of aqueous NaOH (30%, 2 ml) and Et ₂ O (6 ml). After stirring for 20 minutes at 0 ° C., the color of the organic layer changed to yellow, suggesting that an Et ₂ O solution of diazomethane could be prepared. In a separate flask, Et ₂ O solution of diazomethane was added at 0 ° C. to a suspension of Compound 12-11 (289.6 mg) and Pd (OAc) ₂ (24.9 mg, 111 μmol) in Et ₂ O (6 ml). It was. After stirring at 0 ° C. for 15 minutes, the reaction was quenched with H ₂ O and AcOH. Saturated aqueous NaHCO ₃ solution was added and the aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 12-12 (275.7 mg, 530 μmol, 96%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 0.59-0.78 (m, 4H), 1.33-1.44 (m, 4H), 1.48 (s, 9H), 4.02 (ddd, J = 28.9, 9.5, 7.4 Hz, 1H) , 5.34 (d, J = 47.6 Hz, 1H), 7.05 (m, 1H), 7.17 (m, 1H), 7.30 (m, 1H), 7.40-7.49 (m, 3H), 7.54 (m, 1H), 7.79 (m, 2H).

Step 12
To a solution of compound 12-12 (313.6 mg, 602 μmol) in MeOH (3 ml) was added K ₂ CO ₃ (416 mg, 3.01 mmol) at room temperature. After stirring at room temperature for 40 minutes, the reaction was quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 12-13 (233.1 mg, 560 μmol, 93%).
¹ H-NMR (CDCl ₃ ) δ: 0.58-0.78 (m, 4H), 1.45 (m, 1H), 1.53 (s, 9H), 1.84 (s, 3H), 4.04 (dt, J = 29.1, 8.0 Hz , 1H), 5.47 (d, J = 47.2 Hz, 1H), 7.14 (m, 1H), 7.25 (m, 1H), 7.36-7.44 (m, 2H), 10.05 (brs, 1H).

Step 13
Compound 12-13 (233.1 mg, 560 μmol) was dissolved in TFA (2 ml) at room temperature. After stirring at room temperature for 45 minutes, the reaction mixture was cooled to −20 ° C. and H ₂ SO ₄ (0.5 ml) was added. After stirring at 0 ° C. for 5 minutes, the reaction was cooled to −20 ° C. and HNO ₃ (75 μl, 1.68 mmol) was added. After stirring at 0 ° C. for 50 minutes, the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 12-14 (326.3 mg, quantitative). The obtained compound 12-14 was used in the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 0.60-0.78 (m, 4H), 1.39 (m, 1H), 1.69 (s, 3H), 3.85 (ddd, J = 29.6, 9.2, 7.4 Hz, 1H), 5.41 (d, J = 47.4 Hz, 1H), 7.25 (dd, J = 10.7, 8.9 Hz, 1H), 8.23 (ddd, J = 8.9, 4.1, 2.9 Hz, 1H), 8.45 (dd, J = 6.7, 2.9 Hz, 1H).

Step 14
To a solution of compound 12-14 (326.3 mg, quantitative) and Boc ₂ O (325 μl, 1.40 mmol) in CH ₂ Cl ₂ (6 ml) was added DMAP (103 mg, 840 μmol) at room temperature. After stirring at room temperature for 40 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 12-15 (276.1 mg, 492 μmol, 88%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 0.59-0.80 (m, 4H), 1.40 (m, 1H), 1.52 (s, 18H), 1.74 (m, 3H), 3.93 (ddd, J = 28.6, 8.9, 7.0 Hz, 1H), 5.44 (d, J = 47.2 Hz, 1H), 7.29 (dd, J = 10.8, 9.0 Hz, 1H), 8.27 (ddd, J = 9.0, 4.2, 2.9 Hz, 1H), 8.53 ( dd, J = 6.7, 2.9 Hz, 1H).

Step 15
To a solution of compound 12-15 (276.1 mg, 492 μmol) in THF (3 ml) and MeOH (1.5 ml) was added Pd / C (52.4 mg) at room temperature. After stirring at room temperature for 6.5 hours under H ₂ atmosphere, the reaction solution was filtered through Celite (registered trademark), and the residue was washed with AcOEt. The filtrate was concentrated and the residue was purified by silica gel chromatography to give compound 12-16 (240.9 mg, 453 μmol, 92%).
¹ H-NMR (CDCl ₃ ) δ: 0.58-0.77 (m, 4H), 1.39 (m, 1H), 1.52 (s, 18H), 1.71 (m, 3H), 3.57 (brs, 2H), 4.07 (ddd , J = 28.7, 9.7, 6.9 Hz, 1H), 5.43 (d, J = 47.7 Hz, 1H), 6.57 (ddd, J = 8.7, 3.8, 3.0 Hz, 1H), 6.83 (dd, J = 6.5, 3.0 Hz, 1H), 6.87 (dd, J = 11.7, 8.7 Hz, 1H).

Step 16
To a solution of compound 12-16 (70.0 mg, 132 μmol), 5- (fluoromethoxy) pyrazine-2-carboxylic acid (27.2 mg, 158 μmol) and diisopropylethylamine (46 μl, 263 μmol) in DMF (2 ml) was added HATU (60 ml). 0.1 mg, 158 μmol) was added at room temperature. After stirring at room temperature for 50 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 12-17 (86.6 mg, 126 μmol, 96%).
¹ H-NMR (CDCl ₃ ) δ: 0.59-0.77 (m, 4H), 1.38 (m, 1H), 1.54 (s, 18H), 1.76 (m, 3H), 4.05 (m, 1H), 5.45 (d , J = 47.4 Hz, 1H), 6.15 (ddd, J = 50.9, 11.5, 2.0 Hz, 2H), 7.15 (dd, J = 11.5, 8.8 Hz, 1H), 7.48 (dd, J = 6.8, 2.8 Hz, 1H), 8.20 (d, J = 1.5 Hz, 1H), 8.37 (ddd, J = 8.8, 4.0, 2.8 Hz, 1H), 9.08 (d, J = 1.5 Hz, 1H), 9.63 (s, 1H).

Step 17
Compound 12-17 (86.6 mg, 126 μmol) was dissolved in formic acid (1 ml, 26.1 mmol) at room temperature. After stirring at room temperature for 15 hours, the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by trituration in hexanes to give pure compound I-82 (52.8 mg, 109 μmol, 86%).
¹ H-NMR (CDCl ₃ ) δ: 0.64 (m, 2H), 0.73 (m, 2H), 1.38 (m, 1H), 1.67 (s, 3H), 3.95 (ddd, J = 29.9, 10.0, 7.3 Hz , 1H), 4.37 (brs, 2H), 5.45 (d, J = 48.1 Hz, 1H), 6.15 (m, 2H), 7.11 (dd, J = 11.3, 8.9 Hz, 1H), 7.50 (dd, J = 6.8, 2.8 Hz, 1H), 8.03 (ddd, J = 8.9, 4.1, 2.8 Hz, 1H), 8.29 (d, J = 1.4 Hz, 1H), 9.08 (d, J = 1.4 Hz, 1H), 9.52 ( s, 1H).

Synthesis of Compound I-109

Process 1
A solution of compound 3-4 (1.25 g, 2.57 mmol) and silver (I) tetrafluoroborate (1.00 g, 5.14 mmol) in DMSO (6.3 mL) and water (0.63 mL) was added at room temperature. Stir for 3.5 hours. The reaction was quenched with saturated sodium bicarbonate solution. The resulting mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate 2: 1) to give compound 13-1 (560 mg, 58%) as a colorless amorphous.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.89 (s, 3H), 3.17-3.29 (m, 1H), 3.80 (dd, J = 10.8, 7.9 Hz, 1H), 4.04 (dd, J = 10.8, 7.2 Hz, 1H), 5.60 (dd, J = 47.3, 1.6 Hz, 1H), 7.12 (dd, J = 12.2, 8.2 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.35-7.54 ( m, 5H), 8.23 (d, J = 7.3 Hz, 2H).

Process 2
To a stirred suspension of compound 13-1 (560 mg, 0.84 mmol) and sodium hydride (179 mg, 4.46 mmol, 60% in oil) in THF (6 mL) was added iodomethane (0.465 mL, 7.44 mmol) to 0. Added at ° C. After stirring for 2 hours at 0 ° C., the reaction was quenched with saturated ammonium chloride solution. Extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was distilled off under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, hexane: ethyl acetate gradient from 4: 1 to 3: 1) to give compound 13-2 (326 g, 56%) as a colorless amorphous product. Got as.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.88 (s, 3H), 3.21-3.33 (m, 1H), 3.35 (s, 3H), 3.44-3.48 (m, 1H), 3.81 (dd, J = 9.3, 7.3 Hz, 1H), 5.52 (dd, J = 47.2, 2.0 Hz, 1H), 7.12 (dd, J = 12.3, 8.0 Hz, 1H), 7.19 (td, J = 7.6, 1.2 Hz, 1H), 7.34-7.53 (m, 5H), 8.23 (d, J = 7.0 Hz, 2H).

Process 3
A solution of compound 13-2 (326 mg, 0.84 mmol) and hydrazine monohydrate (0.405 mL, 8.35 mmol) in ethanol (5 mL) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (amino silica gel, hexane: ethyl acetate 1: 1) to give compound 13-3 (210 mg, 88%) as a colorless gum. .
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.75 (t, J = 1.5 Hz, 3H), 3.21-3.33 (m, 1H), 3.32 (s, 3H), 3.40-3.44 (m, 1H), 3.77 (dd, J = 9.4, 6.7 Hz, 1H), 5.33 (dd, J = 47.7, 1.8 Hz, 1H), 7.03 (ddd, J = 12.4, 8.2, 1.3 Hz, 1H), 7.12 (td, J = 7.5 , 1.3 Hz, 1H), 7.23-7.30 (m, 2H).

Process 4
To a stirred suspension of compound 13-3 (210 mg, 0.73 mmol) and sulfuric acid (0.520 mL, 9.76 mmol) in trifluoroacetic acid (2.1 mL) is added nitric acid (0.049 mL, 1.10 mmol) to −20. Added at ° C. After stirring for 30 minutes between −20 ° C. and −10 ° C., the reaction was quenched with potassium carbonate solution. Extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was distilled off under reduced pressure to obtain Compound 13-4 (231 mg) as a crude product, which was used in the next reaction without further purification.

Process 5
A suspension of compound 13-4 (231 mg), iron (311 mg, 5.58 mmol), and ammonium chloride (447 mg, 8.37 mmol) in toluene (2 mL) and water (2 mL) was stirred at 80 ° C. for 2 hours. After cooling to room temperature, the reaction was quenched with potassium carbonate solution. The mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated in vacuo to give compound 13-5 (206 mg) as a crude product that was used in the next reaction without further purification.

Step 6
To a stirred solution of compound 13-5 (55.6 mg) in dichloromethane (1.1 mL) was added boron tribromide (0.922 mL, 0.922 mmol, 1 mol / L dichloromethane solution) at -78 ° C. After stirring at 0 ° C. for 3 hours, boron tribromide (0.553 mL, 0.553 mmol) was added at −78 ° C. After stirring for 1 hour at 0 ° C., the reaction was quenched with saturated sodium bicarbonate solution. Extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was distilled off under reduced pressure to obtain Compound 13-6 (58.1 mg) as a crude product, which was used in the next reaction without further purification.

Step 7
To a stirred solution of compound 13-6 (58.1 mg) and hydrochloric acid (0.092 mL, 0.184 mmol, 2 mol / L aqueous solution), 5- (fluoromethoxy) pyrazine-2-carboxylic acid (31.7 mg, 0.184 mmol) was added. ) And WSCD (38.9 mg, 0.203 mmol) were added at room temperature. After stirring at room temperature for 45 minutes, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the crude product was pulverized in hexane to obtain I-109 (64.5 mg, 74%, 4 steps).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.77 (s, 3H), 3.23-3.35 (m, 1H), 3.75 (dd, J = 11.0, 7.3 Hz, 1H), 4.00 (dd, J = 11.0, 7.3 Hz, 1H), 5.44 (d, J = 46.7 Hz, 1H), 6.15 (d, J = 50.2 Hz, 2H), 7.09 (dd, J = 11.5, 8.8 Hz, 1H), 7.34 (dd, J = 6.7, 2.9 Hz, 1H), 7.95-7.99 (m, 1H), 8.30 (s, 1H), 9.08 (s, 1H), 9.48 (s, 1H).

Synthesis of Compound I-94

Process 1
To a suspension of compound 14-1 (537.7 mg, 1.29 mmol) in dimethylacetamide (2.5 ml) and H ₂ O (2.5 ml), zinc (421 mg, 6.45 mmol) was added at room temperature. After stirring at 80 ° C. for 2 hours, the reaction was cooled to 0 ° C. and quenched with aqueous Na ₂ S ₂ O ₃ solution. The resulting mixture was filtered through Celite (registered trademark), and the residue was washed with AcOEt. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 14-2. The obtained compound 14-2 was used in the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 1.80 (s, 3H), 4.45 (d, J = 28.2 Hz, 1H), 4.91 (ddd, J = 17.8, 3.9, 1.3 Hz, 1H), 5.00 (ddd, J = 14.8, 3.9, 1.3 Hz, 1H), 5.29 (d, J = 46.6 Hz, 1H), 6.02 (s, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H) , 7.53 (m, 1H).

Process 2
To a solution of compound 14-2 and Boc ₂ O (748 μl, 3.22 mmol) in CH ₂ Cl ₂ (3.5 ml) was added DMAP (79 mg, 645 μmol) at room temperature. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated. The residue was purified by silica gel chromatography to obtain compound 14-3 (436.3 mg, 1.17 mmol, 91%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (s, 9H), 1.97 (m, 3H), 4.46 (d, J = 29.3 Hz, 1H), 4.91 (ddd, J = 20.2, 4.0, 1.3 Hz, 1H ), 4.99 (ddd, J = 12.3, 4.0, 1.3 Hz, 1H), 5.21 (d, J = 46.3 Hz, 1H), 7.13 (m, 1H), 7.25 (m, 1H), 7.39 (m, 1H) , 7.50 (m, 1H).

Process 3
To a solution of compound 14-3 (456.3 mg, 1.23 mmol) in MeOH (5 ml) was added K ₂ CO ₃ (679 mg, 4.91 mmol) at room temperature. After stirring at room temperature for 15 minutes, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 14-4. The obtained compound 14-4 was used in the next reaction without further purification.
LC / MS (Shimadzu): RT 2.15, MS calculated 346.16 (M + H ⁺ ), found 346.15.

Process 4
To a solution of compound 14-4 in CH ₂ Cl ₂ (5 ml) was added TFA (1 ml, 13.0 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched with a saturated aqueous solution of NaHCO ₃ and K ₂ CO ₃ . The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 14-5 (254.6 mg, 1.04 mmol, 84%, 2 steps).
¹ H-NMR (CDCl ₃ ) δ: 1.77 (s, 3H), 3.89 (d, J = 31.0 Hz, 1H), 4.71 (ddd, J = 22.2, 2.9, 1.4 Hz, 1H), 4.79 (ddd, J = 10.9, 2.9, 1.4 Hz, 1H), 5.09 (dd, J = 44.9, 1.1 Hz, 1H), 7.10 (m, 1H), 7.22 (m, 1H), 7.35 (m, 1H), 7.58 (m, 1H).

Process 5
To a solution of compound 14-5 (254.6 mg, 1.04 mmol) in CH ₂ Cl ₂ (2.5 ml) was added BzNCS (209 μl, 1.56 mmol) at room temperature. After stirring at room temperature for 2.5 hours, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 14-6 (375.5 mg, 919 μmol, 89%).
¹ H-NMR (CDCl ₃ ) δ: 2.30 (s, 3H), 2.56 (d, J = 9.5 Hz, 1H), 4.36 (ddd, J = 25.2, 9.5, 5.0 Hz, 1H), 4.76 (dd, J = 48.9, 3.5 Hz, 1H), 4.85 (dd, J = 17.7, 3.5 Hz, 1H), 5.37 (d, J = 43.9 Hz, 1H), 7.08 (m, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.46-7.56 (m, 3H), 7.63 (m, 1H), 7.87 (m, 2H), 8.89 (s, 1H), 11.85 (s, 1H).

Step 6
To a solution of compound 14-6 (375.5 mg, 919 μmol) in CH ₃ CN (7 ml) was added WSCD hydrochloride (352 mg, 1.84 mmol) at room temperature. After stirring at 50 ° C. for 1 hour, the reaction was cooled to room temperature and quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 14-7. The obtained compound 14-7 was used in the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 1.91 (s, 3H), 4.52 (d, J = 27.7 Hz, 1H), 5.01 (dd, J = 9.0, 4.0 Hz, 1H), 5.09 (dd, J = 23.7 , 4.0 Hz, 1H), 5.43 (d, J = 46.4 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.49 (m, 4H), 7.53 (m, 1H), 8.27 (m, 2H), 11.81 (s, 1H).

Step 7
To a solution of compound 14-7 and Boc ₂ O (427 μl, 1.84 mmol) in CH ₂ Cl ₂ (3.5 ml) was added DMAP (22.5 mg, 184 μmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 14-8 (416.5 mg, 878 μmol, 95%).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (s, 9H), 1.55 (s, 3H), 4.40 (dd, J = 27.5, 2.8 Hz, 1H), 4.80 (dd, J = 49.4, 3.6 Hz, 1H ), 4.95 (dd, J = 17.8, 3.6 Hz, 1H), 5.23 (d, J = 47.2 Hz, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.30 (m, 1H), 7.41 -7.53 (m, 3H), 7.55 (m, 1H), 7.78 (m, 2H).

Process 8
In a test tube, 1-methyl-1-nitrosourea (905 mg, 4.39 mmol, 5 eq) was added at 0 ° C. to a mixture of aqueous NaOH (30%, 4 ml) and Et ₂ O (4 ml). After stirring for 20 minutes at 0 ° C., the color of the organic layer changed to yellow, suggesting that an Et ₂ O solution of diazomethane could be prepared. In a separate flask compound 14-8 (416.5mg, 878μmol) and _{Pd (OAc) 2 (39.4mg,} 176μmol, 0.2 equiv) in _Et 2 O (4 ml) suspension, of the diazomethane Et ₂ O solution was added at -30 ° C. The reaction was stirred at −20 ° C. and the Et ₂ O solution of diazomethane (5 × 5 eq) and Pd (OAc) ₂ (0.2 × ₂ eq) prepared above was added several times until compound 14-8 was completely consumed. Added in portions. After stirring at −20 ° C. for 3 hours after addition of the first diazomethane solution, the reaction was quenched with H ₂ O and AcOH. A saturated aqueous NaHCO ₃ solution was added, and the resulting mixture was filtered through Celite (registered trademark). The filtrate was washed with AcOEt. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 14-9 (259.2 mg, 531 μmol, 60%).
¹ H-NMR (CDCl ₃ ) δ: 0.75-1.20 (m, 4H), 1.43 (s, 3H), 1.47 (s, 9H), 4.25 (dd, J = 28.5, 10.7 Hz, 1H), 5.27 (d , J = 47.6 Hz, 1H), 7.05 (m, 1H), 7.17 (m, 1H), 7.29 (m, 1H), 7.40-7.61 (m, 4H), 7.76 (m, 2H).

Step 9
To a solution of compound 14-9 (259.2 mg, 531 μmol) in MeOH (5 ml) was added K ₂ CO ₃ (367 mg, 2.65 mmol) at room temperature. After stirring at room temperature for 20 minutes, the reaction was quenched with H ₂ O. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 14-10 (117.4 mg, 305 μmol, 58%).
¹ H-NMR (CDCl ₃ ) δ: 0.84-1.17 (m, 4H), 1.52 (s, 9H), 1.85 (s, 3H), 4.35 (dd, J = 28.1, 5.3 Hz, 1H), 5.48 (d , J = 46.9 Hz, 1H), 7.14 (m, 1H), 7.24 (m, 1H), 7.35-7.44 (m, 2H), 10.00 (brs, 1H).

Step 10
Compound 14-10 (117.4 mg, 305 μmol) was dissolved in TFA (1 ml) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was cooled to −20 ° C. and H ₂ SO ₄ (250 μl) was added. After stirring at 0 ° C. for 5 minutes, the reaction was cooled to −20 ° C. and HNO ₃ (41 μl, 916 μmol) was added. After stirring at 0 ° C. for 25 minutes, the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to obtain compound 14-11 (82.8 mg, 251 μmol, 82%).
¹ H-NMR (CDCl ₃ ) δ: 0.81 (m, 1H), 0.91-1.07 (m, 2H), 1.13 (m, 1H), 1.66 (s, 3H), 4.05 (dd, J = 29.1, 9.9 Hz , 1H), 4.35 (brs, 2H), 5.33 (d, J = 47.6 Hz, 1H), 7.23 (dd, J = 10.7, 9.0 Hz, 1H), 8.21 (ddd, J = 9.0, 4.1, 2.9 Hz, 1H), 8.46 (dd, J = 6.7, 2.9 Hz, 1H).

Step 11
To a solution of compound 14-11 (82.8 mg, 251 μmol) and Boc ₂ O (175 μl, 754 μmol) in CH ₂ Cl ₂ (1 ml) was added DMAP (30.7 mg, 251 μmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was concentrated. The residue was purified by silica gel chromatography to give compound 14-12 (83.8 mg, 158 μmol, 63%).
¹ H-NMR (CDCl ₃ ) δ: 0.80 (m, 1H), 0.92-1.09 (m, 2H), 1.16 (m, 1H), 1.53 (s, 18H), 1.74 (s, 3H), 4.23 (dd , J = 28.2, 8.2 Hz, 1H), 5.39 (d, J = 47.1 Hz, 1H), 7.28 (m, 1H), 8.26 (m, 1H), 8.56 (dd, J = 6.7, 2.9 Hz, 1H) .

Step 12
To a solution of compound 14-12 (83.8 mg, 158 μmol) in THF (0.5 ml) and MeOH (1 ml) was added Pd / C (8.4 mg) at room temperature. After stirring at room temperature for 4.5 hours under H ₂ atmosphere, the reaction solution was filtered through Celite (registered trademark), and the residue was washed with AcOEt. The filtrate was concentrated and the residue was purified by silica gel chromatography to give compound 14-13 (65.4 mg, 131 μmol, 83%).
¹ H-NMR (CDCl ₃ ) δ: 0.75-1.20 (m, 4H), 1.52 (s, 18H), 1.70 (m, 3H), 3.57 (brs, 2H), 4.31 (dd, J = 28.6, 10.0 Hz , 1H), 5.35 (d, J = 47.7 Hz, 1H), 6.56 (m, 1H), 6.83-6.90 (m, 2H).

Step 13
To a solution of compound 14-13 (41.0 mg, 82 μmol), 5- (fluoromethoxy) pyrazine-2-carboxylic acid (17.0 mg, 98 μmol) and diisopropylethylamine (29 μl, 164 μmol) in DMF (2 ml) was added HATU (37 0.5 mg, 98 μmol) was added at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to give compound 14-14 (49.4 mg, 76 μmol, 92%).
¹ H-NMR (CDCl ₃ ) δ: 0.75-1.22 (m, 4H), 1.55 (s, 18H), 1.76 (m, 3H), 4.29 (dd, J = 29.1, 9.9 Hz, 1H), 5.37 (d , J = 47.4 Hz, 1H), 6.15 (ddd, J = 51.1, 13.6, 2.0 Hz, 2H), 7.15 (dd, J = 11.5, 9.0 Hz, 1H), 7.51 (dd, J = 6.8, 2.8 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.37 (ddd, J = 9.0, 4.3, 2.8 Hz, 1H), 9.08 (d, J = 1.3 Hz, 1H), 9.64 (s, 1H).

Step 14
Compound 14-14 (49.4 mg, 76 μmol) was dissolved in formic acid (1 ml, 26.1 mmol) at room temperature. After stirring at room temperature for 16.5 hours, the reaction was quenched with aqueous K ₂ CO ₃ solution. The aqueous layer was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was solidified in hexanes to give pure I-94 (25.9 mg, 57 μmol, 76%).
¹ H-NMR (CDCl ₃ ) δ: 0.76-1.20 (m, 4H), 1.67 (s, 3H), 4.11 (dd, J = 29.2, 11.8 Hz, 1H), 5.35 (d, J = 47.9 Hz, 1H ), 6.15 (m, 2H), 7.11 (dd, J = 11.3, 8.9 Hz, 1H), 7.50 (dd, J = 6.8, 2.6 Hz, 1H), 8.02 (m, 1H), 8.29 (s, 1H) , 9.08 (s, 1H), 9.52 (s, 1H).

The following compounds are synthesized in the same manner as described above. In the table, RT represents LC / MS retention time (minutes).

以下に、本発明に係る化合物の試験例を記載する。

Hereinafter, test examples of the compound according to the present invention will be described.

(Test Example 1-1: Measurement of BACE1 inhibitory action: 96-well)
In each well of a 96-well half-area plate (black plate: manufactured by Coaster), 48.5 μl of a substrate peptide (biotin-XSEVNLDAEFRHDSGC-Eu: X = ε-amino-n-caproic acid, Eu = europium cryptate) solution. After adding 0.5 μl of the compound according to the present invention (DMSO solution) and 1 μl of recombinant human BACE1 (manufactured by R & D systems), the mixture was reacted at 30 ° C. for 3.5 hours. The substrate peptide was synthesized by reacting cryptate TBPCOOH mono SMP (manufactured by CIS bio international) with biotin-XSEVNLDAEFRHDSGC (manufactured by Peptide Institute). The final concentration of substrate peptide was 9.7 nmol / L, the final concentration of recombinant human BACE1 was 500 nmol / L, and sodium acetate buffer (50 mmol / L sodium acetate, pH 5.0, 0.008% Triton X-100). The reaction was carried out.
After completion of the reaction, 8.0 μg / ml dissolved in phosphate buffer (150 mmol / L K ₂ HPO ₄ -KH ₂ PO ₄ , pH 7.0, 0.008% Triton X-100, 0.8 mol / L KF). Of streptavidin-XL665 (manufactured by CIS bio international) was added to each well in an amount of 50 μl and allowed to stand at 30 ° C. for 45 minutes. Thereafter, the fluorescence intensity (excitation wavelength: 320 nm, measurement wavelengths: 620 nm and 665 nm) was measured using an ARVO-X4 2030 multilabel reader (manufactured by Perkin Elmer life sciences). The enzyme activity was determined from the count rate (10,000 × count 665 / count 620) at each measurement wavelength, and the concentration (IC ₅₀ ) that inhibits the enzyme activity by 50% was calculated.

(Test Example 1-2: Measurement of BACE1 inhibitory action: 384-well)
In each well of a 384-well plate (black plate: Corning), 5 μl of a substrate peptide (biotin-XSEVNLDAEFRHDSGGC-Eu: X = ε-amino-n-caproic acid, Eu = europium cryptate) solution was added. .1 μl of the compound according to the present invention ((DMSO solution) and 5 μl of recombinant human BACE1 (R & D systems) were added and reacted for 2 hours at 25 ° C. The substrate peptide was biotin-XSEVNLDAFRHDGSGC (Peptide Study). The final concentration of the substrate peptide was 9.7 nmol / L, and the final concentration of the recombinant human BACE1 was 500 nmol, which was synthesized by reacting cryptate TBPCOOH mono SMP (manufactured by CIS Bio International). Is L, the reaction buffer sodium acetate buffer (50 mmol / L sodium acetate, pH5.0,0.008% Triton X-100) was used.
After completion of the reaction, 8.0 μg / ml dissolved in phosphate buffer (150 mmol / L K ₂ HPO ₄ -KH ₂ PO ₄ , pH 7.0, 0.008% Triton X-100, 0.8 mol / L KF). Of streptavidin-XL665 (manufactured by CIS bio international) was added to each well in an amount of 10 μl and allowed to stand at 25 ° C. for 30 minutes. Thereafter, the fluorescence intensity (excitation wavelength: 320 nm, measurement wavelengths: 620 nm and 665 nm) was measured using RUBYstar (manufactured by BMG LABTECH). The enzyme activity was determined from the count rate (10,000 × count 665 / count 620) at each measurement wavelength, and the concentration (IC ₅₀ ) that inhibits the enzyme activity by 50% was calculated.

(Test Example 1-3: Measurement of BACE2 inhibitory action)
In each well of a 96-well plate (black plate: manufactured by Coaster), 89 μL of a substrate peptide (SEVNLDAEFRHDSGYEK-biotin) solution was placed, 1 μl of the compound according to the present invention (DMSO solution) and 10 μl of human BACE2 (human BACE2 ecto) FreeStyle ™ 293-F cells in which the domain is expressed (purified conditioned medium) is added, followed by reaction at 37 ° C. for 1 hour. The final concentration of substrate peptide is 1000 nmol / L, the final concentration of human BACE2 is 20 ng / L, and the reaction buffer is sodium acetate buffer (50 mmol / L sodium acetate, pH 4.5, 0.25 mg / mL bovine serum albumin). Use.
After completion of the reaction, 30 μl of 1M Tris-HCL (pH 7.6) is added to the reaction solution. The reaction solution is put into each well coated with 82E1 (anti-amyloid β antibody; manufactured by Immunobiological Laboratories) and reacted at 4 ° C. overnight. After the reaction, the wells are washed 5 times, Neutravidin-Horeradis Peroxidase conjugated (Thermo Fisher) is added to each well, and allowed to react at room temperature for 1 hour. After 5 washes, 45 μL of a mixture of Supersignal picosolution A and B (Thermo Fisher) is added to each well. The count of chemiluminescence in each well is measured with an ARVO MX 1420 multilabel reader (Perkin Elmer life sciences). The enzyme activity is determined from the count rate (10,000 × count 665 / count 620) at each measurement wavelength, and the concentration (IC ₅₀ ) that inhibits the enzyme activity by 50% is calculated.

(Test Example 2-1: Measurement of β-amyloid (Aβ) production inhibitory action in cells: 96-well)
Neuroblastoma SH-SY5Y cells (SH / APPwt) overexpressing human wild-type βAPP were prepared at 8 × 10 ⁵ cells / mL, and 150 μl per well was seeded in a 96-well culture plate (Falcon). The cells were cultured at 37 ° C. in a 5% carbon dioxide incubator for 2 hours. Thereafter, a solution in which the compound according to the present invention (DMSO (dimethyl sulfoxide) solution) was added and suspended in advance so as to be a 2 μl / 50 μl medium was added to the cell solution. That is, the final DMSO concentration was 1% and the cell culture solution was 200 μl. After 24 hours of incubation from the addition of the test compound, 100 μl of the culture supernatant was collected and the amount of Aβ contained therein was measured.
A method for measuring the amount of Aβ is as follows. Into a 384-well half area microplate (black microplate; manufactured by Coaster), 10 μl of homogeneous time-resolved fluorescence (HTRF) measurement reagent (Amyloid β1-40 peptide; manufactured by CIS bio international) and 10 μl of culture supernatant were added. Then, the mixture was kept light-shielded at 4 ° C. overnight. Thereafter, the fluorescence intensity (excitation wavelength: 337 nm, measurement wavelengths: 620 nm and 665 nm) was measured using a microplate reader (Artemis K-101; Furuno Electric). The amount of Aβ was determined from the count rate of each measurement wavelength (10000 × count 665 / count 620), and the dose that inhibits Aβ production by 50% (IC ₅₀ ) was calculated from at least 6 different doses.
(Test Example 2-2: Measurement of β-amyloid (Aβ) production inhibitory action in cells: 384-well)
Neuroblastoma SH-SY5Y cells (SH / APPwt) overexpressing human wild-type βAPP were prepared at 4 × 10 ⁵ cells / mL, and 50 μl per well were prepared in a 384-well culture plate (Corning). Then, 0.5 μl of the test compound (DMSO solution) according to the present invention was added. The final DMSO concentration was 1% and the cell culture was 50 μl. After seeding the cells and incubating for 24 hours, 5 μl of the culture supernatant was collected and the amount of Aβ contained therein was measured.
A method for measuring the amount of Aβ is as follows. In a 384-well plate (black plate; Corning), 5 μl of homogeneous time-resolved fluorescence (HTRF) measurement reagent (Amyloid β1-40 peptide; CIS bio international) and 5 μl of culture supernatant were added and mixed. The mixture was allowed to stand overnight at 4 ° C. with light shielding. Thereafter, the fluorescence intensity (620 nm and 665 nm) was measured using EnVision (manufactured by Perkin Elmer life sciences). The amount of Aβ was determined from the count rate of each measurement wavelength (count 665 / count 620), and the dose that inhibited Aβ production by 50% (IC ₅₀ ) was calculated from at least six different doses.

(Test Example 3-1: β-amyloid reducing action in rat brain)
The compound according to the present invention is suspended in 0.5% methylcellulose and prepared to a final concentration of 2 mg / mL, so that it is 10 mg / kg for male Crl: SD rats (7-9 weeks old). Oral administration. In the base control group, only 0.5% methylcellulose is administered, and the administration test is performed on 3 to 8 animals in each group. Three hours after administration, the brain is removed, the cerebral hemisphere is isolated and weighed, and then immediately frozen in liquid nitrogen and stored at −80 ° C. until the date of extraction. The frozen cerebral hemisphere was transferred to a Teflon (registered trademark) homogenizer under ice-cooling, and an extraction buffer (1% CHAPS ({3-[(3-chloroamidopropyl) dimethylammonio] -1-propane) having a volume four times the weight was used. Sulfonate}), 20 mmol / L Tris-HCl (pH 8.0), 150 mmol / L NaCl, and Complete (Roche) protease inhibitor) are added, and the mixture is homogenized and solubilized repeatedly for 2 minutes. The suspension is transferred to a centrifuge tube and left on ice for 3 hours or more, and then centrifuged at 100,000 × g, 4 ° C. for 20 minutes. After centrifugation, the supernatant is transferred to an ELISA plate for measurement of β-amyloid 40 (manufactured by Wako Pure Chemical Industries, Ltd .: product number 294-62501). The ELISA measurement is performed according to the attached instructions. The decreasing action is calculated as a ratio of the base control group of each test to β-amyloid 40 in the brain.

(Test Example 3-2: β-amyloid reducing action in mouse brain)
The compound according to the present invention is dissolved in 20% hydroxyl beta cyclodextrin and prepared to a final concentration of 2 mg / mL, and 1-10 mg / mL for male Crl: CD1 (ICR) mice (6-8 weeks old). Orally administered to give kg. The solvent control group receives only 20% hydroxyl beta cyclodextrin, and 3 to 6 animals in each group conduct the administration test. The brain is removed 1 to 6 hours after administration, and the cerebral hemisphere is isolated and weighed, and then immediately frozen in liquid nitrogen and stored at −80 ° C. until the date of extraction.
The frozen cerebral hemisphere is transferred to a homogenization tube containing 8 times volume of extraction buffer (containing 0.4% DEA (diethylamine), 50 mmol / L NaCl, Complete protease inhibitor (Roche)) and ceramic beads for 20 minutes. Keep on ice. Then, using MP BIO FastPrep (registered trademark) -24, homogenize with Lysing matrix D (1.4 mm ceramic beads) at 6 m / s for 20 seconds. The tube is centrifuged for 1 minute, the supernatant is transferred to a tube for centrifugation, and centrifuged at 221,000 × g, 4 ° C. for 50 minutes. After centrifugation, the supernatant is transferred to a Nunc Maxisorp® plate (Thermo Fisher Scientific) coated with an antibody against the N-terminus of β-amyloid and incubated overnight at 4 ° C. for total β-amyloid measurement. The plate was washed with TBS-T (Tris buffer saline containing 0.05% Triton X-100), and HRP-labeled 4G8 dissolved in PBS (pH 7.4) containing 0.1% casein was added to the plate. Incubate for 1 hour at ° C. After washing with TBS-T, a SuperSignal ELISA luminometer chemiluminescent substrate (manufactured by Thermo Scientific) is added to the plate. Chemiluminescence is measured quickly with an ARVO® MX1420 multilabel counter (Perkin Elmer). The decreasing effect is calculated as a ratio to the total brain β-amyloid in the solvent control group of each test.
The following results are ratios relative to total β-amyloid in the brain of the solvent control group at 4 hours after administration (dosage 10 mg / kg).

(Test Example 4-1: CYP3A4 fluorescence MBI test)
The CYP3A4 fluorescence MBI test is a test that examines the enhancement of CYP3A4 inhibition of compounds by metabolic reactions. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration according to the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L ( 6 points).
The enzyme and the compound solution according to the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition. A part of the plate was transferred to another 96-well plate so that it was diluted 1/10 with the substrate and K-Pi buffer, and NADPH, a coenzyme, was added to start the reaction as an indicator (no pre-reaction) After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V) solution. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction exists), and after pre-reaction for a predetermined time, it is diluted to 1/10 with another substrate and K-Pi buffer in another 96-well plate. A part of the system was transferred to and the reaction was started.
After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). In the plate on which each index reaction was performed, the fluorescence value of 7-HFC which is a metabolite was measured with a fluorescence plate reader (Ex = 420 nm, Em = 535 nm).
Instead of the compound solution according to the present invention, DMSO, which is a solvent in which the compound according to the present invention was dissolved, was added to the reaction system as a control (100%). The residual activity (%) at each concentration to which the compound solution according to the present invention was added was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. A case where the difference in IC ₅₀ values was 5 μM or more was positive (+), and a case where the difference was 3 μM or less was negative (−).
The following compounds were negative:
I-2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 40, 41, 42, 43, 44, 45, 71 and 86.

(Test Example 4-2: CYP3A4 (MDZ) MBI Test)
The CYP3A4 (MDZ) MBI test is a test that evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction with respect to CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an index.
Reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; protein content of pooled human liver microsomes, 0.5 mg / mL during pre-reaction , 0.05 pg / mL during reaction (10-fold dilution); concentration of the compound according to the present invention 1, 5, 10, 20 μmol / L (4 points).
Pooled human liver microsomes and the compound solution according to the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the composition of the pre-reaction described above. A part of the plate was transferred to another 96-well plate so that it was diluted 1/10 with the substrate and K-Pi buffer, and NADPH, a coenzyme, was added to start the reaction as an indicator (no pre-reaction) After the reaction for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction exists), and after pre-reaction for a predetermined time, it is diluted to 1/10 with another substrate and K-Pi buffer in another 96-well plate. A part of the system was transferred to and the reaction was started. After the reaction for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS.
Instead of the compound solution according to the present invention, DMSO, which is a solvent in which the compound according to the present invention was dissolved, was added to the reaction system as a control (100%). The residual activity (%) at each concentration to which the inventive compound solution was added was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. The “IC value at the start of pre-reaction / IC value 30 minutes after the start of pre-reaction” was defined as the Shifted IC value, and the case where the Shifted IC value was 1.5 or more was positive and the case where it was 1.0 or less was negative.
The following compounds were negative:
I-50, 52, 54, 56, 64, 65, 75, 77, 81, 82, 88, 89, 90, 91, 94, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 114 and 115.

(Test Example 5: CYP inhibition test)
The CYP inhibition test is a test for evaluating the inhibitory effect of the compound according to the present invention on the typical substrate metabolic reaction of CYP enzyme in human liver microsomes. The following are used as indicator reactions for the major human CYP5 species (CYP1A2, 2C9, 2C19, 2D6, and 3A4); O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9) 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), hydroxylation of terfenadine (CYP3A4). Commercially available human liver microsomes are used as the enzyme source.
The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration according to the present invention 1, 5, 10, 20 μmol / L (4 point).
As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsomes, and a compound according to the present invention were added in a 50 mmol / L Hepes buffer with the above composition. NADPH, a coenzyme, was added to the 96-well plate to initiate metabolic reaction. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was subjected to hydroxytolbutamide (CYP2C9 metabolite), 4′-hydroxymephenytoin (CYP2C19 metabolite), dextrorphan (CYP2D6) with a fluorescent plate reader. Metabolite) and terfenadine alcohol metabolite (CYP3A4 metabolite) were quantified by LC / MS / MS.
Instead of the compound according to the present invention, DMSO as a solvent in which the compound according to the present invention was dissolved was added to the reaction system as a control (100%). The residual activity (%) at each concentration of the compound solution according to the present invention was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate.
CYP1A2 20 μM or more: Compounds I-1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107 , 108, 109, 110, 111, 112, 113, 14 and 116
CYP1A2 10 μM or more and less than 20 μM: Compounds I-29 and 115

CYP2C9 20 μM or more: Compound I-1, 10, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 55, 56, 57, 58, 59, 60, 61, 71, 78, 86, 87, 88, 89, 90, 102 , 105, 106, 112, 113 and 115
CYP2C9 10 μM or more and less than 20 μM: Compound I-2, 3, 4, 5, 11, 16, 49, 62, 63, 75, 77, 79, 80, 81, 94, 95, 96, 99, 103, 104, 107 110 and 114

CYP2C19 20 μM or more: Compounds I-1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 75, 77, 78, 79, 80, 81, 82 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108 , 109, 110, 111, 112, 113, 1 4,115 and 116
CYP2C19 not less than 10 μM and less than 20 μM: Compounds I-6 and 76

CYP2D6 20 μM or more: Compound I-1, 4, 10, 13, 15, 18, 20, 23, 25, 26, 27, 28, 29, 31, 34, 35, 36, 40, 43, 45, 49, 52 53, 64, 85, 87, 88, 89, 90, 96, 102, 103, 104, 105, 106, 107, 112, 113, 114, 115 and 116
CYP2D6 10 μM or more and less than 20 μM: Compounds I-11, 12, 22, 24, 32, 44, 46, 48, 70, 78, 99, 108 and 110

CYP3A4 20 μM or more: Compounds I-1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50, 52, 53 64, 65, 71, 86, 87, 88, 89, 90, 91, 92, 94, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 111, 112, 113, 114, 115 and 116
CYP3A4 10 μM or more and less than 20 μM: Compounds I-51, 55, 56, 57, 61, 66, 68, 69, 70, 78, 79, 80, 81 and 95

(Test Example 6: Fluctuation Ames test)
20 μL each of Salmonella typhimurium TA98 strain and TA100 strain cryopreserved is inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and shake-cultured at 37 ° C. for 10 hours. . 7. Centrifugation (2000 × g, 10 minutes) of 70 mL of the TA98 strain culture solution is performed to remove the culture solution. 7. 70 mL Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: The cells are suspended in 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) 3.42 mL to add to the MicroF buffer). TA100 strain culture solution is added to 130 mL of Exposure medium to prepare a test bacterial solution. Compound DMSO solution according to the present invention (maximum dose 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, 50 μg / mL for TA98 strain as positive control under non-metabolic activation conditions 4-Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, metabolic activation conditions for TA100 strain As a positive control, 40 μg / mL 2-aminoanthracene DMSO solution for TA98 strain and 20 μg / mL 2-aminoanthracene DMSO solution for TA100 strain were each 12 μL and 588 μL of the test bacterial solution (tested under metabolic activation conditions). Mix 498 μL of bacterial solution and 90 μL of S9mix). Incubate at 37 ° C for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the compound according to the present invention was added to an Indicator medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). ) Mix in 2300 μL, dispense 50 μL each into a 48-well / dose microplate, and incubate at 37 ° C. for 3 days. Wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene turn from purple to yellow due to pH change. Bacterial growth wells that turn yellow in 48 wells per dose are counted and assessed for mutagenicity compared to the negative control group. A negative mutagenicity is indicated as (-), and a positive one is indicated as (+).

(Test Example 7: Solubility test)
The solubility of the compound according to the present invention was determined under the condition of adding 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, and add 2 μL of the compound solution according to the present invention to JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution ( (See Table 4) Added to each 198 μL. After allowing to stand at 25 ° C. for 16 hours or shaking at room temperature for 1 hour, the mixed solution was subjected to suction filtration. The filtrate is diluted 10 or 100 times with methanol / water = 1/1 (v / v) or MeCN / MeOH / H ₂ O (= 1/1/2), LC / MS or solid phase extraction (SPE) / MS Was used to measure the compound concentration in the filtrate by the absolute calibration curve method.

*１：２５℃で１６時間静置
*２：室温で１時間振盪

Ａ：０．２ｍｏｌ／Ｌリン酸二水素カリウム溶液を０．２ｍｏｌ／Ｌ水酸化ナトリウム溶液／水＝１／１．５でｐＨ６．８に調整
Ｂ：リン酸二水素カリウム３．４０ｇおよび無水リン酸水素二ナトリウム３．５５ｇを水に溶かし１０００ｍＬとする

* 1: 16 hours at 25 ° C
* 2: Shake at room temperature for 1 hour

A: 0.2 mol / L potassium dihydrogen phosphate solution was adjusted to pH 6.8 with 0.2 mol / L sodium hydroxide solution / water = 1 / 1.5 B: 3.40 g of potassium dihydrogen phosphate and anhydrous phosphorus Dissolve 3.55 g of disodium oxyhydrogen in water to make 1000 mL

(Test Example 8: Metabolic stability test)
A commercially available pooled human liver microsome and the compound according to the present invention were reacted for a certain period of time, and the residual ratio was calculated by comparing the reaction sample with the unreacted sample, and the degree to which the compound according to the present invention was metabolized in the liver was evaluated.
In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound according to the present invention in the centrifuged supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound according to the present invention after the reaction was determined at 0 minutes The amount was calculated as 100%.

(Test Example 9: hERG test)
For the purpose of assessing the risk of prolonging the electrocardiogram QT interval of the compound according to the present invention, CHO cells expressing a human ether-a-go-go related gene (hERG) channel are used to play an important role in the ventricular repolarization process. The action of the compounds according to the invention on the delayed rectifier K ⁺ current (I _Kr ) was investigated.
Cells were held at a membrane potential of −80 mV by whole cell patch clamp method using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S). After applying a leak potential of −50 mV, I _Kr induced when a +20 mV depolarization stimulus was applied for 2 seconds and a −50 mV repolarization stimulus was applied for 2 seconds was recorded.
After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol / L) in which the compound according to the present invention is dissolved at a desired concentration. HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, glucose: 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current was measured using the analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the holding membrane potential. Further, the inhibition rate with respect to the maximum tail current before application of the compound according to the present invention was calculated, and compared with the medium application group (0.1% dimethyl sulfoxide solution), the effect of the compound according to the present invention on I _Kr was evaluated. did.

(Test Example 10: Powder solubility test)
An appropriate amount of the compound according to the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution (dihydrogen phosphate) is added to each container. 1.40 g of potassium and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL, 1 volume of water is added to 1 volume), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA) 200 ml of JP-2 solution is added to make 100 mL). When the total amount of the compound according to the present invention is dissolved after the addition of the test solution, the compound according to the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound according to the present invention is quantified using HPLC by the absolute calibration curve method.

(Test Example 11: Pharmacokinetic test)
Examination Materials for Oral Absorption Experimental Materials and Methods (1) Animal used: mouse or rat (2) Breeding condition: Mouse or rat was allowed to freely take solid feed and tap water.
(3) Setting of dose and grouping: Oral administration and intravenous administration were administered at a predetermined dose. Groups were set as follows (dosage varied for each compound).
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation item: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) was calculated using the nonlinear least squares program WinNonlin (Registered Trademark) for the plasma concentration transition of the compound of the present invention. The bioavailability (BA) of the compound according to the present invention was calculated from the AUC of the intravenous administration group.

(Test Example 12: Brain migration test)
Rats were administered intravenously with a compound according to the invention at a dose of 0.5 mg / mL / kg. Thirty minutes later, the blood was exsanguinated by whole blood collection from the abdominal aorta under isoflurane anesthesia.
Thereafter, the brain was removed and 20-25% homogenate was prepared with distilled water.
On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma was added to the brain sample and control brain homogenate was added to the plasma sample at a ratio of 1: 1, and each sample was measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement was defined as the brain Kp value.

(Test Example 13: Ames test)
The Ames test was carried out under non-metabolic activation conditions and metabolic activation conditions by the preincubation method using Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA as test strains. The presence or absence of gene mutagenesis of the compound according to the present invention is examined.

(Test Example 14: P-gp substrate test)
1. cell:
a. MDR1 / LLC-PK1 (Becton Dickinson)
b. LLC-PK1 (Becton Dickinson)
2. Control substrate:
a. Digoxin (2μM)

Method 1. Add MDR1-expressing LLC-PK1 cells and their parent cells to A medium (199 medium (Invitrogen), 10% FBS (Invitrogen), gentamicin (0.05 mg / mL, Invitrogen) and hygromycin B (100 μg / mL, Invitrogen) ) At 37 ° C. under 5% CO ₂ /95% O ₂ gas. For transport experiments, these cells were seeded in Transwell ™ (96 well, pore size: 0.4 μm, coaster) at a density of 1.4 × 10 ⁴ cells / insert and B medium (10% in 199 medium). FBS and gentamicin 0.05 mg / mL were added) to the feeder tray. These cells were incubated in a CO ₂ incubator (5% CO ₂ /95% O ₂ gas, 37 ° C.), and the apical and basolatal media were changed every 48 to 72 hours after the start of the culture. Cells were used 4-6 days after seeding.
2. In the insert, the medium in which the MDR1-expressing cells or parent cells were cultured was removed by aspiration and rinsed with HBSS. Replace the apical side (140 μL) or the basal lateral side (175 μL) with the transport buffer (containing the control substrate and the compound according to the present invention), then take a predetermined volume (50 μL) of transport buffer on the donor side, The initial concentration of the control substrate and the compound according to the invention was determined. After incubation at 37 ° C. for a fixed time, a predetermined amount (50 μL) of transport buffer was collected on the donor side and the receiver side. The assay was performed twice or three times.
3. The target substrate and the compound according to the present invention in the collected liquid were quantified using LC / MS / MS.
The membrane permeation amount of the MDR1-expressing cell and the parent cell of the analysis monolayer was measured, and the membrane permeability coefficient (Pe) was determined by using the following formula using Excel 2003:
Pe (cm / sec) = membrane permeation amount (pmol) / cell membrane area (cm ² ) / initial concentration (nM) / incubation time (second)
Here, the membrane permeation amount was calculated by multiplying the permeation concentration (nM, concentration on the receiver side) of the substrate after incubation for a predetermined time (second) by the amount (mL), and the cell membrane area was 0.1433 (cm ² ). did.
Efflux Ratio was determined by the following formula:
Efflux Ratio = Pe in the direction from the Basaltal side to the Apical side / Pe in the direction from the Apical side to the Basolatal side

Net flux was determined by the following formula:
Net flux = Efflux Ratio of MDR1-expressing cells / Efflux Ratio of parent cells

(Test Example 15: Inhibitory effect of P-gp transport)
Material 1. cell:
a. MDR1 / LLC-PK1 (Becton Dickinson)
b. LLC-PK1 (Becton Dickinson)
2. Control substrate:
a. [ ³ H] digoxin (1 μM)
b. [ ¹⁴ C] Mannitol (5 μM)
3. Control inhibitor:
Cyclosporine A (10μM)
Method 1. Add MDR1-expressing LLC-PK1 cells and their parent cells to A medium (199 medium (Invitrogen), 10% FBS (Invitrogen), gentamicin (0.05 mg / mL, Invitrogen) and hygromycin B (100 μg / mL, Invitrogen) ) At 37 ° C. under 5% CO ₂ /95% O ₂ gas. For transport experiments, these cells were seeded in Transwell® (24 wells, pore size: 0.4 μm, coaster) at a density of 4 × 10 ⁴ cells / insert, and B medium (10% FBS in 199 medium). And 0.05 mg / mL gentamicin) are added to the feeder tray. These cells are incubated in a CO ₂ incubator (5% CO ₂ /95% O ₂ gas, 37 ° C.), and the apical and basolatal media are changed every 48 to 72 hours after the start of culture. Cells are used 6-9 days after seeding.
2. The medium in which MDR1-expressing cells or parent cells are cultured is removed by aspiration and rinsed with HBSS. The apical side (250 μL) or the basolatal side (850 μL) is replaced with a transport buffer (including a control substrate, in the presence or absence of a compound according to the invention), followed by a predetermined volume on the donor side (50 μL) The transport buffer is taken to determine the initial concentration of the control substrate. After incubation at 37 ° C. for a certain time, a predetermined amount (50 μL) of transport buffer is collected on the donor side and the receiver side. The assay is performed in triplicate.
3. A fixed amount (50 μL) of transport buffer is mixed with 5 mL of scintillation cocktail and the radioactivity is measured with a liquid scintillation counter.
The membrane permeation amount of the MDR1-expressing cell and the parent cell of the analysis monolayer is measured, and the membrane permeability coefficient (Pe) is obtained by the following formula using Excel 2003:
Pe (cm / sec) = membrane permeation amount (pmol) / cell membrane area (cm ² ) / initial concentration (nM) / incubation time (second)

Here, the membrane permeation amount is calculated by multiplying the permeation concentration (nM, concentration on the receiver side) of the substrate after incubation for a predetermined time (second) by the amount (mL), and the cell membrane area is 0.33 (cm ² ). To do.
Efflux Ratio is determined by the following formula:
Efflux Ratio = Pe in the direction from the Basaltal side to the Apical side / Pe in the direction from the Apical side to the Basolatal side
The net flux is determined by the following formula:
Net flux = Efflux Ratio of MDR1-expressing cells / Efflux Ratio of parent cells
The ratio of the control group is determined as the net flux ratio of the control compound in the presence and absence of the compound according to the present invention.
IC ₅₀ values are determined using the WinNonlin® pharmacokinetic analysis program.

(Test Example 16: mdr1a (− / −) B6 mouse P-gp substrate test)
Animal: mdr1a (− / −) B6 mouse (knockout mouse) or C57BL / 6J mouse (wild mouse)
Method 1. The animal may be fed before administration of the compound according to the invention.
2. The compound according to the present invention is administered to three animals at each time point, and blood and brain samples are given at a predetermined time point after administration (eg, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours). Or 24 hours). Blood (0.3 to 0.7 mL) was collected by trunk blood collection using a syringe containing a blood coagulation inhibitor (EDTA and heparin). Blood and tissue (such as brain) samples were immediately chilled on ice.
3. The blood sample was centrifuged (1780 × g, 10 minutes) to remove cells and obtain plasma. Plasma samples were then transferred to a clean tube and stored at -70 ° C until analysis.
4). Tissue (such as brain) samples were homogenized at a tissue weight: distilled water (ml) ratio = 1: 3, transferred to a clean tube and stored at −70 ° C. until analysis.
5. Plasma and tissue (such as brain) samples were analyzed by LC / MS / MS after deproteinization. For measurement, a calibration curve prepared from blank plasma or a blank brain sample and a known amount of analyte was used, and a quality control sample was used to confirm the accuracy and accuracy of the measurement method.
6). Plasma and brain concentration values (ng / mL and ng / g) were entered into the appropriate mathematical method for determining pharmacokinetic parameters. For example, WinNonlin (registered trademark) was used as a pharmacokinetic analysis software program.
Analysis Kp: tissue / blood concentration ratio Kp ratio = Kp value of knockout (KO) mouse / Kp value of wild mouse

KO / Wild ratio of tissue AUC / plasma AUC = {tissue AUC / plasma AUC (KO mouse)} / {tissue AUC / plasma AUC (wild mouse)}

(Test Example 17: Anesthesia guinea pig cardiovascular system test)
Animal: Guinea pig (Slc: Hartley, 4-6 weeks old, male), N = 4
Exam design:
Dose: 3, 10 and 30 mg / kg (in principle)
(Compounds according to the invention are administered cumulatively)
composition:
Medium composition: dimethylacetamide (DMA): polyethylene glycol 400 (PEG400): distilled water (DW) = 1: 7: 2 (in principle)
The compound according to the present invention is dissolved in DMA, and PEG 400 and distilled water (DW) are added. Prepare final concentrations of 1.5, 5 and 15 mg / mL solutions.
Route of administration and schedule:
10-minute intravenous injection (2 mL / kg)
0 to 10 minutes: 3 mg / kg, 30 to 40 minutes: 10 mg / kg, 60 to 70 minutes: 30 mg / kg
The vehicle control group is also administered on the same schedule as above.
Group composition:
Vehicle control group and compound group according to the present invention (4 mice for each group)
Evaluation method:
Evaluation item:
Mean blood pressure (mmHg), heart rate (measured from blood pressure waveform (beats / minute)), QTc (ms) and toxicokinetics (TK)
Test procedure:
Guinea pigs are placed under anesthesia with urethane (1.4 g / kg, ip) and polyethylene tubes are placed in the carotid artery (for blood pressure measurement and blood sampling) and the jugular vein (for infusion of the compounds of the invention). insert. Wear electrodes subcutaneously (lead II). Blood pressure, heart rate and electrocardiogram (ECG) are measured using the PowerLab® system (AD Instruments).
Toxicokinetics:
At each evaluation time, about 0.3 mL of blood (about 150 μL as plasma) is collected from the carotid artery using a syringe containing sodium heparin and immediately cooled on ice. A plasma sample is obtained by centrifugation (4 ° C., 10,000 rpm, 9300 × g, 2 minutes). Plasma separation is performed under ice-cooling or at 4 ° C. The obtained plasma (TK sample) is stored in an ultra-low temperature chamber (set temperature: −80 ° C.).
Analysis method:
Average blood pressure and heart rate are averaged for 30 seconds at each evaluation time point. The ECG parameters (QT interval (ms) and QTc) are measured from the average waveform of 10-second continuous beats at the time of evaluation. QTc (Fredericia correction formula; QTc = QT / (RR) 1/3)) is calculated using the PowerLab (registered trademark) system. Arrhythmia development is assessed visually from all ECG records in all 4 animals from 0.5 hours prior to administration until the end of the study.
Evaluation time:
QTc data analysis pre-dosing and 10, 25, 40, 55, 70 and 85 minutes after the first dose:
Taking the pre-dose value as 100%, the change rate (%) of QTc from the pre-dose value is determined. At the same evaluation time point, the opposite QTc is compared to the vehicle control value.

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the compound according to the present invention
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsules Compound according to the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
The above components are uniformly mixed to form a powder or fine particles. The obtained mixture is filled into a capsule container.

Formulation Example 3 Granules Compound according to the present invention 30 g
Lactose 265g
Magnesium stearate 5g
The above ingredients are mixed well, compression molded, pulverized, sized and sieved to give granules of appropriate size.

Formulation Example 4: Orally disintegrating tablet The compound according to the present invention and crystalline cellulose are mixed, and tableted after granulation to obtain an orally disintegrating tablet.

Formulation Example 5: Dry syrup The compound according to the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.

Formulation Example 6: Injection The compound according to the present invention and a phosphate buffer are mixed to form an injection.

Formulation Example 7: Instillation A compound according to the present invention and a phosphate buffer are mixed to form an injection.

Formulation Example 8: Inhalant The compound according to the present invention and lactose are mixed and finely ground to obtain an inhalant.

Formulation Example 9: Ointment The compound according to the present invention and petrolatum are mixed to obtain an ointment.

Formulation Example 10: Patch The compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.

  The compound according to the present invention can be a medicament useful as a therapeutic or prophylactic agent for diseases induced by production, secretion and / or deposition of amyloid β protein.

Claims (20)

Formula (I):

(Where
X is —S— or —O—;
(I) when X is -S-
R ^3a is alkyl, haloalkyl, hydroxyalkyl or alkyloxyalkyl;
R ^2a is halogen, alkyloxy or haloalkyloxy, and when R ^3a is haloalkyl, R ^2a may be alkyl;
R ^2b is H;
R ^2a and R ^2b together with the carbon atom to which they are attached may form a substituted cycloalkane;
When R ^2a and R ^2b together with the carbon atom to which they are attached form a substituted cycloalkane, R ^3a may be H;

(Ii) when X is -O-
R ^3a is haloalkyl optionally substituted with one or more groups selected from alkyloxy and cycloalkyl, or cycloalkyl substituted with one or more groups selected from halogen;
R ^2a is H, halogen, alkyl, alkyloxy or haloalkyloxy,
R ^2b is H;
R ^2a and R ^2b together with the carbon atom to which they are attached may form a substituted cycloalkane;
When R ^2a and R ^2b together with the carbon atom to which they are attached form a substituted cycloalkane, R ^3a may be H or alkyl;

R ^3b is H or alkyl;

May be,
Ring A is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted nonaromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted nonaromatic heterocyclic ring,
Ring B is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted cycloalkyl;
R ⁵ is halogen or substituted or unsubstituted alkyl;
n is an integer from 0 to 2,
However, the following compounds are excluded.
(1) A compound wherein X is —O—, R ^3a is CH ₂ F or CF ₃ , R ^3b is H, R ^2a is H or F, and R ^2b is H,
(2) a compound wherein X is —O—, R ^3a is CHF ₂ , R ^3b is H, R ^2a is OMe and R ^2b is H, and
(3) The following compounds:

)
Or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein X in the formula (I) is -O-. The pharmaceutical composition according to claim ₂ , wherein R ^3a in formula (I) is CH ₂ F, CHF ₂ , CF ₃ , CH (F) CH ₃ or CF ₂ CH ₃ , and R ^3b is H or CH ₃ . . The pharmaceutical composition according to claim 2 or 3, wherein R ^2a in formula (I) is H, F, CH ₃ , OCH ₃ or OCH ₂ CF ₃ . The R ^2a in formula (I) is H, halogen or alkyl, R ^2b is H, and R ^3a is CHF ₂ , CH (F) CH ₃ or CF ₂ CH ₃ . Pharmaceutical composition. In formula (I), R ^2a is H or halogen, R ^2b is H, R ^3a is CH ₂ F or CF ₃ , R ^3b is alkyl, and R ¹ is unsubstituted alkyl. The pharmaceutical composition according to claim 2. The pharmaceutical composition according to claim 2 or 3, wherein R ^2a in formula (I) is alkyl, alkyloxy or haloalkyloxy. In formula (I)

The pharmaceutical composition according to claim 2, wherein R ⁵ is halogen and n is 1 or 2. The pharmaceutical composition according to claim 2 or 4, wherein in formula (I), R ^3a is a substituted haloalkyl, and the substituent is alkyloxy or cycloalkyl. In formula (I), X is —S—, R ^2a is halogen or alkyloxy, R ^2b is H, R ^3a is alkyl, haloalkyl, hydroxyalkyl or alkyloxyalkyl, and R ^3b is H The pharmaceutical composition according to claim 1, wherein The formula (I), wherein X is -S-, R ^2a is F, R ^2b is H, R ^3a is CH ₃ or CH ₂ F, and R ^3b is H. Pharmaceutical composition. The R ^2a and R ^2b in formula (I) together with the carbon atom to which they are attached form a cycloalkane substituted with halogen, and R ^3a is H or alkyl. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 12, wherein R ¹ in formula (I) is alkyl. In formula (I), ring A is

(Wherein R ⁴ is H or halogen, -Z = is -CH = or -N =)
The pharmaceutical composition according to any one of claims 1 to 13, which is The pharmaceutical composition according to claim 14, wherein R ⁴ in formula (I) is halogen and -Z = is -CH =. In formula (I), ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine or substituted or unsubstituted oxazole. A pharmaceutical composition according to any one of the above. The pharmaceutical composition according to any one of claims 1 to 16, which has BACE1 inhibitory activity. The pharmaceutical composition according to any one of claims 1 to 16, for the treatment or prevention of a disease induced by production, secretion or deposition of amyloid β protein. Treatment or prevention of Alzheimer's type dementia, mild cognitive impairment or amnestic mild cognitive impairment, Alzheimer's dementia, mild cognitive impairment or progression of amnestic mild cognitive impairment, or Alzheimer's dementia The pharmaceutical composition according to any one of claims 1 to 16, for the prevention of progression in an asymptomatic patient at risk for Alzheimer dementia. The pharmaceutical composition according to any one of claims 1 to 16, for treating or preventing Alzheimer-type dementia.