JPH1180131A - Ethynylpyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having strong thyroxine kinase blocking activities and cancer cell growth inhibiting activities, and useful as a carcinostatic agent, an immunosuppressant, a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an antiinflammatory agent, a cancer cell growth inhibitor. SOLUTION: The objective compound is the compound of formula I A and B are each nitro, (CH2 )n 'NR<3> R<4> [(n') is 0 or 1; R<3> and R<4> are each H or a (substituted) 1-5C alkyl] or the like; R<1> is H, a halogen, a (substituted) phenyl or the like; R<2> is formula II [R<3> and R<4> are each H or COR<6> (R<6> is hydroxyl, a 1-5C alkoxy or the like); R<5> is hydroxyl, a 1-5C alkyl or the like] or the like}, e.g. ethynylquinazoline. The compound of the formula I is obtained by reacting the compound having a bicyclic condensed ring with the compound obtained by reacting an aldehyde with carbon tetrabromide or the like, in an etheric solvent such as tetrahydrofuran in the presence of a base such as triethylamine, a palladium complex such as Pd(Pph3 )4 and copper (I) compound such as CuI at 20-200 deg.C for 5 min to 8 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel ethynylpyrimidine derivative. More specifically, the present invention relates to an ethynylpyrimidine derivative having tyrosine-specific protein kinase (hereinafter, tyrosine kinase) inhibitory activity.

[0002]

2. Description of the Related Art In cancer chemotherapy, drugs that inhibit DNA synthesis and drugs that inhibit cell division are often used. These drugs are generally toxic to cells, and their effects may be effective on rapidly dividing cancer cells.However, in many cases, their effects are not limited to cancer cells, so they have strong toxicity. As a result, the current situation is that side effects based on it have become a major problem.

[0003] It is well known that tyrosine kinases play a central role in cell differentiation / proliferation and intracellular signal transduction mechanisms. Therefore, disruption of the regulation of intracellular tyrosine kinase activity leads to abnormalities in cell differentiation and proliferation mechanisms and cell signaling mechanisms, and is considered to be directly involved in the development of many diseases. For example, arteriosclerosis (Am.
J. Physiol. 1991, 260 (4-part
1), C721-C730. ); Biochem. Bi
ophys. Res. Commun. 1993, 192
(3), 1319-1326. Etc.), platelet aggregation (FE
BS Letters. 1990, 263 (1), 10
4-108. FEBS Letters. 1992,
309 (1), 10-14. Etc.), immune abnormalities (FEBS)
Letters. 1991, 279 (2), 319-
322. J Immunol. 1991, 146
(9), 2965-2971. Nature, 199;
2,358,253-255. Etc.), psoriasis (J. Inv.
est. Deruatol. 1990, 95, 75-9
5); Inflammation (Molecular Pharmacol)
ogy. 1990, 37, 519-525. ; Inte
rational Immunology. 199
2,4 (4), 447-453. Etc.). It is also known that tyrosine kinase activity is more frequently detected in tumor cells than in normal cells (Cel).
1, 1987, 50, 823). Above all, HER2, E
Growth factor receptor tyrosine kinases such as GF receptor have been shown to be significantly involved in cancer formation. (Cancer Res. 1991, 51, 4430)
-4435; Cancer Res. 1992, 52,
3636-3641. ; Cancer Chemoth
er. Pharmacol. 1993, 32, 1-1
9. etc). In addition, HER in many tumors such as brain, lung, gastrointestinal, head and neck, bladder, prostate, ovary, esophagus, uterus, etc.
2. It has also been shown that the tyrosine kinase of the EGF receptor is overexpressed (Med. Bull., 1).
991, 47, 87; Expert. Opin. Inv
est. Drugs, 1994, 3 (6), 577-5.
95; JP-A-5-208911). The involvement of the EGF receptor has also been shown in angiogenesis closely related to cancer metastasis (J. Biol. Chem. 1995, 12).
9, 895-898; Cancer Res. 199
5, 55, 3772-3776). Therefore, a drug that inhibits tyrosine kinase activity has a new mechanism of action, in addition to the prevention and treatment of the above-mentioned tyrosine kinase-related diseases such as arteriosclerosis, and has few side effects that can be applied to many cancer types. It is considered to be useful as an anticancer agent.

[0004] Conventional tyrosine kinase inhibitors include, for example, Erbstatin,
Lavendustin, Herbimycin A, Genistein, Benzylidenemalononitrile derivative (JP-A-2-138238), α-cyanocinnamic amide derivative (JP-A-62-39523), 3,5-diisopropyl-4-hydroxystyrene derivatives (JP-A-62-39522),
t-butyl-4-hydroxystyrene derivative (JP-A-6
2-39523) and the like, and recently,
Diallylamine compounds (Exp. Opin. Ther. Patent) represented by quinazoline derivatives (JP-A-6-73025 and JP-A-5-208911).
s, 1995, 5 (12), 1245-57; ibi.
d, 805-817).

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that an ethynylpyrimidine derivative having a specific structure has potent tyrosine kinase inhibitory activity and cancer cell growth inhibitory activity, and has reached the present invention. . That is, the gist of the present invention is to provide an ethynylpyrimidine derivative represented by the following general formula (I), a hydrate thereof, a pharmacologically acceptable salt, an optically active form, a racemic mixture, and a diastereomer mixture (hereinafter, referred to as a mixture). , "Ethynylpyrimidine derivative of the present invention"),

[0006]

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[However, in the above general formula (I), A and B each independently represent (1) a nitro group; (2)-(CH ₂ ) _{n ′}
NR ³ R ⁴ (wherein, n ′ represents 0 or 1, and R ³ , R
⁴ represents each independently (a) a hydrogen atom; or (b) a carboxyl group or a C ₁ -C ₅ alkyl group optionally substituted with a C ₁ -C ₅ alkoxycarbonyl group); B together form a ring,
(3)

[0008]

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Wherein X ^{1 to} X ⁴ are each independently (a) a hydrogen atom, (b) a halogen atom, (c) a nitro group, (d) —OR ′ (where R ′ is (i) ) 1 oxygen atom
A cycloalkyl group or (ii) C ₁ ~C ₅ alkoxy group, an alkyl group optionally C ₁ -C ₅ optionally substituted with an amino group or a morpholino group, a number include optionally C ₃ be not -C ₈ ), (e) C ₁ ~C or an alkyl group substituted with an amino group which may be a _5, or (f) adjacent substituents together form a ring, the C ₁ -C ₅ (Representing an oxyalkylene group); (4)

[0010]

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(Wherein X ^{5 to} X ⁷ each independently represent a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group or an amino group which may be substituted by a C _{1 to} C ₅ alkyl group) Represents); (5)

[0012]

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(Wherein X ^{8 to} X ¹⁰ each independently represent a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group or a C ₁ -C ₅ alkyl group which may be substituted with an amino group. Represents); (6)

[0014]

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(Wherein X ¹¹ and X ¹² represent a hydrogen atom; or a C ₁ -C ₅ alkyl group);

[0016]

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Wherein W represents a nitrogen atom or C—X ¹⁵ (wherein X ¹⁵ represents a hydrogen atom or a C ₁ -C ₅ alkyl group), and X ¹³ and X ¹⁴ represent a hydrogen atom or C _{1 to} C
₅ represents an alkyl group]; (8)

[0018]

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Wherein X ¹⁶ and X ¹⁷ represent a hydrogen atom or a C ₁ -C ₅ alkyl group, and R ¹ is (1)
Hydrogen atom; (2) a halogen atom; (3) a phenyl group optionally substituted by a halogen atom; (4) an alkyl group optionally C ₁ -C ₅ substituted phenyl group; (5)
Alkoxy groups of the carboxyl group or C ₁ -C ₅ alkoxycarbonyl which may be substituted with a group C ₁ ~C _5; (6) a hydroxyl group; or (7) C ₁ alkyl or C ₁ ~ of -C ₅ R ² represents an amino group which may be substituted with a C ₅ alkanoyl group;

[0020]

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Wherein R ³ and R ⁴ are each independently
(A) hydrogen atom; (b) a halogen atom, a pyridyl group, an alkyl group of a pyridazinyl group or a C ₃ -C ₈ cycloalkyl group C ₁ may be substituted with -C _5,;
(C) —COR ⁶ (wherein R ⁶ is (i) a hydroxyl group; (ii) a C ₁ -C ₅ alkoxy group; (iii) C ₁ -C
_An amino group optionally substituted with ₅ alkyl groups; or (iv) a phenyl group optionally substituted with a halogen atom or a C ₁ -C ₅ alkoxy group);

[0022]

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(Where j represents 0, 1, 2 or 3;
Z ¹ , Z ² and Z ³ are each independently: (i) a hydrogen atom; (ii) a halogen atom; (iii) a hydroxyl group;
v) an alkoxy group having C ₁ -C _5; or (v) C ₁ -C
₅ represents an alkoxycarbonyl group); or R ³ ,
R ⁴ is forms a ring together, (e) (i) alkyl groups of C ₁ -C _{5 or, (ii) - (CH 2} ) n "R 20 ( wherein,
n "is 0, 1 or 2, R ²⁰ is either a carboxyl group or a carboxyl group or a C ₁ -C ₅ alkoxycarbonyl C ₃ optionally substituted by a group -C
_An amino group which may be substituted with (f) a cycloalkyl group of ₈ );

[0024]

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Wherein R ²¹ is a carboxyl group or C ₁
An alkoxycarbonyl group ~C _5); (g)

[0026]

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(Where k represents 1, 2, 3 or 4;
R ⁷ is (i) a hydroxyl group; represents a or (iii) an alkoxy group having _{C 1 ~C 5);; (} ii) a hydroxyl group or a C ₁ -C ₅ alkyl amino group which may be substituted with group (h )

[0028]

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(I)

[0030]

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(J)

[0032]

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Or (k)

[0034]

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Represents R ⁵ is (a) a hydroxyl group;
(B) an alkyl group of C ₁ ~C _5; (c) an alkoxycarbonyl group having C ₁ ~C _5; (d) alkanoyloxy groups C ₁ ~C _5; (e) a carboxyl group; (f)

[0036]

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[Wherein m represents 0 or 1, n is 0,
1, 2, or 3, wherein E is (i) an oxygen atom; (ii)-
NHSO ₂ —; (iii) —NHCO—; or (iv) —N
R ⁷ - (wherein, R ⁷ is 1) a hydrogen atom; 2) alkyl groups of C ₁ -C _5; or 3) a hydroxyl group, a carboxyl group, or a substituted alkoxycarbonyl group of C ₁ -C ₅ Represents a C ₁ -C ₅ alkyl group)
Wherein Y ¹ , Y ² and Y ³ are each independently (i)
(Ii) halogen atom; (iii) hydroxyl group; (iv) C ₁ -C ₅ alkyl group; or (v) C ₁
An alkoxy group -C _5]; (g) -O- (CO)
During _p -G-COR ⁸ [wherein, p is 0 or 1, G is (i) an alkylene group having a hydroxyl group or optionally substituted with acetoxy group C ₁ -C _5; or (ii)

[0038]

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Wherein R ⁸ is (i) a hydroxyl group;
(Ii) an alkoxy group having C ₁ -C _5; or (iii) C ₁ ~
Represents an alkyl group substituted with an amino group which may be the C _5]; ⁹ R ¹⁰ {wherein ^{(h) -NR, R 9,} R 10 are each independently, (i) a hydrogen atom; (ii) cycloalkyl group (iii) C ₁ ~C ₅ alkoxy optionally substituted by a carbonyl group _{C 3 ~C 8; C 1 ~C} 5 alkyl group;
Or (iv)-(CO) _q -L- (CO) _r R ^{11 wherein} q and r represent 0 or 1, and L is 1) which may be substituted with a hydroxyl group or an acetoxy group;
A C ₁ -C ₅ alkylene group which may be via an oxygen atom; or 2) a C ₃ -C ₈ cycloalkylene group, wherein R ¹¹ is 1) a hydroxyl group; 2) a C ₁ -C ₂₀ alkoxy group. ; ¹² R ¹³ (wherein or 4) -NR, R ¹² is a) a hydrogen atom; 3) pivaloyloxymethoxy group b) a hydroxyl group; an alkyl group or c) C ₁ ~C _5, R ¹³ is a) a hydrogen atom; b) C which may be substituted with a phenyl group, a carboxyl group or a hydroxyl group
Alkoxycarbonyl group c) C ₁ ~C _7;; alkyl group ₁ -C ₅ d) a cyano group; e) phenyl or C
₁ -C ₅ carbamoyl group which may be substituted by an alkyl group; f) optionally a sulfonyl group which may be substituted with an alkyl group having a phenyl group or a C ₁ -C _5; or g) C
Or represents represents)] alkanoyl group ₁ -C _5, or R ^9, R ¹⁰ are taken together to form a ring, (v)

[0040]

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Wherein t and u represent 0, 1 or 2; R ¹⁴ represents 1) a hydroxyl group; 2) a C ₁ -C ₂₀ alkoxy group; 3) a pivaloyloxymethoxy group; N
(Wherein, R ¹⁵ is a) R ¹⁵ R ¹⁶ a hydrogen atom; b) a hydroxyl group; an alkyl group or _{c) C 1 ~C 5, R} 16
Is a) a hydrogen atom; b) C ₁ optionally substituted with a phenyl group, a carboxyl group and / or a hydroxyl group.
It represents a or c) a cyano group)]; alkyl -C _5;
(Vi)

[0042]

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[Wherein, s represents 0, 1, or 2;
¹⁷ is 1) a hydroxyl group; 2) a C ₁ -C ₂₀ alkoxy group; 3) a pivaloyloxymethoxy group; or 4) an amino group optionally substituted with a hydroxyl group or a C ₁ -C ₅ alkyl group. Represents>) represents｝, or represents (2)

[0044]

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(Where CyA represents a benzene ring, a pyridine ring, or a pyrrole ring, Q represents a phenyl group optionally substituted with a halogen atom, V is (1) a hydrogen atom, (2) C ₁ alkoxycarbonyl group -C _5,
(3) carboxyl represents group or a (4) represents a C ₁ -C ₅ alkoxycarbonyl group C ₁ or may be substituted with a carboxyl group -C ₅ alkyl group),];
A pharmaceutical composition comprising these compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention is a prophylactic and / or therapeutic agent for a disease caused by enhanced tyrosine kinase activity, specifically, an anticancer agent, an immunosuppressant,
It is used as a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, and a cancer cell growth inhibitor. Hereinafter, in the present invention, these are also simply referred to as “tyrosine kinase inhibitors”.

[0046]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The compound of the present invention is an ethynylpyrimidine derivative represented by the general formula (I). In the general formula (I),
Examples of the defined halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the C ₁ -C ₅ alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, neopentyl group and the like. Examples of the C ₁ -C ₅ alkoxy group include a methoxy group, an ethoxy group, and an n-butyl group. −
Propoxy group, iso-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, ter
Examples thereof include a t-butoxy group, an n-pentyloxy group, and a neopentyloxy group. Examples of the C ₁ -C ₅ alkanoyl group include a formyl group, an acetyl group, a propionyl group,
Butyryl, isobutyryl, valeryl and the like.

The ethynylpyrimidine derivative of the present invention represented by the above general formula (I) is converted into a salt with a corresponding acid or base by a known method. Salts that can be formed include, for example, inorganic acid salts such as hydrochloride, sulfate, carbonate, and phosphate, or formate, acetate, propionate, lactate, oxalate, fumarate, and maleate. Acid salts,
Examples include salts of organic acids such as citrate, tartrate, benzoate, phthalate, methanesulfonate, 4-toluenesulfonic acid, isethionate, glucuronate, and gluconate. When the ethynylpyrimidine derivative has an acidic group such as a carboxylic acid, a salt of an alkali metal such as a sodium salt or a potassium salt, a salt of an alkaline earth metal such as a magnesium salt or a calcium salt, or an ammonium salt or a drug. Physically acceptable organic amines (tetramethylammonium, triethylamine, cyclohexylamine, benzylamine, phenethylamine, monoethanolamine, diethanolamine, tris (hydroxyethyl) amine, lysine, arginine, N-methyl-D
-Glucamine and the like). When the ethynylpyrimidine derivative has a tertiary amino group and / or a pyridyl group, an ammonium salt and a pyridinium salt may be formed, respectively.

The ethynylpyrimidine derivative of the present invention can also form a hydrate. Hereinafter, specific examples of the present invention will be described. Hereinafter, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Ph represents a phenyl group.

[0049]

[Table 1]

[0050]

[Table 2]

[0051]

[Table 3]

[0052]

[Table 4]

[0053]

[Table 5]

[0054]

[Table 6]

[0055]

[Table 7]

[0056]

[Table 8]

[0057]

[Table 9]

[0058]

[Table 10]

[0059]

[Table 11]

[0060]

[Table 12]

[0061]

[Table 13]

[0062]

[Table 14]

[0063]

[Table 15]

[0064]

[Table 16]

[0065]

[Table 17]

[0066]

[Table 18]

[0067]

[Table 19]

[0068]

[Table 20]

[0069]

[Table 21]

[0070]

[Table 22]

[0071]

[Table 23]

[0072]

[Table 24]

[0073]

[Table 25]

[0074]

[Table 26]

[0075]

[Table 27]

[0076]

[Table 28]

[0077]

[Table 29]

[0078]

[Table 30]

[0079]

[Table 31]

[0080]

[Table 32]

[0081]

[Table 33]

[0082]

[Table 34]

[0083]

[Table 35]

[0084]

[Table 36]

[0085]

[Table 37]

[0086]

[Table 38]

[0087]

[Table 39]

[0088]

[Table 40]

[0089]

[Table 41]

[0090]

[Table 42]

[0091]

[Table 43]

[0092]

[Table 44]

[0093]

[Table 45]

[0094]

[Table 46]

[0095]

[Table 47]

[0096]

[Table 48]

[0097]

[Table 49]

[0098]

[Table 50]

[0099]

[Table 51]

[0100]

[Table 52]

[0101]

[Table 53]

[0102]

[Table 54]

[0103]

[Table 55]

[0104]

[Table 56]

[0105]

[Table 57]

[0106]

[Table 58]

[0107]

[Table 59]

[0108]

[Table 60]

[0109]

[Table 61]

[0110]

[Table 62]

[0111]

[Table 63]

[0112]

[Table 64]

[0113]

[Table 65]

[0114]

[Table 66]

[0115]

[Table 67]

[0116]

[Table 68]

[0117]

[Table 69]

[0118]

[Table 70]

[0119]

[Table 71]

[0120]

[Table 72]

[0121]

[Table 73]

[0122]

[Table 74]

[0123]

[Table 75]

[0124]

[Table 76]

[0125]

[Table 77]

[0126]

[Table 78]

[0127]

[Table 79]

[0128]

[Table 80]

[0129]

[Table 81]

[0130]

[Table 82]

[0131]

[Table 83]

[0132]

[Table 84]

[0133]

[Table 85]

[0134]

[Table 86]

[0135]

[Table 87]

[0136]

[Table 88]

[0137]

[Table 89]

[0138]

[Table 90]

[0139]

[Table 91]

[0140]

[Table 92]

[0141]

[Table 93]

[0142]

[Table 94]

[0143]

[Table 95]

[0144]

[Table 96]

[0145]

[Table 97]

[0146]

[Table 98]

[0147]

[Table 99]

[0148]

[Table 100]

[0149]

[Table 101]

[0150]

[Table 102]

[0151]

[Table 103]

[0152]

[Table 104]

[0153]

[Table 105]

[0154]

[Table 106]

[0155]

[Table 107]

[0156]

[Table 108]

[0157]

[Table 109]

[0158]

[Table 110]

[0159]

[Table 111]

[0160]

[Table 112]

[0161]

[Table 113]

[0162]

[Table 114]

[0163]

[Table 115]

[0164]

[Table 116]

[0165]

[Table 117]

[0166]

[Table 118]

[0167]

[Table 119]

[0168]

[Table 120]

[0169]

[Table 121]

[0170]

[Table 122]

[0171]

[Table 123]

[0172]

[Table 124]

[0173]

[Table 125]

[0174]

[Table 126]

[0175]

[Table 127]

[0176]

[Table 128]

[0177]

[Table 129]

Method for Producing the Compound of the Present Invention 1) Among the compounds represented by the above general formula (I), R ¹ is a hydrogen atom; a chlorine atom, a bromine atom; C ₁ -C optionally substituted by a phenyl group. Method for producing compound representing alkyl group ₅ ; unsubstituted amino group; phenyl group which may be substituted with a halogen atom The compound can be produced, for example, by a route such as Scheme 1.

[0179]

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[0180] (wherein, LG represents a leaving group such as a chlorine atom, p-toluenesulfonyl group, R ^1a is R ¹ defined previously
Of these, a hydrogen atom, a chlorine atom, a bromine atom, an amino group, a C ₁ -C ₅ alkyl group which may be substituted with a phenyl group, and a phenyl group which may be substituted with a halogen atom. A, B and R ² are as previously defined. Me represents a metal atom group such as lithium, magnesium halide, and trialkyltin. That is, compound II and compound III are converted to an ether solvent such as tetrahydrofuran or diethyl ether, benzene,
Hydrocarbon solvents such as toluene, dimethylformamide,
In an aprotic solvent such as dimethyl sulfoxide or a mixed solvent thereof, 1 to 10 equivalents of a base such as triethylamine, diethylamine, pyridine, 0.001 to
0.5 equivalents of Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh
₃ ) Reaction at + 20 ° C. to + 200 ° C. for 5 minutes to 48 hours in the presence or absence of a palladium complex such as ₂ or a copper (I) compound such as 0.001 to 0.5 equivalents of CuI or CuCl. Can produce compound I. At this time, instead of compound III, compound III is prepared by reacting an organometallic compound such as butyllithium or ethylmagnesium bromide in an ether solvent such as tetrahydrofuran or diethyl ether or a hydrocarbon solvent such as benzene or toluene. Acetylide III '(Met = lithium, magnesium halide) or a triacetyltin chloride compound or a trialkoxyboron compound, which can be adjusted to obtain III' @ Met = SnR ₃ , B
(OR) ₂ } (R represents a lower alkyl group or a hydrogen atom) can also be used. Compound II can be produced according to its structure as follows (Scheme 2-
4).

[0181]

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(Wherein R ^1b represents a hydrogen atom, a C ₁ -C ₅ alkyl group optionally substituted with a phenyl group, an amino group,
A hydroxyl group, a phenyl group optionally substituted with a halogen atom, and R ^1c represents a hydrogen atom, a C _{1 to} C ₅ alkanoyl group optionally substituted with a phenyl group, or a phenyl group optionally substituted with a halogen atom. Represents a good benzoyl group,
R ′ represents a hydroxyl group or a lower alkoxy group,
R ″ represents CN or CONH ₂ ) a) Compound II is a bicyclic fused ring (excluding a pteridine ring, that is, A and B together form a ring,

[0183]

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Compound II is obtained by converting the corresponding precursor IV into a hydrocarbon solvent such as benzene or toluene, a halogenated hydrocarbon such as dichloromethane or chloroform, or a suitable solvent such as dimethylformamide. Or in the absence or presence of 1 to 10 equivalents of a base such as diethylaniline or pyridine in the absence or presence of a solvent at + 20 ° C. with phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus oxybromide, or a suitable mixture thereof; +200
５II (R ^1a = Cl, Br) and IV (R
^1b = OH). In the case where a compound in which LG represents a paratoluenesulfonyl group, a methanesulfonyl group, or a trifluoromethanesulfonyl group among the compound II is required, the corresponding IV is represented by a base such as pyridine in an appropriate solvent such as tetrahydrofuran, toluene, or dimethylformamide. It can be produced by reacting paratoluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride and the like.

Further, in compound IV, R ^1b is a hydrogen atom,
In the case of a compound representing a C ₁ -C ₅ alkyl group which may be substituted with a phenyl group or a phenyl group which may be substituted with a halogen atom, the amino acid V (R ′ ＝ OH) or its ester V (R ′ = Lower alkoxy group) and the corresponding amide (R ^1b -CONH ₂ ), thioamide (R ^1b -C
SNH ₂ ) in an appropriate solvent, or without solvent or using a reactant as a solvent, at a temperature of + 20 ° C. to + 250 ° C. for 5 minutes to 48 hours, or an amide V (R
ＮＨNH ₂ ) and the ester {R ^1b —CO ₂ R as a reactant
(R = lower alkyl)} or orthoester {R ^1b −
+ 20 ° C. in C (OR ′) ₃ (R ′ = lower alkyl group)} and an appropriate solvent or using a reactant as a solvent
It can be produced by a method of reacting at a temperature of ~ 250C for 5 minutes to 48 hours. Furthermore, the corresponding aminonitrile VI (R ″
= CN) in the presence of an alkali such as an aqueous solution of sodium hydroxide in the presence of 0.1 to 5 equivalents of hydrogen peroxide at + 20 ° C to + 250 ° C.
Compound IV by reacting at a temperature of 5 ° C. for 5 minutes to 48 hours.
Can be manufactured. A method in which aminonitrile VI (R ^1c = H), formic acid and a mixed acid anhydride which can be adjusted from a suitable acid anhydride such as acetic anhydride at a temperature of + 50 ° C. to + 200 ° C. for 5 minutes to 48 hours is also used. (R ^1b = H). When R ^1b represents an amino group among the compounds IV, the ester form (V; R ′ = lower alkoxy group) is converted to 0.5 to 100 equivalents of cyanamide (H ₂ NCN) in a suitable solvent such as methanol or ethanol. + 20 ° C to + 150 ° C
At a temperature of 5 minutes to 48 hours. Further, in the case of compound IV in which R ^1b represents an amino group or a hydroxyl group, as shown in scheme 2 ′, V (R ′ = OH) is hydroxylated in an appropriate solvent such as benzene, dichloromethane and water. It can also be produced by reacting phosgene and triphosgene in the presence of a base such as sodium aqueous solution and triethylamine to obtain V ', and then reacting with urea and a guanidine salt, respectively.

B) When compound II represents a pyrimidine monocyclic ring, that is, in compound II, A and B represent-(CH ₂ ) _{n '} NR ³ R ⁴
Wherein n ′, R ³ and R ⁴ are as defined above,
Or a compound represented by a nitro group. Compound II is prepared by dissolving Compound VII in a suitable solvent such as water, methanol, toluene or diethyl ether in an amount of 0.1 to 10 equivalents of H (CH ₂ ) _{n ′} NR ³ R ⁴ (formula Where n ′, R ³ and R
⁴ as defined above) and 5 at a temperature between 0 ° C. and + 150 ° C.
Minutes to 48 or a method of hours, where the resulting compound _{VIII (A = - (CH 2} ) n 'NR 3 R 4) water, methanol, toluene, a suitable solvent, such as dimethylformamide, zinc, iron, etc. + 20 ° C to + 200 ° C using a reducing agent of
At a temperature of 5 minutes to 48 hours. If necessary, compound VIII can be prepared by nitrating compound IX with concentrated sulfuric acid and fuming nitric acid (Sche
me3).

[0187]

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(Wherein R ^1a and A have the same meanings as described above) c) Compound II forms a pteridine ring, ie, A and B together form a ring,

[0189]

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(Scheme 4) Compound II (A = B = NH ₂ ) which can be produced in b) is converted to an alcohol solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene or toluene, dimethylformamide, or dimethyl sulfoxide. In the case of a pteridine ring in an aprotic solvent such as
5~10 X ¹¹ COCOX ¹² (wherein, X ^11, X ¹² is as already defined) in equivalents), can be prepared by a method of reacting 48 hours 5 minutes at a temperature of + 20 ℃ ~ + 200 ℃. Similarly, in the case of a purine ring, a compound II (A)
= B = NH ₂ ) and X ¹³ CO ₂ H or X ¹³ C (OR ′)
₃ (X ¹³ , R ′ is as defined above) in the above-mentioned solvent or using the reactant as a solvent, from + 20 ° C. to + 200 ° C.
It can also be produced by a method of reacting at a temperature of 5 ° C. for 5 minutes to 48 hours. When further alkylation of the purine ring is necessary, for example, X ¹⁴ -hal in a suitable solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydride, sodium methoxide or potassium carbonate.
(X ¹⁴ is as previously defined, hal is iodine, halogen atom represents a bromine or the like) can be produced by a method for 5 minutes to 48 hours action of a temperature of 0 ℃ ~ + 200 ℃.

[0191]

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(Wherein R ^1a , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ ,
R 'has the same meaning as described above, and hal represents a halogen atom. [Production method of compound III] a) An aldehyde which can be produced by oxidizing the corresponding alcohol is converted to an aldehyde which can be prepared by adding an aldehyde to a suitable solvent such as dichloromethane, carbon tetrachloride or the like. 0.1 to 10 equivalents of carbon tetrabromide and triphenylphosphine at -20 to + 50 ° C. for 5 minutes to 48 hours, or in a solvent such as tetrahydrofuran or diethyl ether or a mixed solvent thereof, for example, (EtO) ₂ P (O) CCl ₃ and n-BuLi are converted to -15
A haloalkene can be produced by reacting a wittig reagent, which can be prepared by reacting at 0 ° C. to + 50 ° C. for 5 minutes to 48 hours, at −150 ° C. to + 100 ° C. for 5 minutes to 48 hours. This haloalkene is further added to a solvent such as tetrahydrofuran and diethyl ether or a mixed solvent thereof,
For example, an organic lithium compound such as n-BuLi is
The compound III can be produced by reacting at a temperature of from + 100 ° C to + 100 ° C for from 5 minutes to 48 hours. This conversion can also be carried out by protecting the functional group present in the compound if necessary (sc
heme5).

[0193]

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[0194] (wherein, either X ^18, X ¹⁹ represents a simultaneous bromine atom, or one represents a chlorine atom, one represents a hydrogen atom, R ² represents the same meaning) b) R ⁵ is In particular, when it represents an amino group, an anilino group, a phenoxy group, an alkoxy group, or an alkanoyloxy group (all may be substituted). In addition to the above method a), it can also be manufactured by the method shown in scheme 6. That is, an ethynylating agent such as ethynylmagnesium halide, lithium trimethylsilylacetylide, or an ethynylcerium compound that can be prepared by reacting these with CeCl _{3 in a} corresponding ketone in a solvent such as tetrahydrofuran, diethyl ether, toluene, hexane, or a mixed solvent thereof. -100 ° C to +1
An acylating agent such as an acid anhydride or an acid chloride can be prepared by reacting an alcohol IIIa, which can be produced by reacting at 00 ° C. for 5 minutes to 48 hours, in a suitable solvent such as dichloromethane, toluene or acetonitrile in the presence of a base such as pyridine or triethylamine. Alternatively, these bases are used also as a solvent, and
By reacting at 50 ° C. for 5 minutes to 48 hours, IIIb
(X ²⁰ = alkanoyloxy group, R ¹⁸ represents a hydrogen atom or a trialkylsilyl group). IIIb (X ²⁰ and R ¹⁸ are as defined above) can also be produced by reacting an ethynylating agent with a ketone and directly capturing the alkoxide generated in the system with an acylating agent such as an acid anhydride or an acid chloride. it can. In IIIb, a compound in which R ¹⁸ represents a silyl group such as trimethylsilyl is added with an acid such as hydrochloric acid or a desilylating agent such as tetrabutylammonium fluoride or cesium fluoride in a suitable solvent such as water, methanol or tetrahydrofuran at 0 ° C. By acting at + 150 ° C. for 5 minutes to 48 hours, it can be converted to IIIb (R ¹⁸ = hydrogen atom).

Compound IIIb (X ²⁰ = alkanoyloxy group, R ¹⁸ represents a hydrogen atom) is reacted in a solvent such as tetrahydrofuran, diethyl ether, dichloromethane, toluene or acetonitrile with a catalytic amount of CuCl, CuI or copper powder. III can be prepared by reacting at 0 ° C. to + 150 ° C. for 5 minutes to 48 hours at 0 ° C. to + 150 ° C., in the presence of a copper compound, with the corresponding amine, aniline or phenol (which may be substituted).

[0196]

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(Wherein, R ¹⁸ represents a hydrogen atom, trialkylsilyl, etc., and R ³ , R ⁴ , R ⁵ , and X ²⁰ have the same meanings as described above.) C) When R ² represents a substituted phenyl group ( scheme
7) In addition to the above method a), the corresponding halobenzene is, for example, n
Aldehyde X can be produced by reacting an organometallic compound of aryllithium or arylmagnesium halide which can be prepared by the action of -BuLi, Mg or the like with, for example, N, N'-dimethylformamide or the like, wherein X is in accordance with the above method a). Thus, III can be produced. Further, for example, a coupling reaction is performed between halobenzene and trimethylsilylacetylene, 3-methyl-1-butyn-3-ol or a metal acetylide thereof in the presence of a metal catalyst such as Pd, Cu, or the like. In a suitable solvent, a base such as potassium hydroxide is added at 50 ° C to + 200 ° C.
III can also be produced by purifying terminal acetylene by reacting at 5 ° C. for 5 minutes to 48 hours.

[0198]

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2) Among the compounds represented by the above general formula (I), R ¹ is a fluorine atom, an iodine atom; a hydroxyl group; an unsubstituted phenyl group; a C ₁ -C ₅ alkyl or a C ₁ -C ₅ An amino group substituted with an alkanoyl group;
Process a) R ¹ is a hydroxyl group of a carboxyl group or a C ₁ -C ₅ alkoxycarbonyl group compound representing the optionally substituted C ₁ -C ₅ alkoxy group; an unsubstituted phenyl group; C ₁
When referring to C ₁ -C ₅ alkoxy group or unsubstituted; amino group substituted with an alkyl group -C ₅

The compound I (R) which can be produced by the above production method 1)
^1a = Cl or Br) in water, methanol, ethanol,
In a polar solvent such as dimethylformamide, in an aromatic hydrocarbon solvent such as toluene, in the presence or absence of a nitrogen-containing base such as triethylamine or diazabicycloundecene, or a base such as sodium hydroxide or sodium hydride, water or alcohols C ₁ -C ₅ or which metal salts,
Or a corresponding HNR ^1e R ^1f (wherein R ^1e and R ^1f represent a hydrogen atom, a phenyl group or a C ₁ -C ₅ alkyl group) at a temperature of 0 ° C. to + 150 ° C. for 5 minutes to 48 hours It can be manufactured by the method of causing. At this time, for example, n-Bu ₄ N
⁺ Br ^- a phase transfer catalyst may coexist, such as. Also,
Here, by reacting aqueous ammonia, compound I (R ^1a =
NH ₂ ) can also be produced.

B) When R ¹ is an amino group substituted with a C ₁ -C ₅ alkanoyl group: Compound I (R ^1a = NH ₂ ) which can be produced by the above-mentioned production method 1) or 2) -a) is converted to water, In a polar solvent such as tetrahydrofuran or dimethylformamide, in an aromatic hydrocarbon solvent such as toluene, in the presence of a nitrogen-containing base such as triethylamine or dimethylaminopyridine, or a base such as sodium hydroxide, the corresponding acid anhydride (R ^1g CO) ₂ O or acid chloride (R ^1g COCl) (in each formula, R ^1g
Represents a C ₁ -C ₅ alkyl group) at 0 ° C. to + 150 ° C.
At a temperature of 5 minutes to 48 hours.

C) When R ¹ represents a fluorine atom or an iodine atom The compound I (R ^1a = Cl or Br) which can be produced by the above production method 1) is dissolved in a polar solvent such as dimethylformamide or dimethylsulfoxide, or a compound such as toluene. In an aromatic hydrocarbon solvent, a corresponding fluorinating agent such as potassium fluoride or sodium fluoride or an iodinating agent such as potassium iodide is added at 0 ° C.
It can be produced by a method of reacting at a temperature of ~ 150C for 5 minutes to 48 hours. Compound I (R ^1a = NH ₂ ) is reacted with a iodinating agent such as potassium iodide in a polar solvent such as water or ethanol, or without solvent under the conditions of a diazotization reaction such as sodium nitrite / hydrochloric acid or acetic acid. By letting
Compound I (R ^1a = I) was converted to borofluoric acid (HB
By acting an aqueous solution of F ₄ ), compound I (R ^1a =
F) can be manufactured. In the latter case, sodium nitrite / H
A BF ₄ aqueous solution may be used.

D) R ¹ is a carboxyl group or C _1-
Compound I (R ^1a = Cl or Br) in dimethyl formamide case can be produced by the above production method 1) representing the alkoxycarbonyl-substituted C ₁ optionally -C ₅ alkoxy group group of C _5, polarity such as dimethyl sulfoxide In a solvent or an aromatic hydrocarbon solvent such as toluene, the corresponding HO— (CH ₂ ) _W —COORw
(Wherein, w represents an integer of 1 to 5, Rw represents a hydrogen atom or a C _{1 to} C ₅ alkyl group) and an alkoxide prepared from sodium hydride, potassium hydride or the like, or butyllithium or the like. It can be produced by reacting. Those in which Rw represents a C ₁ -C ₅ alkyl group can be further hydrolyzed in a suitable solvent such as methanol, water or dichloromethane by the action of a base such as sodium hydroxide or an acid such as hydrochloric acid or trifluoroacetic acid. By
Those wherein R ¹ represents a C ₁ -C ₅ alkoxy group substituted with a carboxylic acid can be prepared.

3) Method for producing compounds having ester, amide, sulfonamide and the like in the molecule among the compounds represented by the above general formula (I) As shown in the above production method 1), III (or III ′)
Is a compound having an ester, an amide, a sulfonamide or the like, and in addition to the method of performing a coupling reaction, for example, III having a corresponding alcohol, carboxylic acid, or amine is coupled according to the method of production method 1), followed by esterification, The target product can also be produced by amidation or the like.

The ethynylpyrimidine derivatives of the present invention have a tyrosine kinase inhibitory activity and a cancer cell growth inhibitory effect, and are used as anticancer agents, immunosuppressants, platelet aggregation inhibitors, therapeutic agents for arteriosclerosis, anti-inflammatory agents or cancer cell growth inhibitors. It can be used as In order to use the compound of the present invention represented by the above general formula (I) for the above purpose, it is usually administered systemically or locally in an oral or parenteral form. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like. It is usually administered orally, once to several times daily, in the range of 1 mg to 1.0 g per adult per dose, or 1 to 4 times per adult per dose.
It is administered parenterally once to several times a day in the range of mg to 5 g, or continuously intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or administration outside the range may be necessary.

When the compound of the present invention is administered, it is used as a solid composition, liquid composition and other compositions for oral administration, injection, external preparation, suppository and the like for parenteral administration. Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc., if necessary, or with two or more layers. Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable solutions, emulsions, suspensions, syrups, elixirs and the like, and commonly used inert diluents ( Purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition may contain, in addition to the inert diluent, buffers such as sodium chloride, sodium citrate, or citric acid which provide isotonicity with stabilizers such as sodium bisulfite. The method of producing the spray is described in detail in, for example, U.S. Pat. Nos. 2,868,691 and 3,095,355.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the production of a sterile solid composition, for example, dissolved in sterile water or a sterile solvent for injection before use of the freeze-dried product. Other compositions for parenteral administration include one or more active substances, topical solutions, molasses, liniments, formulated in a conventional manner.
Suppositories, pessaries and the like.

[0209]

The present invention will be described below in more detail with reference to Synthesis Examples and Examples. However, the present invention is not limited thereto without departing from the gist thereof. In the Synthesis Examples and Examples, the reactions were performed under a nitrogen atmosphere unless otherwise specified. In Examples and Synthesis Examples, solvents, reagents, substituents and the like are abbreviated as follows. Diethyl ether (ether or E
t ₂ O); tetrahydrofuran (THF); n-hexane (Hex or hexane); ethyl acetate (EtOA
c); dimethylformamide (DMF); dimethylsulfoxide (DMSO); Hexamethylphos
phoramide (HMPA); Dimethyla
minopyridine (DMAP); 1,8-Di
azacyclo [5,4,0] undec-7-
ene; 1,3-Dicyclohexylcarbo
diimide (DCC); Diisobutyral
uminhydride (DIBAL); tB
Utoxycarbonyl (Boc); acetyl group (Ac). Synthesis Example 1

[0210]

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PhC (S) NH ₂ (5.0 g, 36.4)
mmol) and anthranilic acid (5.0 g, 36.4 mm)
ol) was heated and stirred at 120 ° C. for 2 hours and at 160 ° C. for 30 minutes. Cyclohexanone (15 ml) was added to the reaction mixture and stirred at 130 ° C. for 5 minutes. After cooling to room temperature, the product 4a was collected by filtration (4.0 g, 49%). Phosphorus pentachloride (5.3 g, 25.2 mmol) and phosphorus oxychloride (4.8 ml, 51.5 mmol) were added to 4a, and 13
Stirred at 0 ° C. for 2 hours. Excess phosphorous oxychloride and low-boiling substances were removed under reduced pressure, and ice water was added little by little to the residue. The product was extracted with ethanol (100 ml × 2),
The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml × 2), and the ether extract was concentrated under reduced pressure. The residue was suspended in hexane (50 ml) and stirred while heating (hereinafter, this operation is referred to as "washing with hexane"). After the suspension was cooled to room temperature, the precipitate was collected by filtration, and the target compound, 4
-Chloro-2-phenylquinazoline (2a) (3.18
g, 72%). 2a: ¹ H NMR (250 MHz, CDCl ₃ ) δpp
m: 7.53 (m, 3H), 7.66 (dt, J = 0.
7, 7.6 Hz, 1H), 7.94 (dt, J = 1.
2,7.6 Hz, 1H), 8.10 (d, J = 1.2,
8.2 Hz, 1H), 8.58 (m, 2H). Synthesis Example 2 Aminoacetylene 3a

[0212]

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G. F. The method of Hennion et al. (JA)
m. Chem. Soc. , 1960, 82, 4908)
Manufactured according to 3a: ¹ H NMR (300 MHz, CDCl ₃ ) δp
pm: 1.08 (t, J = 7.2 Hz, 6H), 1.4
0 (s, 6H), 2.21 (s, 1H), 2.66
(Q, J = 7.2 Hz, 4H). Synthesis Examples 3 and 4 Chloroquinazolines 2b and 2c were obtained in the same manner as in Synthesis Example 1.

[0214]

[Table 130]

Example 1 Ethinylquinazoline 1a

[0216]

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Aminoacetylene 3a produced in Synthesis Example 2
(500 mg, 3.59 mmol) in a THF solution (10
ml) at room temperature in EtMgBr (3.55 ml, 3.55 ml).
(mmol, 1.0 M THF solution) and refluxed for 40 minutes to prepare ethynyl Grignard. On the other hand, Pd (PPh
₃ ) ₂ Cl ₂ (21 mg, 0.03 mmol) and PPh
₃ (31 mg, 1.2 mmol) in THF (5 m
l) was stirred at room temperature for 40 minutes and 2a (480
mg, 2.00 mmol) and the above-mentioned ethynyl Grignard were added at room temperature and stirred for 3 hours. After cooling the reaction solution, water was added and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (20 ml) and EtOAc (30 ml) were added to the residue, and the organic layer was separated. After drying the organic layer over Na ₂ SO ₄ , the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography to obtain a coupling product 1a (700 mg, quantitative). 1a: ¹ H NMR (300 MHz, CDCl ₃ ) δpp
m: 1.19 (t, J = 7.2 Hz, 6H), 1.64
(S, 6H), 2.88 (q, J = 7.2 Hz, 4
H), 7.40-7.60 (m, 3H), 7.61
(M, 1H), 7.88 (m, 1H), 8.06 (m, 1H)
1H), 8.27 (m, 1H), 8.60 (m, 2
H). Example 2

[0218]

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The 1a obtained in Example 1 (140 mg,
0.4 mmol) was dissolved in Et ₂ O (2 ml) and stirred in an ice bath with a 4N HCl / EtOAc solution (0.1 ml).
ml, 0.4 mmol) was slowly added dropwise. After warming to room temperature, the product was collected by filtration, dried, and hydrochloride of 1a (1a.
HCl) as white powder crystals (70 mg, 46%). 1a · HCl: ¹ H NMR (300 MHz, CDC
l ₃ ) δ ppm: 1.66 (m, 6H), 2.18
(M, 6H), 3.43 (brs, 2H), 3.66.
(Br s, 2H), 7.50-7.60 (m, 3
H), 7.69 (m, 1H), 7.95 (m, 1H),
8.10-8.25 (m, 2H), 8.60 (m, 2
H), 12.6 (brs, 1H); IR (KBr) νcm ^-1 ; 3449, 2986, 241
5,2236,1613,1562,1534,148
7,1022,768,706; mp 165-168C

Examples 3 to 6 The chloroquinazolines 2a to 2c prepared in Synthesis Examples 1 to 4 and the aminoacetylenes 3a and 3b (the method for preparing 3b is described in Synthesis Example 8).
And the same procedures as in Examples 1 and 2 were used to produce the target compound. The structure, yield and physical properties are shown below.

[0221]

[Table 131]

[0222]

[Table 132]

Synthesis Example 5 4-Chloroquinazoline (2d) 1)

[0224]

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Anthranilic acid (11.45 g, 83.5
mmol) and formamide (8.5 ml) in 135
The mixture was stirred at 2 ° C. for 2 hours, cooled, and the precipitate was collected by filtration. After washing with acetone, the precipitate was collected by filtration to obtain the desired product, quinazolin-4-one (4d) (4.06 g, 33%). 4d: ¹ H NMR (DMSO-d, 250 MHz) δp
pm: 7.50 (t, J = 7.5 Hz, 1H), 7.6
5 (d, J = 8.1 Hz, 1H), 7.80 (m, 1
H), 8.09 (s, 1H), 8.10 (d, J = 8.
2Hz, 1H), 12.25 (brs, 1H). 2)

[0226]

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The quinazolin-4-one (4d) (4.
15 g (28.4 mmol) in PCl ₅ (5.9 g, 2
8.4 mmol) and POCl ₃ (30 ml).
Refluxed for hours. Under reduced pressure, excess POCl ₃ and low-boiling substances were distilled off, and then CHCl ₃ (50 m
l) and saturated aqueous NaHCO ₃ (50 ml) were added. The CHCl ₃ layer was dried (Na ₂ CO ₃ ), concentrated, washed with hexane, and the precipitate was collected by filtration to obtain chloroquinazoline (2d) (4.01 g, 86%). 2c: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 7.73 (m, 1H), 7.96 (m, 1H),
8.07 (d, J = 8.4 Hz, 1H), 8.27
(D, J = 8.4 Hz, 1H), 9.05 (s, 1
H). Synthesis Example 6

[0228]

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The method reported by Johannsen et al. (Chimica Scripta, 1986, 26,
347-351)
ylfuro [2,3-d] pyrimidin-4
POCl ₃ (4 ml) was added to (3H) -one (1.08 g, 6.62 mmol) and the mixture was refluxed. Under reduced pressure, excess POCl ₃ and low boilers were distilled off, and the residue was washed with CHCl 3.
₃ (15 ml). While stirring on an ice bath, 28% aqueous ammonia was added until the liquid phase became alkaline.
Extract with CHCl ₃ (20 ml × 2) and dry (Na ₂ S
O ₄ ) and concentrated to give 2e (960 mg, 79
%) As a pale yellow solid. 2e: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 2.34 (s, 3H), 2.45 (s, 3H),
8.63 (s, 1H). Synthesis Example 7 Acetate 5

[0230]

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0.5M ethynylmagnesium chloride T
The HF solution (500 ml, 0.25 mol) was cooled with ice and the phenylacetone (30.0 g, 0.224 mol) T
An HF solution (20 ml) was added dropwise. After stirring for 1.5 hours, acetic anhydride (30 ml, 0.316 mol) was added dropwise and stirred for 1 hour. After the reaction solution was concentrated under reduced pressure, a saturated aqueous solution of ammonium chloride (500 ml) was poured. After the reaction mixture was extracted with ether (300 ml × 1, 100 ml × 1), the organic layer was washed with a saturated aqueous solution of NaHCO ₃ and saturated saline in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (silica 250 g, hexane → hexane: Et)
OAc = 8: 1) and purified by acetate 5 (39.34).
g, 87%).

5: ¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 1.64 (s, 3H), 2.38 (s,
3H), 2.60 (s, 1H), 3.19 (d, J = 1
3.5 Hz, 1 H), 3.25 (d, J = 13.5 H)
z, 1H), 7.27-7.30 (m, 5H). Synthesis Example 8 Aminoacetylene 3b

[0233]

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Acetate 5 produced in Synthesis Example 7 (1.3
9g, 6.86mmol), CuCl (47mg, 0.
47 mmol) and Et ₂ NH (1.67 ml, 1
(6.1 mmol) in THF (15 ml) was refluxed for 1 hour. The solvent was distilled off under reduced pressure, ether (10 ml) was added, and the mixture was extracted with a 3N aqueous HCl solution (10 ml × 2). The extract is stirred on an ice bath and K ₂ until the aqueous layer is alkaline.
CO ₃ was added in small portions and the product was washed with CH ₂ Cl ₂ (10 m
l) Subsequent extraction with EtOAc (20 ml). The organic layer was washed with 10% aqueous ammonia (15 ml) and then dried (N
a ₂ SO ₄ ), concentrated, and the resulting residue was purified by silica gel column chromatography (silica 15 g, hexane: EtOAc = 9: 1) to give the desired product 3b (0.
(35 g, 24%) as an oil.

3b: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 1.13 (t, J = 7.2 Hz, 6
H), 1.25 (s, 3H), 2.29 (s, 1H),
2.75 (d, J = 13.0 Hz, 1H), 2.78
(Q, J = 7.2 Hz, 4H), 3.10 (d, J = 1
3.0 Hz, 1 H), 7.15-7.35 (m, 5
H). Synthesis Example 9 Aminoacetylene 3c

[0236]

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Using benzylacetone as a starting material,
The same operation as in Synthesis Examples 7 and 8 was performed to obtain 3c (yield: 22
%) As an oil. 3c: ¹ H NMR (300 MHz, CDCl ₃ ) δpp
m: 1.09 (t, J = 7.2 Hz, 6H), 1.42
(S, 3H), 1.84-2.40 (m, 2H), 2.
72 (s, 1H), 2.60-2.84 (m, 6H),
7.13-7.35 (m, 5H). Synthesis Examples 10 and 11 Anilinoacetylene 3d, 3e

[0238]

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R.I. S. Hansel et al. (JA)
m. Chem. Soc. , 1960, 82, 4908)
Respectively. 3d: ¹ H NMR (250 MHz, CDCl ₃ ) δpp
m: 1.40 (s, 6H), 2.39 (s, 1H),
2.85 (s, 3H), 7.14 (m, 1H), 7.2
2-7.40 (m, 4H). 3e: ¹ H NMR (300 MHz, CDCl ₃ ) δpp
m: 1.61 (s, 6H), 2.35 (s, 1H),
6.79 (t, J = 7.4 Hz, 1H), 6.94
(D, J = 7.7 Hz, 2H), 7.19 (m, 2
H). Synthesis Example 12 Aminoacetylene 3f

[0240]

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1) Diethylamino- (3-p
Concentrated hydrochloric acid was added little by little to (yridyl) -acetonitrile Et ₂ NH (7.2 g, 98.6 mmol) to neutralize, and 3-pyridinecarbo
xaldehyde (7.1 ml, 75.0 mmol)
Was added. An aqueous solution (15 ml) of KCN (4.88 g)
Was added, and the mixture was refluxed for 3 hours. Then, water (30 ml) was added, and the mixture was extracted with ether (50 ml × 1, 20 ml × 1). The organic layer was washed with water (30 ml × 2) and a saturated saline solution (30 ml), dried (Na ₂ SO ₄ ), concentrated and concentrated in Diethyla.
mino- (3-pyridyl) -acetonit
rifle (12.55 g, 88%) was obtained. 2) Diethylamino- (3-pyridy
l) -acetonitrile (888 mg, 4.6
9 mmol) of THF (15 ml) -HMPA (5 m
l) Cool the solution to -68 ° C and add 1.0M Lite
ium bis (trimethylsilyl) a
mid (7.0 ml, 7.0 mmol) was added slowly. After stirring at this temperature for 45 minutes, benzyl bromide (0.67 ml, 5.63 mmol) was added dropwise, and the reaction solution was gradually warmed to room temperature. After stopping the reaction by adding water, the reaction mixture was concentrated and extracted with ether (50 ml). The extract was washed with water (40 ml × 2) and dried (Na
₂ SO ₄ ) and concentrated. The residue (1.90 g) was stirred on an ice bath while stirring 0.5M ethynyl magnesium bromide TH.
An F solution (36.5 ml, 18.3 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was ice-cooled, the reaction was stopped by adding water, and the mixture was concentrated and ether (50 ml × 2).
Extracted. The ether layer was extracted with dilute hydrochloric acid.
An aqueous solution of N sodium hydroxide was added until the liquid phase became alkaline, and the mixture was extracted with dichloromethane (20 ml × 2). The organic layer is dried and concentrated, and the resulting residue is subjected to silica gel column chromatography (hexane: EtOAc = 4:
Purification in 1) gave the desired product 3f (840 mg, 65%) as an oil.

3f: ¹ H NMR (300 MHz, CDC
l ₃ ) δ ppm: 1.13 (t, J = 7.2 Hz, 3
H), 2.54 (2dq, J = 14.0, 7.1, 2)
H), 2.63 (s, 1H), 2.83 (2dq, J =
14.0, 7.1 Hz, 2H), 2.93 (d, J = 1
2.2 Hz, 1 H), 3.46 (d, J = 12.2 H)
z, 1H), 6.67-6.76 (m, 2H), 6.9.
6-7.12 (m, 4H), 7.63 (dt, J = 8.
0, 2.0 Hz, 1H), 8.40 (dd, J = 1.
7, 4.7 Hz, 1H), 8.69 (m, 1H). Synthesis Example 13 Aminoacetylene 3 g

[0243]

Embedded image

1) Methyl 3-ethylami
A solution of nopropionate EtNH ₂ (33 g, 720 mmol) in MeOH (150 ml) at 4-6 ° C. was treated with methyl acrylate (54 m 2).
1, 600 mmol) was added dropwise over 20 minutes. 2
Four hours later, MeOH was distilled off at normal pressure, and further distilled under reduced pressure to obtain methyl3-ethylaminopropi.
Onate (32.94 g, 42%) was obtained as a clear, colorless liquid. bp 70 ° C./20 mmHg; ¹ H NMR (300 MH
z, CDCl ₃ ) δ ppm: 1.11 (t, J = 7.1)
Hz, 3H), 2.52 (t, J = 6.6 Hz, 2
H), 2.66 (q, J = 7.1 Hz, 2H), 2.8
9 (t, J = 6.6 Hz, 2H), 3.69 (s, 3
H).

2) Methyl 3-e as starting material
The same operation as in Synthesis Example 8 was carried out using thylaminopropionate and acetate 5 (Synthesis Example 7) to obtain 3 g as a pale yellow oily substance (yield 41%). 3g: ¹ H NMR (300 MHz, CDCl ₃ ) δpp
m: 1.12 (t, J = 7.2 Hz, 3H), 1.25
(S, 3H), 2.31 (s, 1H), 2.52-2.
62 (m, 2H), 2.70-2.90 (m, 3H),
3.20-3.12 (m, 3H), 3.67 (s, 3
H), 7.18-7.35 (m, 5H). Synthesis Example 14 Aminoacetylene 3h

[0246]

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As a starting material, N-methylethyla
The same operation as in Synthesis Example 8 was performed using nolamine and acetate 5 (Synthesis Example 7) to obtain 3h as a pale yellow oily substance (yield 77%). 3h: ¹ H NMR (300 MHz, CDCl ₃ ) δpp
m: 1.26 (s, 3H), 2.36 (s, 1H),
2.40 (s, 3H), 2.74-2.83 (m, 3
H), 3.09 (d, J = 13.2 Hz, 1H);
55-3.68 (m, 2H), 7.20-7.40
(M, 5H). Synthesis Examples 15, 16 Aminoacetylenes 3i, 3j

[0248]

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As a starting material, acetate 5 (Synthesis Example 1)
7) and Ethyl 4-piperidinecar
boxylate and 1- (Ethoxycarbo
The same operation as in Synthesis Example 8 was carried out using nylmethyl) piperazine to produce 3i and 3j, respectively (purification methods are shown in parentheses after the compound numbers). 3i: (washed with hexane); yield: 59%; pale yellow crystals;
¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.22 (s, 3H), 1.26 (t, J = 7.1H)
z, 3H), 1.78 (m, 2H), 1.97 (m, 2
H), 2.24-2.43 (m, 3H), 2.36.
(S, 1H), 2.84 (d, J = 13.3 Hz, 1
H), 3.05 (d, J = 13.3 Hz, 1H), 3.
10 (m, 1H), 3.24 (m, 1H), 4.14
(Q, J = 7.1 Hz, 2H), 7.15-7.36
(M, 5H).

3j: (suspension with EtOH-H ₂ O); yield 50%; ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 1.21 (s, 3H), 1.28 (t, J =
7.1 Hz, 3H), 2.36 (s, 1H), 2.61
-2.73 (m, 4H), 2.80 (d, J = 13.2)
Hz, 1H), 2.80-2.90 (m, 4H), 3.
07 (t, J = 13.2 Hz, 1H), 3.22 (s,
2H), 4.27 (q, J = 7.1 Hz, 2H), 7.
20-7.40 (m, 5H). Synthesis Example 17 Aminoacetylene 3k

[0251]

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In the same manner as in Synthesis Example 7 except that phenylacetaldehyde was used instead of phenylacetone, 3-ace
Toxyl-4-phenyl-1-butyne was converted into Ethyl 4-piperidin.
Using e-carboxylate, 3k was produced in the same manner as in Synthesis Example 8. 3k: 22% yield; ¹ H NMR (CDCl ₃ , 300
MHz) δ ppm: 1.25 (t, J = 7.1 Hz, 3
H), 2.65-2.86 (m, 2H), 2.86-
2.04 (m, 2H), 2.24-2.40 (m, 3
H), 2.50 (dt, J = 3.0, 11.3 Hz, 1
H), 2.70-2.80 (m, 1H), 2.84-
3.07 (m, 3H), 3.54 (ddd, J = 2.
2,5.6,9.3 Hz, 1H), 4.14 (q, J =
7.1 Hz, 2H), 7.08-7.40 (m, 5
H). Synthesis Example 18 Anilinoacetylene 3 m

[0253]

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W. S. The method of Johnson et al.
m. Chem. Soc. , 1949, 71, 1901).
Β-anilinoprop manufactured by
ionate and 3-Chloro-3-methyl-
Synthesis Example 10 Using 1-butyne S. Ha
nzel et al. (J. Am. Chem. Soc., 1).
960, 82, 4908)} to produce 3k. 3m: 28% yield; ¹ H NMR (CDCl ₃ , 300
MHz) δ ppm: 1.31 (s, 6H), 2.26
(T, J = 7.2 Hz, 2H), 2.39 (s, 1
H), 3.45 (t, J = 7.2 Hz, 2H), 3.6
2 (s, 3H), 7.12 (m, 1H), 7.25-
7.38 (m, 4H). Example 7 Preparation of Compound 1

[0255]

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Aminoacetylene 3 produced in Synthesis Example 15
i (7.34 g, 24.6 mmol) and 4-chloro-6,7-diethoxyquinazoline (Synthesis Example) (6.21)
g, 24.6 mmol) in DMF (120 ml) was bubbled with nitrogen for 40 minutes with stirring. Et ₃ N
(8.2 ml, 59.0 mmol), Pd (PPh ₃ )
₄ (710 mg, 0.61 mmol) and CuI (3
70 mg, 1.94 mmol) and the reaction mixture was
The mixture was heated and stirred at 00 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure,
Saturated aqueous sodium bicarbonate solution (100 ml) and EtO
Partitioned into Ac (100 ml). Dry the organic layer (Na ₂
SO ₃ ), concentrated, and the residue was subjected to silica gel column chromatography (hexane → hexane: EtOAc = 2: 3).
To give the desired product as a reddish brown tar-like substance (1
0.58 g, 83%).

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.26 (t, J = 7.1 Hz, 3
H), 1.45 (s, 3H), 1.50 (t, J = 7.
1 Hz, 3H), 1.56 (t, J = 7.0 Hz, 3
H), 1.72-1.95 (m, 2H), 1.93-
2.10 (m, 2H), 2.36 (tt, J = 4.0,
11.5 Hz, 1 H), 2.46 (dt, J = 2.5,
11.4 Hz, 1 H), 2.56 (dt, J = 2.5,
11.4 Hz, 1H), 3.05 (d, J = 13.4H)
z, 1H), 3.27 (d, J = 13.4 Hz, 1
H), 3.22-3.35 (m, 1H), 3.45 (b
rd, J = 11.2 Hz, 1H), 4.05 (q, J
= 7.1 Hz, 2H), 4.15 (q, J = 7.1H)
z, 2H), 4.28 (q, J = 7.0 Hz, 2H),
7.10-7.30 (m, 5H), 7.30-7.45
(M, 2H), 9.08 (s, 1H). IR (film) νcm ^-1 : 2982, 2936, 28
09, 2213, 1732, 1613, 1568, 10
45,855,756,702. Example 8 Preparation of Compound 1

[0258]

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The ester prepared in Example 7 (10.01
g, 19.4 mmol) in EtOH (100 ml)
To the mixture was added a 2N aqueous solution of NaOH (25 ml, 50 mmol), and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated to dryness under reduced pressure, EtOH (2 ml) was added to the residue, and a 10% aqueous citric acid solution (180 ml) was added with stirring. After stirring at room temperature for 30 minutes, the precipitate was collected by filtration, washed (water-EtOH), and dried to obtain the desired product as pale yellow powdery crystals (9.04 g,
96%). Further successively suspension washing with toluene and EtOH-H ₂ O, to give a purified product as a white powder crystals.

1: ¹ H NMR (CDCl ₃ , 300M
Hz) δ ppm: 1.44 (t, J = 7.0 Hz, 3
H), 1.49 (s, 3H), 1.56 (t, J = 7.
0 Hz, 3H), 1.84-2.08 (m, 2H),
2.07-2.29 (m, 2H), 2.50-2.70
(M, 2H), 2.77 (br t, J = 10.7H
z, 1H), 2.97 (d, J = 13.1 Hz, 1
H), 3.28-3.56 (m, 2H), 3.38
(D, J = 13.1 Hz, 1H), 3.89 (m, 2
H), 4.28 (q, J = 7.0 Hz, 2H), 7.0
9 (s, 1H), 7.18-7.44 (m, 6H),
9.20 (s, 1H). IR (KBr) cm ^-1 : 3409, 2984, 293
7,2213,1717,1612,1499,145
8,1235,1204,1032,936,704,
662. m. p. 212-215 ° C P-SIMS m / z 488 (M + H) ⁺

Examples 9 to 90 Inventive compounds were produced using the halogenated nitrogen-containing compound and the acetylene compound (including those described below) produced in the above Synthesis Examples. The structure, method, yield, physical properties and the like are shown below. The method column shows the method used and the purification method, and is represented as follows. Method (Coupling reaction) The methods of Examples 1 and 7 were A and B, respectively. When there was a change in the reaction solvent or palladium catalyst, the one used was indicated in parentheses.

(Hydrochlorination) The procedure of Example 2 was designated as C, and the case where the reaction solvent was changed was described in parentheses. (Hydrolysis reaction) The operation of Example 8 was designated as D, and the case where the reaction solvent was changed was described in parentheses. Purification method In purification by silica gel column chromatography, an eluate of hexane-EtOAc system was designated as P1a, and an eluate of CHCl ₃ -MeOH system was designated as P1b. Purification by ODS column chromatography
Marked as 2. P3 means purification by suspension washing or recrystallization,
The solvent used at that time is shown in parentheses. In each case, the final purified product was dried under reduced pressure.

[0263]

[Table 133]

[0264]

[Table 134]

[0265]

[Table 135]

[0266]

[Table 136]

[0267]

[Table 137]

[0268]

[Table 138]

[0269]

[Table 139]

[0270]

[Table 140]

[0271]

[Table 141]

[0272]

[Table 142]

[0273]

[Table 143]

[0274]

[Table 144]

[0275]

[Table 145]

[0276]

[Table 146]

[0277]

[Table 147]

[0278]

[Table 148]

[0279]

[Table 149]

[0280]

[Table 150]

[0281]

[Table 151]

[0282]

[Table 152]

[0283]

[Table 153]

[0284]

[Table 154]

[0285]

[Table 155]

[0286]

[Table 156]

[0287]

[Table 157]

[0288]

[Table 158]

[0289]

[Table 159]

[0290]

[Table 160]

[0291]

[Table 161]

[0292]

[Table 162]

[0293]

[Table 163]

[0294]

[Table 164]

[0295]

[Table 165]

[0296]

[Table 166]

[0297]

[Table 167]

[0298]

[Table 168]

[0299]

[Table 169]

[0300]

[Table 170]

[0301]

[Table 171]

[0302]

[Table 172]

[0303]

[Table 173]

Embodiment 91

[0305]

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The carboxylic acid prepared in Example 8 (389 m
g, 0.8 mmol), ClCH ₂ OCO-t-Bu
(138 μl, 0.96 mmol) and DBV (13
2 μl, 0.96 mmol) in toluene (10 m
l) was stirred at 80 ° C for 2 hours. Water (40m
1) and EtOAc (40 ml) were added, and the organic layer was separated. The extract was washed (saturated aqueous NaHCO ₃ , 10% aqueous citric acid, water), dried (Na ₂ SO ₄ ), concentrated,
The residue was purified by silica gel column chromatography (hexane: EtOAc = 4: 1 → 2: 3) to give an ester as an amorphous (405 mg, 84%).

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.21 (s, 9H), 1.45 (s,
3H), 1.49 (t, J = 7.0 Hz, 3H), 1.
56 (t, J = 7.0 Hz, 3H), 1.73-1.9
4 (m, 2H), 1.95-2.12 (m, 2H),
2.37-2.62 (m, 3H), 3.04 (d, J =
13.3 Hz, 1 H), 3.27 (d, J = 13.3 H)
z, 1H), 3.22-3.32 (m, 1H), 3.4
4 (m, 1H), 4.03 (br q, J = 7.0H
z, 2H), 4.28 (q, J = 7.0 Hz, 1H),
5.77 (s, 2H), 7.16-7.30 (m, 5
H), 7.30-7.40 (m, 2H), 9.07
(S, 1H). Example 92

[0308]

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The 2-amino compound (20) produced in Example 39
0 mg, 0.48 mmol), a 42% aqueous HBF ₄ solution (4 ml) and a trace amount of EtOH were added, cooled to −20 ° C., and a 5.1 M aqueous NaNO ₂ solution (150 μl,
0.75 mmol) was added. The temperature was slowly increased, and the reaction solution was divided into several portions of 5.1 M NaN while the temperature reached + 20 ° C.
O ₂ aqueous solution (1.55 ml), was added NaNO ₂ aqueous solution of 7.8 M (0.5 ml). HBF ₄ aqueous solution (2m
1) Addition and stirring at room temperature for 30 minutes, followed by 6N NaOH at 0 ° C.
An aqueous solution and a 10% aqueous solution of Na ₂ CO ₃ were added until the solution became neutral. The product was treated with EtOAc (30 ml × 1, 20
ml × 1), and the extract is washed (saturated NaHCO _3).
Aqueous solution), dried (Na ₂ SO ₄ ) and concentrated. The residue is subjected to silica gel column chromatography (hexane: EtO
Ac = 1: 0 → 1/1, chloroform: methanol =
1: 0 → 30: 1) to give 2-fluoride (21m
g, 10%).

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.20 (t, J = 7.1 Hz, 6
H), 1.48 (s, 3H), 2.86-3.05.
(M, 5H), 3.31 (d, J = 13.2 Hz, 1
H), 3.84 (s, 3H), 4.05 (s, 3H),
7.17-7.30 (m, 5H), 7.32-7.40
(M, 2H). ¹⁹ F NMR (CDCl ₃ , 280 MHz) δ ppm:
-49.3 Example 93

[0311]

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The same operation as in Example 2 was carried out using the 2-fluorinated compound produced in Example 92 to obtain the desired hydrochloride as white powder crystals (yield 74%). ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.67 (t, J = 7.7 Hz, 3H), 1.69
(T, J = 8.2 Hz, 3H), 1.96 (s, 3
H), 3.25-3.55 (m, 2H), 3.55-
3.80 (m, 4H), 3.86 (s, 3H), 4.0
6 (s, 3H), 7.10-7.34 (m, 5H),
7.37-7.50 (m, 2H), 12.90 (s, 1
H). ¹⁹ F NMR (CDCl ₃ , 280 MHz) δ ppm:
−49.4 IR (KBR) νcm ⁻¹ : 3430,2980,294
0,2450,2238,1618,1580,154
9,1306,1242,1015,1001,84
3,770,708. m. p. 182-187 ° C Example 94

[0313]

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The 2-amino compound (60) produced in Example 39
mg, 0.14 mmol) of pyridine (0.5 ml)
The acetic anhydride (0.5 ml) solution was left overnight, and then heated and stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (hexane: EtOAc = 4: 1 →
0: 1) to give the desired 2-acetylamino form (24 mg, 36%). ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.20 (t, J = 7.1 Hz, 3H), 1.46
(S, 3H), 2.56 (br s, 3H), 2.85
-3.05 (m, 5H), 3.30 (d, J = 13.2)
Hz, 1H), 3.84 (s, 3H), 4.04 (s,
3H), 7.12-7.30 (m, 5H), 7.30-
7.48 (m, 2H), 8.14 (brs, 1H). Example 95

[0315]

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The 2-chloro compound (15) produced in Example 25
6 mg, 0.36 mmol) in methanol (4 m
1) was stirred on an ice bath and a 28% NaOMe methanol solution (0.5 ml) was added. After heating and stirring at 80 ° C. for 30 minutes, the mixture was concentrated, water and CH ₂ Cl ₂ were added, and the organic layer was separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to obtain the desired 2-methoxy compound (160 mg, quantitative). ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.19 (t, J = 7.1 Hz, 3H), 1.45
(S, 3H), 2.85-3.10 (m, 5H), 3.
31 (d, J = 13.2 Hz, 1H), 3.81 (s,
3H), 4.03 (s, 3H), 4.09 (s, 3
H), 7.12 (s, 1H), 7.17-7.30
(M, 4H), 7.35-7.42 (m, 2H). Example 96

[0317]

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The same operation as in Example 2 was carried out using the 2-methoxy compound prepared in Example 95 to obtain the desired hydrochloride as white powder crystals (yield 78%). ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.64 (t, J = 7.5 Hz, 3H), 1.71
(T, J = 7.4 Hz, 3H), 1.95 (s, 3
H), 3.33-3.90 (m, 4H), 3.59
(D, J = 12.4 Hz, 1H), 3.76 (s, 3
H), 3.90 (d, J = 12.4 Hz, 1H), 4.
05 (s, 3H), 4.10 (s, 3H), 6.97
(Br s, 1H), 7.15 (s, 1H), 7.25
-7.35 (m, 3H), 7.42-7.50 (m, 2
H), 12.65 (brs, 1H). IR (KBr) νcm ^-1 : 3426,2990,294
6,2361,1620,1555,1501,147
4,1426,1410,1310,1061,100
1,860,791,708. m. p. 172-175 ° C Example 97

[0319]

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The 2-chloro compound (36) produced in Example 25
0mg, 0.82mmol) benzene solution (4ml)
The _{^{n-Bu 4 N + Br -}} (30mg) and 50% NaOH
An aqueous solution (3 ml) was added, and the mixture was refluxed for 48 hours. After neutralization by adding concentrated hydrochloric acid, a saturated aqueous solution of NaHCO ₃ was added, and the product was extracted with EtOAc (20 ml × 2). The extract was concentrated, MeOH (15 ml) was added to the residue, and the resulting precipitate was collected by filtration to give the desired 2-hydroxy (2-oxo) compound (130 mg, 38%) as white powder crystals.

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.19 (br peak, 6H),
1.43 (s, 3H), 2.40-3.20 (br p
eak, 4H), 3.09 (d, J = 13.5 Hz, 1
H), 3.58 (d, J = 13.5 Hz, 1H), 4.
00 (s, 3H), 4.10 (s, 3H), 5.66
(S, 1H), 6.72-6.85 (m, 2H), 7.
05-7.20 (m, 3H), 7.58 (s, 1H),
7.64 (s, 1H). Example 98 Preparation of compound 2

[0322]

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Ethyl glycolate (210 mg, 2.0 mg
mmol) in DMF solution (2 ml) at room temperature with 60% Na
H (10 mg, 0.25 mmol) and 2-chloro form 1
(130 mg, 0.30 mmol) was added and the mixture was heated and stirred at 80 ° C. After one hour, further ethyl glycolate 620
mg (5.96 mmol), 60% NaH (240 m
g, 6.0 mmol) and 2-chloro form 1 (100 m
g, 0.23 mmol) and stirred at room temperature for 10 minutes. Water and EtOAc were added to the reaction, the aqueous layer was concentrated,
An aqueous solution of N NaOH (5 ml) was added. After stirring at room temperature for 2 hours, the aqueous layer was washed with Et ₂ O (10 ml) and neutralized with a 10% aqueous citric acid solution (20 ml). The product is E
Extract with tOAc (20 ml × 2), dry (Na ₂ SO 4)
₄ ) After concentration, the residue was purified by silica gel column chromatography to obtain the desired 2- (carboxymethyl) oxy form 2 (46 mg, 16%). 2: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 1.27 (t, J = 7.1 Hz, 3H), 1.55
(S, 3H), 3.00-3.25 (m, 5H), 3.
30 (d, J = 15.4 Hz, 1H), 3.70 (s,
3H), 3.89 (s, 3H), 5.00 (s, 2
H), 6.90 (s, 1H), 6.99 (s, 1H),
7.10-7.40 (m, 5H), 12.55 (br
s, 1H). Example 99

[0324]

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The alcohol compound (40) produced in Example 11
0 mg, 1.47 mmol) in CH ₂ Cl ₂ solution (6 m
1) phthalic anhydride (327 mg, 2.2 mmol) at room temperature
l), triethylamine (0.30 ml, 2.2 mmol
l) and DMAP (44 mg, 0.36 mmol) were added, stirred for 12 hours, and left for 3 days. Saturated NaH
An aqueous solution of CO ₃ (10 ml) and EtOAc (30 ml) were added, and the mixture was stirred well. The precipitate obtained by filtering the mixture and the precipitate formed when the organic layer is washed with dilute hydrochloric acid are combined and washed with water to obtain the desired half-ester (336 m
g, 54%) as a white powder solid.

¹ H NMR (DMSO-d ₆ , 300 M
Hz) δ ppm: 1.91 (s, 6H), 3.86
(S, 3H), 4.00 (s, 3H), 7.38 (s,
1H), 7.62 (s, 1H), 7.63-7.80.
(M, 4H), 9.05 (s, 1H), 13.35 (b
rs, 1H). IR (KBr) νcm ^-1 : 3434,2986,294
0, 2477, 2234, 1912, 1730, 150
5,1430,1368,1240,1119,107
3,993,918,885,801,745. m. p. 162-165 ° C Example 100

[0327]

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The carboxylic acid prepared in Example 8 (439 m
g, 0.90 mmol) and Et ₃ N (0.19 m
l, 1.37 mmol) in a THF solution (15 ml)
After cooling to 5 ° C, i-BuOCOCl (0.126 ml,
0.99 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 5 minutes, and then cyanamide (63 mg, 1.50 mmol) was added. The reaction mixture was stirred at −5 to 0 ° C. for 30 minutes, gradually heated to room temperature, and then water was added to stop the reaction. The product is E
Extract with tOAc (20 ml × 2), dry (Na ₂ SO 4)
₄ ) Concentrated. EtOAc was added to the residue, and the resulting solid was washed with EtOAc and collected by filtration.
g, 21%) as white powder crystals.

¹ H NMR (CDCl ₃ + D ₂ O, 30
0 MHz) δ ppm: 1.46 (t, J = 6.9 Hz,
3H), 1.56 (t, J = 7.0 Hz, 3H), 1.
65 (s, 3H), 2.00-2.30 (m, 4H),
2.63 (m, 1H), 2.78-3.10 (m, 2
H), 3.20 (d, J = 13.1 Hz, 1H), 3.
44 (d, J = 13.1 Hz, 1H), 3.58-3.
82 (m, 2H), 3.93 (q, J = 7.0 Hz, 2
H), 4.27 (q, J = 6.9 Hz, 2H), 7.0.
4 (s, 1H), 7.20-7.50 (m, 7H),
9.05 (s, 1H). IR (KBr) νcm ^-1 : 3395,2984,293
8,2654,2513,2249,2166,172
5,1613,1543,1499,1460,139
7, 1366, 1231, 1032, 706. m. p. 141-145 ° C Example 101

[0330]

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The carboxylic acid prepared in Example 60 (100
mg, 0.21 mmol) in chloroform solution (5 m
l) was cooled to -10 ° C and i-BuOCOCl (27
1, 0.21 mmol) and Et ₃ N (30 μl, 0.21 mmol).
1 mmol) and stirred for 15 minutes. Nonyl alcohol (50 μl, 0.28 mmol) was added, the temperature was raised to room temperature over 30 minutes, and the reaction solution was diluted with CH ₂ Cl ₂ .
The organic layer was washed (NaHCO ₃ saturated aqueous solution, citric acid aqueous solution, saturated saline), dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification by EtOAc = 15: 1 → 3: 1) gave the desired ester (45 mg, 36%) as a yellow-brown oil.

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 0.90 (t, J = 6.5 Hz, 3
H), 1.20-1.70 (m, 26H), 2.60
(T, J = 6.8 Hz, 2H), 2.90 (m, 4
H), 3.20 (m, 2H), 4.10 (m, 4H),
4.30 (q, J = 8.6 Hz, 2H), 7.23
(M, 5H), 7.38 (s, 1H), 7.4 (s, 1
H), 9.05 (s, 1H). IR (film) νcm ^-1 : 2928,2214,17
32, 1613, 1568, 1535, 1497, 13
64, 1308, 1229, 1046, 934, 85
5,702. Rf=0.6@hexane: EtOAc = 1: 1, Sil
icagel 60F ₂₅₄ (MERCK)}. Example 102

[0333]

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The carboxylic acid prepared in Example 60 (150
mg, 0.32 mmol) in dichloromethane (5 m
l) is N, N'-dicyclohexylcarbodiimide (7
4 mg, 0.35 mmol) and N-hydroxysuccinimide (40 mg, 0.34 mmol) were added. The mixture was stirred for 1 hour at room temperature and the resulting precipitate was filtered off,
The filtrate was concentrated. The residue was diluted with EtOH (7 ml) and dichloromethane (7 ml), and a 28% aqueous NH ₄ OH solution was added, followed by stirring at room temperature for 1 hour. After the solvent was distilled off, the residue was dissolved in CH ₂ Cl ₂ (100 ml) and washed (sat.
HCO ₃ aqueous solution, saturated saline), dried (MgSO ₄ ),
Concentrated. The residue was purified by silica gel column chromatography (CHCl ₃ : MeOH = 50: 1) to give an amide (127 mg, 81%) as a reddish brown foam.

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.24 (t, J = 7.0 Hz, 3
H), 1.47 (t, J = 7.0 Hz, 3H), 1.5
3-1.58 (m, 6H), 2.58 (m, 2H),
2.98 (m, 3H), 3.27 (m, 3H), 3.9
6 (q, J = 7.0 Hz, 2H), 4.27 (q, J =
7.0 Hz, 2H), 5.30 (brs, 2H),
7.10-7.45 (m, 7H), 9.00 (s, 1
H). IR (KBr) νcm ^-1 : 3347,3187,298
2,2934,2213,1672,1612,147
4,1366,1308,1231,1202,110
9, 1044, 934, 853, 702. Rf = 0.5 ｛CHCl ₃ : MeOH = 15: 1, Si
licagel 60F ₂₅₄ (MERCK)｝ Example 103

[0336]

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The alcohol derivative 1 (3) produced in Example 61
5 mg, 0.086 mmol) of dichloromethane (2 m
1) Succinic anhydride (34 mg, 0.34
4 mmol) dimethylaminopyridine (52 mg, 0.1 mg).
043 mmol), triethylamine (35 mg, 0.1 mg).
344 mmol) and stirred. Eight days later, the reaction solution was subjected to silica gel column chromatography (developing solvent H
ex → chloroform-methanol system) and suspended washing (solvent, E
Purification by t ₂ O) gave the desired product 2 (17 mg, 39%). Object 2

M. p. 175 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.43 to 1.47 (m, 2H), 1.79 (s, 3
H), 2.69 (s, 4H), 3.42 (s, 2H),
4.68-4.75 (m, 1H), 4.83-4.91
(M, 1H), 7.22-7.35 (m, 6H), 7.
46 (s, 1H), 8.79 (s, 1H). IR (KBr) νcm ^-1 : 3426,2980,293
6,2728,2523,2363,2234,189
0,1740,1609,1574,1497,143
7, 1370, 1314, 1236, 1155, 110
9,1082,1061,955,928,835,7
43,702,588,569,515. Example 104

[0339]

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The nitropyrimidine derivative 1 (457 mg, 0.87 mmol) produced in Example 66 was treated with ethanol (1
0 ml) solution and zinc powder (561 mg) and H ₂ O (2 m
l) was added and refluxed. Five hours later, after filtration, H
₂ O (50 ml) was added, extracted with EtOAc (200 ml), washed with saturated saline, dried (Na ₂ SO ₄ ), and concentrated. The residue obtained was purified by silica gel column chromatography (Hex-EtOAc). Object 2 (100
mg, 23%). 2

Oil ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.26 (t, J = 7.2 Hz, 3H), 1.31
(T, J = 7.2 Hz, 3H), 1.38 (s, 3
H), 1.75-1.83 (m, 2H), 2.00-
2.04 (m, 2H), 2.34-2.50 (m, 3
H), 2.94 (d, J = 13.5 Hz, 1H), 3.
19 (d, J = 13.5 Hz, 1H), 3.17-3.
22 (m, 1H), 3.35-3.38 (m, 1H),
3.44 (s, 2H), 4.14 (q, J = 7.2H)
z, 2H), 4.26 (q, J = 7.2 Hz, 2H),
4.23 (s, 2H), 5.20 (m, 1H), 7.2
4-7.36 (m, 5H), 8.21 (s, 1H). IR (neat) νcm ^-1 : 3349,3243,29
82,2936,2812,2367,2211,17
30, 1589, 1468, 1263, 1188, 11
25,1046,752,702. Example 105

[0342]

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Isonipecotinic acid compound 1 produced in Example 8
1-pentadecanol (171 mg, 0.75 m) in a DMF (4 ml) solution of (250 mg, 0.5 mmol)
mol) in DMF (2 ml) and stirred at room temperature while triethylamine (152 mg, 1.5 mmol) was added.
l), 1-hydroxybenzotriazole (101 m
g, 0.75 mmol) and N, N'-dicyclohexylcarbodiimide (129 mg, 0.625 mmol) were added in an ice bath, and the mixture was stirred at 60 ° C. After 3 hours, the mixture was concentrated under reduced pressure, a saturated aqueous solution of NaHCO ₃ was added thereto, extracted with EtOAc, washed with saturated saline, dried (Na ₂ SO ₄ ), and concentrated to obtain a residue (0.63 g). This was subjected to silica gel column chromatography (developing solvent Hex-EtOAc).
The resulting product was purified by suspending and washing (solvent, Et ₂ O) to obtain the desired long-chain ester 2 (135 mg, 39%).

Long-chain ester 2 oily substance ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
0.88 (t, J = 6.9 Hz, 3H), 1.26
1.30 (m, 26H), 1.45 (s, 3H), 1.
50 (t, J = 7.2 Hz, 3H), 1.56 (t, J
= 7.2 Hz, 3H), 1.76-1.88 (m, 2
H), 1.97-2.03 (m, 2H), 2.32-
2.60 (m, 3H), 3.05 (d, J = 13.5H)
z, 1H), 3.28 (d, J = 13.5 Hz, 1
H), 3.52-3.30 (m, 1H), 3.43-
3.48 (m, 1H), 4.03-4.10 (m, 4
H), 4.28 (q, J = 7.2 Hz, 2H), 7.2
2-7.29 (m, 5H), 7.34-737 (m, 2
H), 9.07 (s, 1H). IR (neat) νcm ^-1 : 2926,2855,28
09,2751,2361,223,1890,17
32, 1613, 1497, 1456, 1397, 13
64, 1304, 1262, 1231, 1202, 11
28,1046,959,934,855,760,7
02,440. Example 106

[0345]

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Isonipecotinic acid compound 1 prepared in Example 8
(268 mg, 0.54 mmol) in THF (20 m
l) A solution of isobutyl chloroformate (88 mg, 0.65 mmol) in THF (1 ml) was added dropwise to the solution at -5 ° C. After stirring for 10 minutes, triethylamine (6
(6 mg, 0.65 mmol) in THF (1 ml) was added dropwise, and the mixture was stirred for 10 minutes, and then a 28% aqueous ammonia solution (4 ml) was added dropwise. Ten minutes later, a saturated aqueous solution of NaHCO ₃ (10 ml) was added to the residue obtained by concentration under reduced pressure.
Extracted with EtOAc (30 ml), saturated brine (10 m
1), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to obtain crude crystals (278 mg). Wash this (solvent EtOA)
Purified in c), the desired amide (164 mg, 63%)
I got

White crystals m. p. 198 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.45 (s, 3H), 1.49 (t, J = 6.9H)
z, 3H), 1.56 (t, J = 6.9 Hz, 3H),
1.68-2.04 (m, 4H), 2.20-2.30
(M, 1H), 2.42-2.46 (m, 1H), 2.
53-2.57 (m, 1H), 3.05 (d, J = 1
3.5 Hz, 1 H), 3.28 (d, J = 13.5 H)
z, 1H), 3.30-3.35 (m, 1H), 3.4
9-3.53 (m, 1H), 4.02 (q, J = 6.9)
Hz, 2H), 4.28 (q, J = 6.9 Hz, 2
H), 5.39 (s, 1H), 5.51 (s, 1H),
7.22-7.29 (m, 5H), 7.34-7.37
(M, 2H), 9.07 (s, 1H). IR (KBr) νcm ⁻¹ : 3304,3135,298
0,2938,2814,2367,2209,169
0, 1611, 1564, 1535, 1497, 145
8, 1360, 1310, 1231, 1109, 102
8,932,858,826,762,704,65
4. Example 107

[0348]

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The carboxylic acid derivative 1 prepared in Example 8 (25
0 mg, 0.50 mmol) in N, N-dimethylformamide solution (6 ml).
g, 0.75 mmol), triethylamine (152 m
g, 15 mmol), 1-hydroxyvinzotriazole (102 mg, 0.75 mmol), N, N-dicyclocarbodiimide (129 mg, 0.625 mmol)
Was added successively at room temperature, followed by stirring at 50 ° C. One hour later, the mixture was concentrated under reduced pressure, a saturated aqueous solution of NaHCO ₃ was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried (Na ₂ S).
O ₄ ), and the residue obtained by concentration was subjected to silica gel column chromatography (solvent: ethyl acetate-methanol system),
Purification by hanging washing (solvent: methanol-diethyl ether system) gave the desired product 2 (65 mg, 24%).

M. p. 149 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.14 (d, J = 6.6 Hz, 6H), 1.45
(S, 3H), 1.49 (t, J = 7.2 Hz, 3
H), 1.56 (t, J = 6.9 Hz, 3H), 1.7
7-2.11 (m, 5H), 2.37-1.57 (m, 5H)
2H), 3.04 (d, J = 13.5 Hz, 1H),
3.28 (d, J = 13.5 Hz, 1H), 3.26-
3.34 (m, 1H), 3.51-3.52 (m, 1
H), 4.02 (q, J = 6.9 Hz, 2H), 4.0.
9 (q, J = 6.6 Hz, 1H), 4.28 (q, J =
7.2 Hz, 2H), 5.22-5.25 (m, 1
H), 7.24-7.26 (m, 5H), 7.35-
7.36 (m, 2H), 9.07 (s, 1H). IR (KBr) νcm ^-1 : 3283,3063,297
6,2936,2811,2121,1730,164
0, 1537, 1499, 1474, 1456, 136
4,1231,1202,1128,1111,104
6,853,828,702,666,569. Example 108 Preparation of compound 5

[0351]

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1) Sodium hydride (460 mg, 1
(1.5 mmol, 60% in oil) was washed with dry hexane, DMF (30 ml) was added, and the mixture was stirred on an ice bath. Compound 1 (1.90 g, 9.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then propargyl bromide (0.8 m
1, 10.6 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added under ice cooling to stop the reaction, and the product was extracted with ether (60 ml). The extract was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain Compound 2 (1.51 g, 66%). 2: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 1.46 (s, 9H), 2.24 (t, J = 2.4
Hz, 1H), 4.36 (d, J = 2.4 Hz, 2
H), 7.10-7.50 (m, 5H).

2) PdCl ₂ (PPh ₃ ) ₂ (10 m
g, 0.014 mmol) and PPh ₃ (15 mg, 0.1 g).
056 mmol) in THF (7 ml) was stirred at room temperature for a while and then added to Compound 1 (250 mg, 1.
1 mmol), 4-iodo-6,7-dimethoxyquinazoline (3) (144 mg, 0.5 mmol), CuI
(10 mg, 0.053 mmol) and Et ₃ N
(0.5 ml, 3.6 mmol) and refluxed for 1 hour.
Left at room temperature overnight. NH ₄ Cl aqueous solution, Na
A saturated aqueous solution of HCO ₃ was added and the product was extracted with EtOAc. The extract was dried and concentrated, and the residue was purified by silica gel column chromatography to give compound 4 (100 mg, 5 mg).
0%). 4: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 1.46 (s, 9H), 3.96 (s, 3H),
4.06 (s, 3H), 4.80 (s, 2H), 7.2
0-7.50 (m, 7H), 9.09 (s, 1H).

3) Compound 3 (100 mg, 0.245 m
mol) was cooled on ice and 4N HCl AcOEt solution (2 ml) was added. The temperature was raised to room temperature over 30 minutes with stirring, and the reaction solution was concentrated. Et ₂ O (10 ml)
Was added and the product was collected by filtration. The residue was washed with CH ₂ Cl ₂ (40
ml) -NaHCO ₃ saturated aqueous solution (20 ml), and the CH ₂ Cl ₂ layer was dried and concentrated. The resulting residue was washed with EtOAc-Et ₂ O to give the desired compound 5
(40 mg, 53%). 5: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 4.06 (s, 3H), 4.08 (s, 3H),
5.38 (d, J = 2.4 Hz, 2H), 6.98
(T, J = 2.4 Hz, 1H), 7.15-7.40
(M, 3H), 7.47 (t, J = 7.9 Hz, 2
H), 7.72 (d, J = 7.9 Hz, 2H), 9.0
8 (s, 1H). IR (KBr) νcm ⁻¹ : 3395,2182,179
0, 1665, 1576, 1503, 1431, 138
5,1300,1238,1115,974,845,
758. Example 109

[0355]

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Diisopropylamine (43 mg, 0.4
3 mmol) in a THF solution (2 mM) at -78 ° C at 1.6 M nBuLi in hexane (0.268 ml,
0.43 mmol) was added dropwise. This was added to a solution of the alcohol form (100 mg, 0.287 mmol) obtained in Example 33 in THF (1 ml), and the mixture was brought to room temperature. Then, phthalic anhydride (44 mg, 0.3 mmol) was added. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled off under reduced pressure.
The residue was purified by column chromatography, and the resulting crystals were poured into Et ₂ O and collected by filtration.
g, 0.034 mmol, yield 12%). Since then
This half ester synthesis method is referred to as esterification method A.

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 1.95 (s, 3H), 3.47 (d,
J = 13.7 Hz, 1H), 3.62 (d, J = 13.
7 Hz, 1H), 3.99 (s, 3H), 4.00
(S, 3H), 6.98 (s, 1H), 7.36-7.
41 (m, 5H), 7.49-7.60 (m, 4H),
7.93-8.0 (m, 1H), 8.66 (s, 1
H). Example 110

[0358]

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The alcohol compound obtained in Example 33 (100 m
g, 0.29 mmol) and succinic anhydride (45 mg,
0.29 mmol) by the esterification A method,
The desired product (19 mg, 0.042 mmol, 15%) was obtained. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.83 (s, 3H), 2.68-2.79 (m, 4
H), 3.38-3.52 (m, 2H), 3.90
(S, 3H), 4.12 (s, 3H), 7.15 (s,
1H), 7.27-7.43 (m, 6H), 8.69.
(S, 1H). Example 111

[0360]

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The alcohol compound obtained in Example 22 (120 m
g, 0.33 mmol) and succinic anhydride (33 mg,
0.33 mmol) by the esterification A method,
The desired product (8 mg, 0.017 mmol, 5%) was obtained. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.82 (s, 3H), 2.63-2.75 (m, 4
H), 3.37 (s, 2H), 3.90 (s, 3H),
4.13 (s, 3H), 6.70-7.07 (m, 2
H), 7.16 (s, 1H), 7.33-7.38.
(M, 2H), 7.45 (s, 1H), 8.72 (s,
1H). Example 112

[0362]

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The propargyl alcohol compound (3z) and 4-
3: 1 mixture of fluorophenylacetone (560 m
g, 2.4 mmol) and chloroquinazoline (2j) (5
(00 mg, 1.98 mmol) was reacted in the same manner as in Example 7 to obtain the desired compound (720 mg, 92%). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.52 (t, J = 7.0 Hz, 3H), 1.57
(T, J = 7.0 Hz, 3H), 1.75 (s, 3
H), 3.07-3.22 (m, 2H), 4.06.
(Q, 2H, J = 7.0 Hz), 4.27 (q, 2H,
J = 7.0 Hz), 7.01 (dd, J = 8.7, 8.
7 Hz, 2H), 7.14 (s, 1H), 7.26
(S, 1H), 7.38 (dd, J = 8.7, 5.4H
z, 2H), 9.06 (s, 1H). Example 113

[0364]

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The alcohol compound obtained in Example 112 (720
mg, 1.83 mmol) in CH ₂ Cl ₂ (5 m
l) has succinic anhydride (400 mg, 4 mmol), 4
-Dimethylaminopyridine (50 mg, 0.41 mmol
l), triethylamine (1.5 ml, 10.8 mmol)
l) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was partitioned between chloroform and a 1N aqueous hydrochloric acid solution, and the organic layer was washed with saturated saline, dried over Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. After the residue was purified by column chromatography, the residue was washed with ether-hexane (1: 1) solvent (215).
(mg, 0.434 mmol, 24% yield).

Hereinafter, this half ester synthesis method is referred to as esterification method B. Single yellow crystal m. p. 129-131 ° C. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.55 (t, J = 6.8 Hz, 3H), 1.57
(T, J = 6.8 Hz, 3H), 1.79 (s, 3
H), 2.64-2.84 (m, 4H), 3.30-
3.50 (m, 2H), 4.13 (q, 2H, J = 6.
8Hz), 4.25-4.50 (m, 2H), 6.99
-7.06 (m, 2H), 7.15 (s, 1H), 7.
25-7.36 (m, 3H), 8.68 (s, 1H). IR (KBr) νcm ^-1 : 3423,2984,293
7, 2363, 1741, 1371, 1315, 123
6,1157,1062,937,827,653,5
69, 420. Example 114

[0367]

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Propardyl alcohol (3ae) (32
0 mg, 2.0 mmol) and chloroquinazoline (2
j) (500 mg, 1.98 mmol) was reacted in the same manner as in Example 7 to give the target compound (594 mg, 1.98 mmol).
(56 mmol, 80%). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.50 (t, J = 7.0 Hz, 3H), 1.56
(T, J = 7.0 Hz, 3H), 1.68 (s, 3
H), 3.12 (d, J = 13.3 Hz, 1H), 3.
22 (d, J = 13.3 Hz, 1H), 4.03 (q,
J = 7.0 Hz, 2H), 4.27 (q, J = 7.0H)
z, 2H), 7.15 (s, 1H), 7.27-7.3.
2 (m, 4H), 7.39-7.44 (m, 2H),
9.07 (s, 1H). Example 115

[0369]

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The alcohol compound obtained in Example 114 (300
mg, 0.80 mmol) and succinic anhydride (80 mg,
0.80 mmol) was reacted by the esterification B method to obtain the desired product (28 mg, 0.059 mmol, 7.4%). White crystals m. p. 148-150 ° C ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.52-1.58 (m, 6H), 1.81 (s, 3
H), 2.60-2.80 (m, 4H), 3.35-
3.50 (m, 2H), 7.16 (s, 1H), 7.2
6-7.40 (m, 6H), 8.70 (s, 1H). IR (KBr) νcm ^-1 : 3427,2984,293
7, 2363, 1612, 1577, 1500, 146
7, 1439, 1400, 1371, 1059, 93
9,827,706 Example 116

[0371]

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3,4-dichlorophenylacetone (1
g, 6.0 mmol) in THF (10 ml) was added to ethynylmagnesium chloride (0.5 M in THF).
12 ml, 6 mmol). An aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Mixture of starting materials 3,4-dichlorophenylacetone and propargyl alcohol (NMR ratio,
1: 2) (1.21 g) was obtained (65%). This mixture (200 mg, 0.64 mmol) and chloroquinazoline (2j) (176 mg, 0.70 mmol) were reacted in the same manner as in Example 7 to obtain a coupling product and DMF.
To give a 1: 1 mixture (164 mg, 49%).

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 1.52 (t, J = 6.9 Hz, 3
H), 1.56 (t, J = 7.9 Hz, 3H), 1.7
4 (s, 3H), 3.07 (d, J = 13.8 Hz, 1
H), 3.14 (d, J = 13.8 Hz, 1H), 4.
05 (q, J = 6.9 Hz, 2H), 4.26 (q, J
= 7.0 Hz, 2H), 7.11 (s, 1H), 7.2
3 (m, 2H), 7.36 (d, J = 8.2 Hz, 1
H), 7.51 (d, J = 1.8 Hz, 1H), 9.0
5 (s, 1H). Example 117

[0374]

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The alcohol compound obtained in Example 116 and DMF
(164 mg) was reacted by the esterification method B to obtain the desired product (122 mg, 65%). Pale yellow crystals m. p. 124-126 ° C ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.54 (t, J = 6.9 Hz, 3H), 1.58
(T, J = 7.0 Hz, 3H), 1.82 (s, 3
H), 2.60-2.88 (m, 4H), 3.31.
(D, J = 13.8 Hz, 1H), 3.39 (d, J =
13.8 Hz, 1 H), 4.14 (q, J = 6.9 H)
z, 2H), 4.28-4.38 (m, 2H), 7.1
7 (s, 1H), 7.24 (dd, J = 8.1, 1.8
Hz, 1H), 7.38 (s, 1H), 7.41 (d,
J = 8.1 Hz, 1H), 7.47 (d, J = 1.8H)
z, 1H), 8.72 (s, 1H). IR (KBr) νcm ^-1 : 3427,2984,293
7, 2364, 2235, 1741, 1612, 157
5,1500,1469,1371,1236,115
3, 1032, 933, 825, 652, 567. Example 118

[0376]

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Chloroquinazoline (2i) (100 mg,
0.55 mmol) and propargyl alcohol (3z)
(157 mg, 0.664 mmol) was reacted in the same manner as in Example 7 to obtain an oily substance (180 mg) containing a coupling product. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.75 (s, 3H), 3.05-3.20 (m, 2
H), 6.19 (s, 2H), 7.04 (dd, J =
8.5, 8.5 Hz, 2H), 7.13 (s, 1H),
7.38 (dd, J = 8.5, 5.5 Hz, 2H),
9.04 (s, 1H). Example 119

[0378]

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The oil containing the coupling product obtained in Example 118 (180 mg) and succinic anhydride (163 m
g, 1.63 mmol) was reacted by the esterification method B, and the desired product (65 mg, 0.14 mmol, Example 11) was obtained.
7 from 2i). Pale yellow crystals m. p. 152-154 ° C. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.81 (s, 3H), 2.60-2.85 (m, 4
H), 3.36 (s, 2H), 6.14 (s, 2H),
7.02 (t, J = 8.6 Hz, 2H), 7.05
(S, 1H), 7.27 (s, 1H), 7.31 (t,
J = 8.6 Hz, 1 H), 7.34 (t, J = 8.6 H)
z, 1H), 8.96 (s, 1H). IR (KBr) νcm ^-1 : 3425,3055,293
2,2364,2237,1901,1736,161
6,1545,1510,1467,1367,121
9,1153,1066,1035,906,877,
841,652,611,565. Example 120

[0380]

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The propargyl alcohol 3w (280 mg, 1.19 mmol) obtained in Synthesis Example 137 and chloroquinazoline (2j) (250 mg, 0.99 mmol) were
The reaction was carried out in the same manner as in Example 7 to obtain a coupling product (530 mg, AcOEt containing a solvent). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.43 (t, J = 7.0 Hz, 3H), 1.55
(T, J = 7.0 Hz, 3H), 3.19 (d, J = 1
3.4 Hz, 1 H), 3.26 (d, J = 13.4 H)
z, 1H), 3.79 (q, J = 7.0 Hz, 2H),
4.24 (q, J = 7.0 Hz, 2H), 6.90
(S, 1H), 7.22-7.34 (m, 7H), 7.
41-7.46 (m, 4H), 9.04 (s, 1H). Example 121

[0382]

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The product obtained in Example 120 (530 mg)
Was reacted with succinic anhydride (150 mg, 1.5 mmol) by esterification method B, and the target product (107 mg,
0.19 mmol, 19% from 2j of Example 119). White crystals m. p. 156.5-158 ° C. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.51 (t, J = 6.9 Hz, 3H), 1.54
(T, J = 6.9 Hz, 3H), 2.61-2.73
(M, 4H), 3.44 (s, 4H), 4.11 (q,
J = 6.9 Hz, 2H), 4.18 (q, J = 6.9H)
z, 2H), 7.07 (s, 1H), 7.21 (s, 1
H), 7.29-7.41 (m, 10H), 8.27.
(M, 1H). IR (KBr) νcm ^-1 : 3429,2982,293
5,2498,2233,1919,1739,161
2,1575,1500,1471,1439,137
1,1317,1238,1163,1039,93
3,877,827,746,700,565. Example 122

[0384]

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The propargyl alcohol 3x (315 mg, 1.8 mmol) obtained in Synthesis Example 38 and chloroquinazoline (2j) (380 mg, 1.5 mmol) were reacted in the same manner as in Example 7 to couple them. Product (5
88 mg, 1.5 mmol, quantitative). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.27 (t, J = 7.4 Hz, 3H), 1.50
(T, J = 7.0 Hz, 3H), 1.56 (t, J =
7.0 Hz, 3H), 3.07 (d, J = 13.4H)
z, 1H), 3.23 (d, J = 13.4 Hz, 1
H), 4.04 (q, J = 7.0 Hz, 2H), 4.2
7 (q, J = 7.0 Hz, 2H), 7.19 (s, 1
H), 7.25-7.36 (m, 4H), 7.40-
7.44 (m, 2H), 9.06 (s, 1H). Example 123

[0386]

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The coupling product (588 mg, 1.5 mmol) obtained in Example 122 was combined with succinic anhydride (2
Reaction with 25 mg, 2.25 mmol) by esterification method B, and the desired product (347 mg, 0.707 mmol,
47%). White crystals m. p. 158-159 ° C ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.22 (t, J = 7.3 Hz, 3H), 1.55
(T, J = 6.9 Hz, 3H), 1.60 (t, J =
6.9 Hz, 3H), 2.04 (dq, J = 7.3,
9.3 Hz, 2H), 2.58-2.75 (m, 4
H), 3.42 (d, J = 13.7 Hz, 1H), 3.
57 (d, J = 13.7 Hz, 1H), 4.05-4.
13 (m, 2H), 4.28-4.46 (m, 2H),
7.16 (s, 1H), 7.27-7.30 (m, 5
H), 7.48 (s, 1H), 8.66 (s, 1H). IR (KBr) νcm ^-1 : 3429,2982,293
7, 2363, 1739, 1612, 1577, 150
0, 1467, 1439, 1373, 1317, 123
8, 1170, 1035, 978, 939, 702, 6
52,567. Example 124

[0388]

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Propardyl alcohol (3Y) (1.7
g, 9.8 mmol) and chloroquinazoline (2j)
(2.5 g, 9.8 mmol) was reacted in the same manner as in Example 7, and the coupling product (2.55 g, 6.5 m) was obtained.
mol, 67%). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.43-1.50 (m, 3H), 1.53-1.60
(M, 3H), 1.77 (s, 3H), 2.21 (d
d, J = 10.1, 6.9 Hz, 2H), 2.99−
3.09 (m, 2H), 4.10-4.21 (m, 2
H), 4.23-4.32 (m, 2H), 7.15-
7.33 (m, 6H), 7.39-7.41 (m, 1
H), 9.08 (bs, 1H). Example 125

[0390]

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The product obtained in Example 124 (950 mg,
2.43 mmol) with succinic anhydride (500 mg, 5 m
mol) with the esterification B method, and the desired product (6
42 mg, 1.31 mmol, 54%). White crystals mp. 123-125 ° C ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.42 (t, 3H, J = 6.9 Hz), 1.44
(T, 3H, J = 6.9 Hz), 1.86 (s, 3
H), 2.30-2.38 (m, 2H), 2.49-
2.68 (m, 5H), 2.80-2.95 (m, 2
H), 3.28-3.46 (m, 1H), 4.25
(Q, J = 6.9 Hz, 2H), 4.28 (q, J =
6.9 Hz, 2H), 7.13-7.35 (m, 5
H), 7.36 (s, 1H), 7.54 (s, 1H),
9.03 (s, 1H). IR (KBr) νcm ^-1 : 3416,2984,293
7,2507,2366,2233,1896,174
1,1612,1575,1500,1467,137
1,1317,1236,1153,1087,103
2,933,827,748,700,567,54
3,412. Example 126

[0392]

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Carboxylic acid (prepared in Example 79) (350
mg, 0.69 mmol), L-alanine methyl ester hydrochloride (96 mg, 0.69 mmol), 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (133 mg, 0.69 mmol), 1-hydroxybenzotriazole (93 mg, 0.69 mmol)
l), triethylamine (96 μl, 0.69 mmol)
l) was dissolved in dichloromethane (2 ml) and stirred for 12 hours at room temperature. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain an amide (310 mg). This (250 mg) was reacted in the same manner as in Example 8 to obtain the desired product (159 mg, 0.28 mmol, 50%) in a yield.

Yellow crystals m. p. 162 ° -172 ° C. ¹ H NMR (d ₆ -DMSO, 250 MHz) δpp
m: 1.20 (d, J = 7 Hz, 3H), 1.35
(S, 3H), 1.41 (t, J = 6.9 Hz, 3
H), 1.42 (t, J = 6.9 Hz, 3H), 1.5
0-1.90 (m, 4H), 2.10-2.42 (m, 4H)
3H), 3.40-3.58 (m, 1H), 3.99-
4.18 (m, 3H), 4.25 (q, J = 6.9H
z, 2H), 7.10 (dd, J = 8.9, 8.9H
z, 2H), 7.25 (s, 1H), 7.32-7.4.
0 (m, 3H), 7.62-7.66 (m, 1H),
9.00 (s, 1H). IR (KBr) νcm ^-1 : 3406,2984,293
5,2812,2363,2214,1612,149
8, 1458, 1396, 1365, 1305, 123
0,1157,1109,1043,958,933,
854, 825, 653, 569, 424. Example 127

[0395]

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The carboxylic acid (prepared in Example 60) (400
mg, 0.84 mmol), L-alanine methyl ester hydrochloride (117 mg, 0.84 mmol), 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol), 1-hydroxybenzotriazole (114 mg, 0.84 mm)
ol), triethylamine (118 μl, 0.84 mm)
ol) in dichloromethane (2 ml) and 16
Stirred for hours. An aqueous ammonium chloride solution was poured into the reaction solution, and extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain an amide (440 mg). This (4
30 mg) was reacted in the same manner as in Example 8 to give the desired product (1
(06 mg, 0.19 mmol, 24%).

Single yellow crystal m. p. 129-142 ° C ¹ H NMR (d ₆ -DMSO, 250 MHz) δpp
m: 1.13 (t, J = 6.9 Hz, 3H), 1.19
(T, J = 5.8 Hz, 3H), 1.35-1.45
(M, 9H), 2.33-2.51 (m, 2H), 2.
80-3.0 (m, 3H), 3.02-3.20 (m,
2H), 3.22-3.38 (m, 1H), 3.98-
4.17 (m, 3H), 4.25 (q, J = 7.0H
z, 2H), 7.19-7.30 (m, 4H), 7.3.
3 (s, 1H), 7.34-7.40 (m, 2H). IR (KBr) νcm ^-1 : 3406, 2982, 293
5,2361,2341,214,1612,149
8, 1458, 1437, 1396, 1365, 130
7,1230,1109,1043,933,854,
763, 702, 669, 569, 420. Synthesis Example 19 Production of 4-chloro-6,7-dimethoxyquinazoline (2f) 1)

[0398]

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Formamide (264 ml) was added to 4,5-dimethoxyanthranilic acid methyl ester (51.85 g, 264 mmol), and the mixture was reacted at 170 ° C. for 10 hours. After cooling, water was added, the resulting precipitate was filtered and the residue was washed with water to give 6,7-dimethoxyquinazolin-4-one (34.52 g, 63%). ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
3.87 (s, 3H), 3.90 (s, 3H), 7.1
3 (s, 1H), 7.44 (s, 1H), 7.98
(S, 1H), 12.04 (br s, 1H).

2) 6,7-dimethoxyquinazoline-4-
On (34.5 g, 167 mmol) in toluene (34
0 ml) and POCl ₃ (56.44 g, 368 mm)
ol) and refluxed for 3 hours. After evaporating the solvent under reduced pressure and adding ice water, K ₂ CO ₃ was added until the aqueous layer became alkaline, and the mixture was extracted with chloroform (500 ml × 2).
The extract was concentrated, and the residue was washed with ether to give the title compound (31.09 g, 83%). 2f: ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 4.07 (s, 3H), 4.08 (s, 3H),
7.34 (s, 1H), 7.40 (s, 1H), 8.8
7 (s, 1H). Synthesis Example 20 4,6,7-Trichloroquinazoline (2
g) manufacture

[0401]

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The method described in the literature (Synth. Commu)
n. 1992, 22 , 3067-3074) to give 4,5-dichloroanthranilic acid (1) (yield 85%). 1 (2 g, 11.7 mmol) and formamide (5 ml) were heated under reflux at 200 ° C. for 12 hours. The reaction solution was diluted with water, and the resulting crystals were collected by filtration and dried under reduced pressure to obtain crystals (3.7 g). This is added to toluene (20
ml) and mixed with phosphorus oxychloride (2.2 ml, 23.6 ml).
mmol) and heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was poured, and the mixture was extracted with chloroform. After filtering off the insolubles using Celite, the organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 4,6,7-trichloroquinazoline (2 g) (683 mg, 25%). ^{2g: 1 H NMR (DMSO-} d 6, 250MHz)
δ ppm: 8.50 (s, 1H), 8.54 (s, 1
H), 9.18 (s, 1H). Synthesis Example 21 Production of 2-amino-4-chloro-6,7-dimethoxyquinazoline (2h)

[0403]

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1) A solution of methyl 4,5-dimethoxyanthranilate (1) (2.11 g, 10.0 mmol) in methanol (20 ml) was stirred under reflux while stirring with H ₂ NCN.
(0.40 g, 9.5 mmol) and concentrated hydrochloric acid (0.1 m
l) was added every 2 hours for a total of 10 additions. Concentrated hydrochloric acid (1.0 ml) was added, the mixture was stirred for about 30 minutes, and then cooled with ice. The product was separated by filtration, washed with cold water (10 ml), methanol (10 ml), Et ₂ O (10 ml), dried under reduced pressure, and dried with 2-amino-6,7-dimethoxyquinazoline-4
-On (4h) (1.92 g, 86%) was obtained.

4h: ¹ H NMR (DMSO-d ₆ , 2
50 MHz) δ ppm: 3.84 (s, 3H), 3.8
9 (s, 3H), 6.99 (s, 1H), 7.34
(S, 1H), 8.38 (br s, 2H), 12.7
0 (br s, 1H). 2) Compound 4h obtained above (1.916 g, 8.62 m)
mol), POCl ₃ (13 ml), Me ₂ NPh
(0.26 ml) was refluxed for 2 hours and concentrated, and ice water was added to the residue under ice cooling. The resulting solid is filtered off and 10% Na ₂ C
The mixture was partitioned between O ₃ aqueous solution and THF, and the THF layer was separated. The aqueous layer was extracted several times with THF, and the combined extracts were dried and concentrated. The residue was purified by silica gel column chromatography to obtain the desired 2-amino-4-chloro-6,7-dimethoxyquinazoline (2h) (580 mg, 28%). 2h; ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 3.99 (s, 3H), 4.00 (s, 3H),
5.06 (br s, 2H), 6.93 (s, 1H),
7.23 (s, 1H). Synthesis Example 22 Production of 2-amino-4-chloro-6,7-diethoxyquinazoline 1)

[0406]

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The reaction was carried out in the same manner as in Synthesis Example 22.
The product was filtered off, suspended in 7% aqueous ammonia,
After stirring for a while, the mixture was collected by filtration, dried, and treated with 2-amino-6,7-
Diethoxyquinazolone was obtained (88% yield). ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 1.34 (t, J = 7.2 Hz, 3H), 1.36
(T, J = 7.2 Hz, 3H), 4.02 (q, J =
6.9 Hz, 2H), 4.09 (q, J = 6.9 Hz,
2H), 6.16 (br s, 2H), 6.66 (s,
1H), 7.24 (s, 1H), 11.80 (br
s, 1H). 2)

[0408]

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2-Amino-6,7-diethoxyquinazolone (5.55 g, 22.25 mmol), N, N'-dimethylaniline (7 ml), POCl ₃ (7.3 ml,
78.3 mmol) was dissolved in toluene (100 ml) and refluxed for 2 hours. After concentrating the reaction solution, the residue was iced water,
NaHCO ₃ aqueous solution was added and extracted with EtOAc (200 m
1 × 4), and the extract was washed with a saturated aqueous solution of NaHCO ₃ (300 ml). The extract was dried and concentrated, and then purified by silica gel column chromatography. The desired 4-chloro-6,7-diethoxyquinazoline (370 mg,
6.2%).

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 3.99 (s, 3H), 4.00 (s,
3H), 5.10 (brs, 2H), 6.93 (s,
1H), 7.23 (s, 1H). ¹³ C NMR (CDCl ₃ , 75 MHz) δ ppm: 5
6.1, 56.3, 103.6, 104.6, 113.
4,147.9,151.0,157.2,158.
3,160.2 Synthesis Example 23 Production of 4-chloro-6,7-methylenedioxyquinazoline (2i)

[0411]

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[0412] Methyl 4,5-methylen
edoxy-2-Nitrobenzoate (1)
(4.5 g, 20.0 mmol) in MeOH (20 m
l) 10% palladium carbon (170 mg) was added to a -EtOAc (40 ml) solution, and the mixture was stirred overnight under a hydrogen atmosphere. The insolubles were filtered and the filtrate was concentrated to 2 (2.99 g,
Quantitative). 2: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 3.82 (s, 3H), 5.73 (brs, 2
H), 5.88 (s, 2H), 6.16 (s, 1H),
7.25 (s, 1H).

The same operation as in Synthesis Example 19 was performed for 2,
7-methylenedioxy-quinazolin-4-one (4i)
(67%) and 4-chloro-6,7-methylenedioxyquinazoline (2i) (16%). 4i: ¹ H NMR (DMSO-d ₆ , 250 MHz)
δ ppm: 6.20 (s, 2H), 7.12 (s, 1
H), 7.41 (s, 1H), 7.98 (s, 1H),
12.20 (br s, 1H). Synthesis Example 24 Synthesis of 4-chloro-6,7-diethoxyquinazoline 3

[0414]

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The desired product, 4-chloro-6,7-diethoxyquinazoline (2j), was synthesized from the starting material anthranilic acid methyl ester 1 in a two-step reaction as shown above. 1) 6,7-diethoxyquinazolin-4-one (4j)
Synthesis of anthranilic acid methyl ester 1 (138 g, 0.5
9 mol), and refluxed with formamide (763 ml). After 3.5 hours, ice water (1.1 liter) was added, and the mixture was stirred in an ice bath for 1 hour. The residue obtained by filtration was washed with ice water (1 liter), and then toluene (350 ml ×
2) was added and water contained in the residue was azeotropically distilled off. After drying under reduced pressure, 6,7-diethoxyquinazolin-4-one (118
g, 87%).

6,7-diethoxyquinazolin-4-one (4j): ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.38 (t, J = 6.9 Hz, 3H), 1.39
(T, J = 6.9 Hz, 3H), 4.13 (t, J =
6.9 Hz, 2H), 4.17 (t, J = 6.9 Hz,
2H), 7.11 (s, 1H), 7.43 (s, 1
H), 7.96 (s, 1H), 12.03 (s, 1H)
H).

2) Synthesis of the desired product 4-chloro-6,7-diethoxyquinazoline (2j) 6,7-diethoxyquinazolin-4-one (4j) (2j)
06.47 g, 0.881 mol) in toluene (1.4).
Liter) and phosphorus oxychloride (167 ml)
Was added dropwise at room temperature, toluene (0.1 liter) was added, and the mixture was refluxed. Two hours later, excess phosphorus oxychloride and toluene were distilled off under reduced pressure, and ice water (1 liter) was slowly added to the residue in an ice bath, followed by extraction with chloroform (2 liter). This extract was added to a 10% aqueous Na ₂ CO ₃ solution (1
Liter × 2), washed with saturated saline (1 liter × 2), dried (MgSO ₄ ), and concentrated to obtain crude crystals (247 g).

A solution of the obtained crude crystals in chloroform (60
0 ml), activated carbon (5 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes.
t ₂ O) to purify the desired product 4-chloro-6,7-
Diethoxyquinazoline (2j) (168.49 g, 76
%). 4-Chloro-6,7-diethoxyquinazoline (2j): ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.57 (t, J = 6.9 Hz, 3H), 1.58
(T, J = 6.9 Hz, 3H), 4.28 (q, J =
6.9 Hz, 2H), 4.29 (q, J = 6.9 Hz,
2H), 7.30 (s, 1H), 7.37 (s, 1
H), 8.84 (s, 1H). Synthesis Example 25 Synthesis of 4-chloro-6,7-diisopropoxyquinazoline (2k)

[0419]

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As shown above, the desired compound was synthesized from the starting material 3,4-dihydroxybenzoic acid (1) in 6 steps. The synthesis example of each step is shown below. 1) Synthesis of 3,4-diisopropoxybenzoic acid (2) 3,4-dihydroxybenzoic acid 1 (10.9 g, 71 m
mol) in a tetrahydrofuran solution (48 ml) and a 2N aqueous sodium hydroxide solution (142 ml, 282 mmol).
l) and isopropyl iodide (30
g, 177 mmol) in tetrahydrofuran (48
ml) was added dropwise over 20 minutes and then refluxed.

Four days later, tetrahydrofuran in the reaction solvent was distilled off under reduced pressure, and the residue was washed with normal hexane (300 ml). The resulting aqueous layer was acidified by adding concentrated hydrochloric acid, extracted with ethyl acetate (600 ml), washed with brine, dried (MgSO ₄ ), and concentrated, and the resulting residue was subjected to silica gel column chromatography (solvent, Purified with chloroform-methanol system, and the desired product 2 (2.9 g, 17
%). 3,4-diisopropoxybenzoic acid 2 ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.36 (d, J = 6.1 Hz, 12H), 4.51
(Dq, J = 6.1, 6.1 Hz, 1H), 4.62
(Dq, J = 6.1, 6.1 Hz, 1H), 6.93
(D, J = 8.5, 1H), 7.65 (d, J = 1.9
Hz, 1H), 7.72 (dd, J = 8.5, 1.9H)
z, 1H).

2) Synthesis of 4,5-diisopropoxy-2-nitrobenzoic acid (3) 3,4-diisopropoxybenzoic acid (2) (2.4 g,
10.0 mmol) in dichloromethane (50 ml) at a temperature of -55 to 65 ° C. in a dichloromethane (20 ml) solution of fuming nitric acid (1 ml) in anhydrous dichloromethane (1.4 ml) in dichloromethane (20 ml). 1
It was dropped simultaneously over 5 minutes. 30 minutes later, ice water (100m
l) was slowly added, extracted with dichloromethane (300 ml), washed with saturated saline (100 ml), and dried (MgSO4).
O ₄ ) and the residue obtained by concentration were purified by silica gel column chromatography (solvent: chloroform-methanol system) to obtain the desired product 3 (2.42 g, 80%). 4,5-diisopropoxy-2-nitrobenzoic acid 3 ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 1.28-1.33 (m, 12H), 4.68-
4.76 (m, 2H), 7.29 (s, 1H), 7.5
7 (s, 1H).

3) Synthesis of 4,5-diisopropoxy-2-nitrobenzoic acid methyl ester (4) 4,5-diisopropoxy-2-nitrobenzoic acid (2.
Methanol (10 ml) and diethyl ether (40 ml) were added to dimethylaminopyridine (51.3 mg, 5 mol%) and dicyclohexylcarbodiimide (1.91 g, 9.2 mmol) at room temperature.
l) was added and stirred. After 5 hours, filter through celite,
After washing with diethyl ether, the mother liquor was washed with 10% Na ₂
The residue was washed with a CO ₃ aqueous solution (40 ml) and a saturated saline solution (20 ml), dried (MgSO ₄ ) and concentrated, and the obtained residue was purified by silica gel column chromatography (solvent, chloroform-methanol system). , 69
%).

4,5-diisopropoxy-2-nitrobenzoic acid methyl ester (4) ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.36-1.44 (m, 12H), 3.90 (s, 3
H), 4.59 (dt, J = 6.1 Hz, 1H), 4.
63 (dt, J = 6.1 Hz, 1H), 7.08 (s,
1H), 7.46 (s, 1H).

4) Synthesis of 3,4-diisopropoxyanthranilic acid methyl ester (5) Methanol of 4,5-diisopropoxy-2-nitrobenzoic acid methyl ester (4) (1.32 g, 4.4 mmol) After the solution (40 ml) was replaced with nitrogen, palladium carbon (60 mg) was added, the mixture was replaced with hydrogen, and the mixture was vigorously stirred at room temperature. After 7 hours, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to give the desired product 5 (1.18).
g, 99%).

3,4-diisopropoxyanthranilic acid methyl ester (5) ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.28 (d, J = 6.2 Hz, 6H), 1.36
(D, J = 6.2 Hz, 6H), 3.83 (s, 3
H), 6.13 (s, 1H), 7.42 (s, 1H). 5) Synthesis of 6,7-diisopropoxyquinazolin-4-one (6) Formamide (10 ml) was added to 4,5-diisopropoxyanthranilic acid methyl ester (5) (1.4 g, 5.2 mmol). Refluxed. Two hours later, ice water (30
ml), and the residue obtained by filtration was washed with ice water and dried to obtain the desired product 6 (876 mg, 64%).

6,7-diisopropoxyquinazoline-4
-On (6) ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 1.30 (d, J = 6.3 Hz, 6H), 1.33
(D, J = 6.3 Hz, 6H), 4.59 (dt, J =
6.3, 6.3 Hz, 1H), 4.76 (dt, J =
6.3, 6.3 Hz, 1H), 7.13 (s, 1H),
7.46 (s, 1H), 7.95 (s, 1H), 12.
02 (s, 1H). 6) Synthesis of 4-chloro-6,7-diisopropoxyquinazoline (2k) 6,7-diisopropoxyquinazolin-4-one 6 (8
76 mg, 3.34 mmol) of toluene (30 ml)
After adding phosphorus oxychloride (7 ml) to the solution at room temperature,
Refluxed. Two hours later, after concentration, an aqueous 10% Na ₂ CO ₃ solution was added, extracted with chloroform, washed with brine, dried (MgSO ₄ ), and concentrated. The residue obtained was purified by silica gel column chromatography (solvent, n-hexane- The residue was purified with ethyl acetate to give the desired product 2k (577 mg, 61
%).

4-Chloro-6,7-diisopropoxyquinazoline (2k) ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.46 (d, J = 6.1 Hz, 6H), 1.48
(D, J = 6.1 Hz, 6H), 4.72 (dt, J =
6.1, 6.1 Hz, 1H), 4.76 (dt, J =
6.1, 6.1 Hz, 1H), 7.31 (s, 1H),
7.44 (s, 1H), 8.83 (s, 1H).

Synthesis Example 26 Synthesis of 2 L of 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine

[0430]

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The desired product 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine (3) is a starting material 6-fluoropyrido [3,2-d] pyrimidine-
It was synthesized in two steps from 4-one (1). (1) Synthesis of 6-dimethylaminopyrido (3,2-d) pyrimidine (2) According to the method of WA Denney et al. (J. Med. Ch.
em. 1996, 39, 1823-1835) To a prepared 6-fluoropyrido [3,2-d] pyrimidin-4-one (1) (540 mg, 3.27 mmol) was added a 50% aqueous dimethylamino solution (7 ml), and ethanol (50 m
l) was added, and the mixture was sealed and stirred at 100 ° C.

After 4 hours, the temperature was returned to room temperature and the mixture was allowed to stand overnight, and then concentrated to obtain 2 (527 mg). 6-dimethylaminopyrido [3,2-d] pyrimidine-
4-one (2) ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 3.13 (s, 6H), 7.19 (d, J = 9.3)
Hz, 1H), 7.77 (d, J = 9.3 Hz, 1
H), 7.84 (s, 1H).

(2) Synthesis of 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine (2 L) 6-dimethylaminopyrido [3,2-d] pyrimidine-
Phosphorous oxychloride (15 ml) was added to 4-one (2) (360 mg, 2.04 mmol) and the mixture was refluxed. After 30 minutes, excess phosphorus oxychloride was distilled off under reduced pressure, and ice water (100 ml) was slowly added in an ice bath. EtOAc (200m
1), washed (saturated saline) and dried (Na ₂ SO 4)
₄ ) and concentrated to obtain 2 L of the desired product (203 mg, 51%). 4-chloro-6-dimethylaminopyrido [3,2-d] pyrimidine (2 L) ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 3.25 (s, 6H), 7.62 (d, J = 9.3)
Hz, 1H), 8.07 (d, J = 9.3 Hz, 1
H), 8.74 (s, 1H). Synthesis Example 27 Synthesis of 4-chloropyrido [2,3-d] pyrimidine (2m)

[0434]

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[0435] R. K. Robins, G .; H. Hitc
hings method (J. Am. Chem. So
c. , 77, 2256 (1995). 4-chloropyrido [2,3-d] pyrimidine (2 m) ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 7.92 (dd, J = 8.3, 4.3 Hz, 1
H), 8.75 (dd, J = 8.3, 1.7 Hz, 1
H), 9.30 (s, 1H), 9.38 (dd, J =
4.3, 1.7 Hz, 1H). Synthesis Example 28 Synthesis of ethyl 4-chloro-5-amino-6-pyrimidylaminoacetate (2n)

[0436]

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[0437] W. R. According to the method of Boon et al.
hem. Soc. 96 (1951)) Ethyl 4
-Chloro-5-amino-6-pyrimidylaminoacetate (2n) was synthesized. Ethyl 4-chloro-5-amino-6-pyrimidylaminoacetate (2n) ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 1.19 (t, J = 7.1 Hz, 3H), 4.13
(Q, J = 7.1 Hz, 2H), 4.19 (d, J =
5.7 Hz, 2H), 8.49 (s, 1H), 8.82
(T, J = 7.1 Hz, 1H). Synthesis Example 29 Synthesis of acetylene compound 3n

[0438]

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60% NaH (1.4 g, 34.4 mmol)
l) was washed with THF to give a suspension of THF (10 ml) in 1 (1.38 g, 8.61 mmol) of THF.
The solution (10 ml) was added dropwise at room temperature. After stirring for 10 minutes, the bromoacetic acid (1.79 g, 12.9 mmol) T
An HF solution (10 ml) was added dropwise at room temperature. Further THF
(15 ml) and the mixture was stirred in a suspended state. Two days later, H ₂ O (60 ml) was added, and Et ₂ O (30 ml) was added.
After washing with water, the aqueous layer was adjusted to pH 2 with dilute sulfuric acid and EtOAc
Extracted with 100 ml. The extract was washed with a saturated saline solution, dried (Na ₂ SO ₄ ) and concentrated to obtain crude crystals of the carboxylic acid compound (2.04 g).

In a methanol solution (8 ml) of the obtained crude crystals (640 mg), trimethylsilyldiazomethane was added.
A 10% hexane solution (14 ml) was added dropwise. After concentrating this, silica gel column chromatography (el
uent: Hex / EtOAc = 10/1)
The desired product 3n (505 mg, 80%) was obtained. Acetylene derivative 3n; ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.42 (s, 3H), 2.53 (s, 1H), 2.9
7 (d, J = 13.2 Hz, 1H), 3.10 (d, J
= 13.2 Hz, 1H), 3.75 (s, 3H), 4.
24 (d, J = 10.8 Hz, 1H), 4.29 (d,
J = 10.8 Hz, 1H), 7.26-7.34 (m,
5H). Synthesis Example 30 Production of acetylene compound 3p

[0441]

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[0442] Methyl 4-hydroxyben
Zoate (2.10 g, 13.8 mmol) in CH ₃
The CN solution (30 ml) was stirred under ice-cooling, and DBV (2.7
ml, 17.9 mmol), CuCl ₂ -2H ₂ O
(2.5 mg, 0.014 mmol) and then 3-
Chloro-3-methyl-1-butyne
A solution of (1.84 g, 17.9 mmol) in CH ₃ CN (8 ml) was added dropwise over 20 minutes. After the temperature was raised to room temperature and allowed to stand overnight, CuCl ₂ .2H ₂ O (6 mg) was used.
And 3-Chloro-3-methyl-1-bu
Tyne (0.5 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the residue was treated with a 1N aqueous HCl solution (30%).
ml) and toluene (50 ml).
HCl aqueous solution (30 ml × 2), 10% Na ₂ CO ₃
After washing with an aqueous solution (30 ml × 2) and a saturated saline solution (30 ml), drying (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain the target acetylene 3p (2.93 g, quantitative). 3p: ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 1.69 (s, 6H), 2.62 (s, 1H),
3.88 (s, 3H), 7.24 (d, J = 8.9H)
z, 2H), 7.97 (d, J = 8.9 Hz, 2H). Synthesis Example 31 Production of acetylene compound 3q

[0443]

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The same operation as in the above Synthesis Example was performed using ethyl salicylate as a starting material. The crude product is purified by silica gel column chromatography (hexane: EtOAc =
1: 0 → 6/1) and purified acetylene 3q
(1.95 g, 72%). 3q: ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 1.39 (t, J = 7.2 Hz, 3H), 1.6
8 (s, 6H), 2.57 (s, 1H), 4.35
(Q, J = 7.2 Hz, 2H), 7.09 (dd, J =
1.1, 7.6 Hz, 1H), 7.36-7.43
(M, 1H), 7.58 (dd, J = 1.1, 8.3H
z, 1H), 7.75 (dd, J = 1.8, 7.7H
z, 1H). Synthesis Example 32 Production of aminoacetylene 3r

[0445]

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NaH (435 mg, 10.9 mmol,
60% in mineral oil was washed with dry hexane, DMF (5 ml) was added, and the mixture was stirred on an ice bath.
The aminoacetylene 3h (591m) produced in Synthesis Example 14
g, 2.72 mmol) in THF (2 ml) was added, followed by BrCH ₂ CO ₂ H (567 mg, 4.08 mm).
ol) was added dropwise and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the reaction solution was poured into a 10% aqueous citric acid solution. The product was extracted with CH ₂ Cl ₂ (20 ml × 2), and the extract was dried (Na ₂ SO ₄ ) and concentrated to obtain a DMF solution (79 wt%) of the desired product 3r (210 mg, reduced yield 22).
%).

3r: ¹ H NMR (CDCl ₃ , 300
MHz) δ ppm: 1.41 (s, 3H), 2.54
(S, 1H), 2.69 (s, 3H), 2.93 (d,
J = 12.7 Hz, 1H), 2.92-3.18 (m,
2H), 3.27 (d.J = 12.7 Hz, 1H),
3.81 (m, 2H), 4.14 (2d, J = 17.5)
Hz, 2H), 7.27-7.40 (m, 5H). Synthesis Example 33 Production of acetylene 3s

[0448]

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The compound was produced according to the following scheme.

[0450]

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1) Ethyl 4-piperidin
ecarboxylate (4.45 g, 28.3 mm
ol) and Et ₃ N (4.7 ml, 34.0 mmol)
l) THF solution (50 ml) was stirred on an ice bath, and (t-
(BuOCO) ₂ O (6.80 g, 31.1 mmol) and DMAP (73 mg) were added, and the mixture was allowed to stand at room temperature overnight. The reaction was concentrated, water (50 ml) and EtOAc
(100 ml), and the organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, a 1N aqueous solution of hydrochloric acid, and then with a saturated aqueous solution of sodium hydrogencarbonate, dried (Na ₂ SO ₄ ) and concentrated to give the intended product 1 as a pale brown oil (7.22 g, 9
9%).

1: ¹ H NMR (CDCl ₃ , 300M
Hz) δ ppm: 1.26 (t, J = 7.0 Hz, 3
H), 1.46 (s, 9H), 1.52-1.70.
(M, 2H), 1.80-1.95 (m, 2H), 2.
43 (tt, J = 3.9, 11.0 Hz, 1H);
84 (m, 2H), 4.01 (br d, J = 12.8)
Hz, 2H), 4.14 (q, J = 7.0 Hz, 2
H). 2) The above THF solution (40 ml) was cooled to −65 ° C., and 1M lithium bis (trimethy) was added.
lsilyl) amide THF solution (14.7m
1, 14.7 mmol) was added dropwise. After 40 minutes, benzyl bromide (1.67 ml, 14.1 mmol) was added dropwise, and the mixture was stirred at -65 ° C for 30 minutes, and then slowly heated to room temperature. The reaction solution was cooled to 0 ° C., a saturated NH ₄ Cl aqueous solution was added to stop the reaction, and the mixture was concentrated. The residue was water (40 ml)
-Partitioned between EtOAc (40 ml) and the aqueous layer was separated with EtOAc
(30 ml). Dry the organic layer (Na ₂ S
O ₄ ) and after concentration, the residue was purified by silica gel column chromatography (hexane: EtOAc = 9: 1) to give 2 (4.23 g, 91%).

2: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 1.18 (t, J = 7.1 Hz, 3
H), 1.44 (s, 9H), 1.32-1.65.
(M, 4H), 2.09 (br d, J = 12.7H
z, 2H), 2.70-2.90 (m, 2H), 2.8
2 (s, 2H), 3.80-4.00 (m, 2H),
4.10 (q, J = 7.1 Hz, 2H), 7.00-
7.10 (m, 2H), 7.18-7.30 (m, 3
H). 3) The toluene solution of 2 (20 ml) was cooled to −65 ° C., and a 1.1 M DIBAL toluene solution (8.0 ml,
8.77 mmol) was added dropwise. After 5 minutes, add dilute hydrochloric acid,
Stirred at room temperature for a while. Dry the organic layer (Na ₂ S
O ₄ ) concentrated and the residue purified by silica gel column chromatography to give aldehyde 4 (381 mg, 17%)
And alcohol 3 (306 mg, 14%) were obtained as product.

4: ¹ H NMR (CDCl ₃ , 300M
Hz) δ ppm: 1.44 (s, 9H), 1.40 −
1.66 (m, 4H), 1.93 (br d, J = 1
3.7 Hz, 2H), 2.78 (s, 2H), 2.85
(Br t, J = 12.7 Hz, 2H), 3.87 (b
rd, J = 13.2 Hz, 2H), 7.02-7.1.
0 (m, 2H), 7.18-7.35 (m, 3H),
9.57 (s, 1H). 3: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 1.46 (s, 9H), 1.40-1.50 (m,
4H), 2.72 (s, 2H), 3.33-3.58
(M, 4H), 3.40 (s, 2H), 7.12-7.
32 (m, 5H).

4) Alcohol 3 (306 mg, 1.4 m)
mol), NaBr (430 mg, 4.2 mmol) and 4-Hydroxy-2,2 ', 6,6'-tet
ramethylpiperidine-N-oxid
e (25 mg) in dichloromethane (6 ml) -saturated Na
A mixed solution of an aqueous HCO ₃ solution (10 ml) was stirred on an ice bath, and a 5% aqueous NaOCl solution (2 ml) was added dropwise thereto. After 10 minutes, EtOH (0.5 ml) was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (10 ml). The extract was dried over MgSO ₄ , the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain aldehyde 2 (287 mg, 68%).

5) (EtO) ₂ P (O) CCl ₃ (J.
Am. Chem. Soc. , 1947, 69, 100
2) (766 mg, 3.0 mmol) in THF (4m
l) Cool the -Et ₂ O (6 ml) solution to -100 ° C,
1.61 M n-BuLi hexane solution (1.8 ml,
2.9 mmol) was added dropwise. Add aldehyde 2 (3
78mg, 1.25mmol) THF (2.5ml)
It was added dropwise -Et ₂ O (2.5ml) solution, after raising the temperature to room temperature over the reaction mixture for 5 hours, refluxed for 15 minutes. The reaction mixture was cooled to −30 ° C., aqueous NH ₄ Cl was added, and extracted with EtOAc (20 ml × 2). The extract was dried (Na ₂ SO ₄ ) and concentrated, and the residue was purified by silica gel column chromatography to obtain dichloro form 5 (414 mg, 48%). 5: ¹ H NMR (CDCl ₃ , 300 MHz) δpp
m: 1.45 (s, 9H), 1.22-1.52 (m,
2H), 1.98 (br d, J = 12.4 Hz, 2
H), 1.75-1.93 (m, 2H), 2.83.
(S, 2H), 3.82-4.00 (m, 2H), 5.
59 (s, 1H), 7.07-7.17 (m, 2H),
7.20-7.35 (m, 3H).

6) Under ice cooling, 5 (394 mg, 1.1 mm)
ol) in a THF solution (10 ml) of 1.6 M n-Bu.
Li hexane solution (1.52 ml, 2.43 mmol)
Was added dropwise, and the temperature was slowly raised to room temperature. An aqueous NH ₄ Cl solution was added to the reaction mixture to stop the reaction, and the product was extracted with a hexane-EtOAc mixture. The extract is dried (Na
₂ SO ₄ ) and concentrated to give 6a. 6a to EtOAc
(0.5 ml) and 4N HCl / EtO under ice-cooling.
An Ac solution (2 ml) was added and stirred for 10 minutes. After further stirring at room temperature for 1 hour, Et ₂ O (4 ml) was added and the resulting precipitate was collected by filtration to give 6b · HCl as white powder crystals (210 mg, 81%). 6b · HCl: ¹ H NMR (DMSO-d ₆ , 300
MHz) δ ppm: 1.70-1.95 (m, 4H),
2.81 (s, 2H), 2.86 (s, 1H), 3.0
0-3.20 (m, 2H), 3.22-3.35 (m,
2H), 7.27 (m, 5H), 9.12 (brs,
1H), 9.30 (brs, 1H).

7) 6b · HCl (203 mg, 0.86
mmol), K ₂ CO ₃ (178 mg, 1.29 mmol)
l), BrCH ₂ CO ₂ Et (114 μl, 1.03 m
mol) of toluene (5 ml) was stirred at room temperature for 2 hours. After K ₂ CO ₃ (178 mg) was added and the mixture was allowed to stand at room temperature overnight, insolubles were removed by filtration. The filtrate was concentrated and the residue was combined with a saturated aqueous solution of NaHCO ₃ (10 ml) and EtOAc.
c (10 ml) was added. Dry the organic layer (Na ₂ S
O ₄ ), concentrated, and the residue was purified by silica gel column chromatography to obtain the target acetylene 3s as an oil (130 mg, 53%). 3s: ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 1.26 (t, J = 7.1 Hz, 3H), 1.5
8-1.78 (m, 4H), 2.24 (s, 1H),
2.51 (2 dt, J = 3.5, 11.3 Hz, 2
H), 2.76 (s, 2H), 2.81 (m, 2H),
3.21 (s, 2H), 4.18 (q, J = 7.1H)
z, 2H), 7.16-7.32 (m, 5H). Synthesis Example 34 Production of acetylene compound 3t

[0459]

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The compound was produced according to the following scheme.

[0461]

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1) N- (t-Butox) as a starting material
ycarbonyl) -4-piperidone
2 (quantitative) by the same operation as in Synthesis Examples 7 and 8 using (1)
And 4 were obtained as a crude product. 2: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 1.46 (s, 9H), 1.93 (2ddd, J =
(3.9, 9.4, 13.2 Hz, 2H), 2.07
(S, 3H), 2.15 to 2.25 (m, 2H), 2.
67 (s, 1H), 3.34 (2ddd, J = 3.6,
9.7, 13.5 Hz, 2H), 3.72 (m, 2
H).

2) Et of crude purified 4 (1.08 g)
_{The 2} O solution (1 ml) was stirred on an ice bath and 4N HCl / E
A tOAc solution (4 ml) was added dropwise. After stirring at room temperature for a while, the product 5 was collected by filtration. The crude product (890)
mg), BrCH ₂ CO ₂ Et (0.61 ml, 5.5
mmol) and K ₂ CO ₃ (2.2 g, 15.9 mm
ol) in toluene (10 ml),
Stirred at C for 4 hours. After allowing the reaction mixture to cool, water (40 m
1), EtOAc (40 ml) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (15 ml), and the extract was dried (Na ₂ SO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography (hexane: EtOAc = 4:
Purification was carried out by 1: 1: 1) to obtain acetylene 3t (460 mg, yield 37% from 1).

3t: ¹ H NMR (CDCl ₃ , 300
MHz) δ ppm: 1.28 (t, J = 7.1 Hz, 3
H), 1.93 (2ddd, J = 3.7, 10.6, 1
3.5Hz, 2H), 2.22 (m, 2H), 2.49
(S, 1H), 2.66 (2ddd, J = 2.6, 1
0.5 Hz, 2H), 2.82 (m, 2H), 3.25
(S, 2H), 4.19 (q, J = 7.1 Hz, 2
H), 6.79 (m, 1H), 6.94 (m, 2H),
7.18 (m, 2H). Synthesis Example 35 Acetylene 3u

[0465]

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The compound was produced according to the following scheme.

[0467]

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1) CeCl ₃ : 7H ₂ O (10.12)
g, 27.2 mmol) was dried at 140 ° C. under reduced pressure with stirring for 4 hours. To this was added THF (70 ml) at room temperature, and the mixture was stirred for 1 hour. On the other hand, a THF solution (20 ml) of trimethylsilylacetylene (3.84 ml, 27.2 mmol) was cooled in a dry ice-EtOH bath,
1.6 M n-BuLi hexane solution (16.9 ml,
27.0 mmol) was added dropwise, and the temperature was slowly raised to room temperature. This solution was prepared by the method described above, added dropwise to the CeCl ₃ THF suspension cooled to -65 ° C, and stirred for 30 minutes. Add this suspension to indanone (3.30 g, 25.0 m
mol) in THF (9 ml) was added dropwise, and after stirring for 1 hour, acetic anhydride (3.1 ml, 32.4 mmol) was added. The reaction solution was slowly warmed to room temperature, left overnight, and then added with an aqueous NH ₄ Cl solution and concentrated. The product is treated with EtO
Extract with Ac, wash the extract with saturated aqueous NaHCO ₃ , dry (Na ₂ SO ₄ ) and concentrate. The residue was subjected to short silica gel column chromatography (hexane: EtOA).
c = 4/1) to give an oil containing 2. This was dissolved in THF (20 ml), and 1 M n-Bu ₄ NF
A THF solution (1 ml, 1.0 mmol) was added and stirred at room temperature for 1 hour. Saturated aqueous NH ₄ Cl was added to the reaction solution and the product was extracted with EtOAc (50 ml). The extract was dried (Na ₂ SO ₄ ), concentrated, and the residue was subjected to silica gel column chromatography (hexane: EtOAc = 1).
Purification from 5: 1 to 9: 1) afforded 4 as a crystalline solid (1.71 g, 34%).

4: ¹ H NMR (CDCl ₃ , 300M
Hz) δ ppm: 2.02 (s, 3H), 2.57
(S, 1H), 3.56 (2d, J = 17.5 Hz, 2
H), 358 (2d, J = 17.5 Hz, 2H), 7.
21 (s, 4H). 2) 4 and Ethyl 4-piperi as starting materials
The same operation as in Synthesis Example 8 was performed using Dinecarboxylate to obtain the desired product 3u as white powder crystals (yield: 20%). 3u: ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 1.26 (t, J = 7.1 Hz, 3H), 1.7
2-1.90 (m, 3H), 1.94-2.02 (m, 3H)
2H), 2.16 (s, 1H), 2.28-2.48
(M, 3H), 2.93 (m, 2H), 3.15 (d,
J = 14.7 Hz, 2H), 3.27 (d, J = 14.
7 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2
H), 7.10-7.25 (m, 4H). Synthesis Example 36 Acetylene 3v

[0470]

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The compound was produced according to the following scheme.

Embedded image 1) Diethyl Benzylmalonate
(1.00 g, 4.0 mmol) in THF (40 m
t-BuOK (494 mg, 4.4 mmol) was added to 1), and the mixture was stirred at room temperature for 30 minutes, and then cooled in an ice-methanol bath. [(Trimethylsilyl) ethylny
l] (phenyl) iodoniumTriflat
e (J. Org. Chem. 1991, 56, 3912).
(Prepared according to the method described in (1)) (1.80 g, 4.0 mmol) in THF (20 ml), and the mixture was stirred at room temperature for 3 hours.
Partition with water-CH ₂ Cl ₂ and dry the organic layer (Na ₂ SO
₄ ), concentrated, the residue was subjected to silica gel column chromatography, and Diethyl benzyl [(tri
methylsilyl) ethyln] malon
ate (2) was obtained.

2: ¹ H NMR (CDCl ₃ , 300M
Hz) δ ppm: 0.16 (s, 9H), 1.23
(T, J = 7.1 Hz, 6H), 3.38 (s, 2
H), 4.21 (q, J = 7.1 Hz, 4H), 7.1
2-7.36 (m, 5H). 2) the 2 was dissolved in water THF (10 ml), 1M of n-Bu ₄ NF THF solution (0.1 ml, 0.1 mm
ol) and stirred at room temperature for 1 hour. EtOAc (30
ml) and a saturated aqueous NH ₄ Cl solution (30 ml), the organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated, and the residue was purified by silica gel column chromatography to obtain the desired 3v (390 mg, 1 to 32%). 3v: ¹ H NMR (CDCl ₃ , 300 MHz) δp
pm: 1.25 (t, J = 7.1 Hz, 6H), 2.5
2 (s, 1H), 3.41 (s, 2H), 4.23
(Q, J = 7.1 Hz, 4H), 7.16-7.34
(M, 5H). Synthesis Example 37

[0473]

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Dibenzyl ketone (2.1 g, 10 mmol
To l) was added a 0.5 M ethynylmagnesium chloride THF solution (24 ml, 12 mmol) and the mixture was stirred. An aqueous ammonium chloride solution was poured, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product 3w (2.28 g,
9.7 mmol, 97%). 3w: ¹ H NMR (CDCl ₃ , 250 MHz) δp
pm: 2.49 (s, 1H), 3.02 (s, 4H),
7.27-7.38 (m, 10H). Synthesis Example 38

[0475]

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1-phenyl-2-butanone (2.96)
g, 20 mmol) in THF (3 ml) at 0.5 M
Ethinyl magnesium chloride THF solution (60 ml,
30 mmol). An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.

The target substance 3x (3.18 g, 18.3 mmo
1, 91%). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.11 (t, J = 7.4 Hz, 3H), 1.74
(Q, J = 7.4 Hz, 2H), 2.46 (s, 1
H), 2.88 (d, J = 13.2 Hz, 1H), 3.
00 (d, J = 13.2 Hz, 1H), 7.25-7.
50 (m, 5H). Synthesis Example 39

[0478]

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Benzyl acetone (7.4 g, 50 mmol
l) in THF (20 ml) was added to a 0.5 M ethynylmagnesium chloride THF solution (110 ml, 55 mm
ol). 1N HCl was poured into the reaction solution, and the organic layer was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to give propargyl alcohol 3Y (8.8 g, 0.1 g). 05 mol quantitative). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.55 (s, 3H), 1.94-2.03 (m, 2
H), 2.51 (s, 1H), 2.83-2.90
(M, 2H), 7.16-7.32 (m, 5H). Synthesis Example 40

[0480]

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4-fluorophenylacetone (250 m
g (1.64 mmol) in THF (3 ml).
5M ethynylmagnesium chloride THF solution (3.
(5 ml, 1.75 mmol). An aqueous ammonium chloride solution was added to the reaction solution, and the organic layer was extracted with ethyl acetate, washed with brine, dried over sodium sulfate,
The solvent was distilled off under reduced pressure to obtain a mixture of propargyl alcohol 3Z and the raw material (215 mg, NMR ratio 3: 1, 57%). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.54 (s, 3H), 2.47 (s, 1H), 2.8
9 (d, J = 13.4 Hz, 1H), 2.98 (d, J
= 13.4 Hz, 1H), 6.97-7.06 (m, 2
H), 7.26-7.32 (m, 2H). Synthesis Example 41 2 was synthesized by the following method.

[0482]

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1) 3,4-Dichlorophenylacetic acid (2
Thionyl chloride (11.8) was added to a solution of 0.0g (97.5 mmol) in 1,2-dichloroethane (100 ml).
g, 99.2 mmol) and one drop of DMF, and the mixture was heated under reflux for 3 hours and concentrated under reduced pressure to obtain 23.3 g of an oily substance. Metallic magnesium (2.56 g, 107 mmo
l), carbon tetrachloride (0.2 ml) was added to a mixed solution of ethanol (2 ml) and THF (30 ml), and then a solution of diethyl malonate (16.8 g, 105 mmol) in ethanol (10 ml) and THF (8 ml) was added. . The oil obtained above (23.3 g) in THF (10 ml) was then obtained.
The solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a 2N aqueous solution of sulfuric acid (50 ml) and water (20 ml) were added, and the mixture was stirred. The oil layer was separated, and the aqueous layer was extracted with ethyl acetate. Distilled off. Acetic acid (24 ml), water (16 ml) and concentrated sulfuric acid (3 ml) were added thereto, and the mixture was refluxed under heating (115 ° C to 145 ° C, 8 ml).
Time). After the reaction solution was extracted with ether and washed with a 20% aqueous sodium hydroxide solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 3,4-dichlorophenylacetone (1) (15.3 g, 91 mmol) was used.
1, yield 94%).

2) 0.30 g of 3,4-dichlorophenylacetone (1) (1.28 g, 7.6 mmol) was added under ice cooling.
5M ethynylmagnesium chloride THF solution (16
ml, 8 mmol) was added dropwise, followed by acetic anhydride (0.8
2 ml, 8.6 mmol) were added dropwise. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, and concentrated under reduced pressure to obtain an oily substance (1.55 g).
In the same manner as above, 8.1 g of an oily substance was obtained from 3,4-dichlorophenylacetone (7 g, 41.8 mmol).

The oily substances were combined, and THF (100 m
l) and diethylamine (20 ml, 193 m
mol) and copper (I) chloride (200 mg, 2 mmol) were added and the mixture was heated under reflux. The reaction solution was extracted with ethyl acetate, washed with an aqueous ammonium chloride solution, and the solvent was distilled off under reduced pressure. The residue was washed by column chromatography, and propargylamine 3aa (1.74 g, 6.2 mmol, yield 12)
%). ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.11 (t, J = 7.2 Hz, 6H), 1.24
(S, 3H), 2.32 (s, 1H), 2.71-2.
79 (m, 5H), 2.98 (d, J = 13.2 Hz,
1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1
H), 7.39 (d, J = 8.4 Hz, 1H), 7.4
3 (d, J = 1.8 Hz, 1H). Synthesis Example 42

[0486]

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According to the above route, aminoacetylene (3ab) was synthesized. Shown below. 1) J. Org. Chem. 22, 939 (195
7), C.I. Osuch, R .; According to the description of Levine, 4-pyridylacetone (1) was synthesized. That is, 4-picoline (23.9 g, 257 mmol)
To a solution of methyllithium (1.
_{5M in Et 2 O, 170ml,} 255mmol)
Was added dropwise. To this was added methyl acetate (9.5 g, 12
8 mmol) in ether (20 ml) was added dropwise.
Heated to reflux for h. Water was added to the reaction solution, and the mixture was extracted with ether and ethyl acetate in this order. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform → chloroform: methanol = 9: 1), and 4-pyridylacetone (1) (2.7 g, 20
mmol, 15%).

1: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 2.22 (s, 3H), 3.73
(S, 2H), 7.13-7.16 (m, 2H), 8.
55-8.58 (m, 2H). 2) Trimethylsilylacetylene (3.65 ml, 2
NBuL in 5.8 mmol) of THF (20 ml) solution
i (1.66 M in Hexane 15.6 ml,
25.9 ml) was added dropwise at -78 ° C. This was dropped at -78 ° C to cerium trichloride heptahydrate (10.38g, 28mmol) which was dried by heating at 140 ° C for 2 hours under reduced pressure. 1 (2.69 g, 20 mmol) in this solution
After stirring for 1 hour, acetic anhydride (2.3 ml, 2 ml
4 mmol) was added. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Hexan
e: AcOEt 4: 1 → 1: 1) to separate and purify
(0.9 g, 3.3 mmol, 16%).

2: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 0.15 (s, 9H), 1.68
(S, 3H), 2.12 (s, 3H), 3.06 (d,
J = 13.2 Hz, 1H), 3.29 (d, J = 13.
2Hz, 1H), 7.22-7.26 (m, 2H),
8.51-8.55 (m, 2H). 3) 2 (0.9 g, 3.3 mmol) of THF (10 m
l) Add nBu ₄ NF (1M in THF, 0.8
ml, 0.8 mmol) and stirred at room temperature for 3.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue containing 3 (700 mg). This was used for the next reaction without purification.

3: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 1.69 (s, 3H), 2.04
(S, 3H), 2.62 (s, 1H), 3.13 (d,
J = 13.3 Hz, 1H), 3.27 (d, J = 13.3 Hz).
3Hz, 1H), 7.24-7.26 (m, 2H),
8.53-8.56 (m, 2H). 4) An oil containing 3 (700 mg) and diethylamine (2.78 ml, 27 mmol) in THF (20 ml).
Copper (I) chloride (15 mg, 0.15 mmol) was added to the solution, and the mixture was refluxed for 3 hours. The reaction solution was extracted with ethyl acetate, washed with an aqueous ammonium chloride solution, and then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate 4: 1 → 1: 1) to give the desired product 3ab (1
01 mg, 14% from 0.47 mmol 2).

3ab: ¹ H NMR (CDCl ₃ , 25
0 MHz) δ ppm: 1.11 (t, J = 7.4 Hz,
3H), 1.74 (q, J = 7.4 Hz, 2H), 2.
46 (s, 1H), 2.88 (d, J = 13.2 Hz,
1H), 3.00 (d, J = 13.2 Hz, 1H),
7.25-7.50 (m, 5H). Synthesis Example 43

[0492]

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According to the above scheme, 3-ethynyl-4
-Ethyl phenylbenzoate (3ac) was synthesized. It is shown below. 1) Ethyl 4-bromobenzoate (23 g, 100 mmol
l) was added to a mixture of fuming nitric acid (28 g) and concentrated sulfuric acid (37 g) while maintaining the liquid temperature at 20 ° C to 31 ° C. The reaction solution was poured into ice water (1 liter), and the resulting crystals were collected by filtration, washed with ethanol, washed and filtered, and the filtrate after washing was concentrated under reduced pressure. Water was added, and the collected crystals were combined. Dry and dry ethyl 4-bromo-3nitrobenzoate (1) (26.8 g, 9
(8 mmol, 98%).

1; ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 1.42 (t, J = 7.1 Hz, 3
H), 4.43 (q, J = 7.1 Hz, 2H), 7.8
4 (d, J = 8.4 Hz, 1H), 8.08 (dd, J
= 8.4 Hz, 1.9 Hz, 1H), 8.46 (d, J
= 1.9 Hz, 1H). 2) 1 (5.0 g, 18.2 mmol), phenylboric acid (2.67 g, 21.8 mmol), bis (triphenylphosphine) -palladium (II) chloride (63
0 mg, 0.90 mmol), triethylamine (7.
5 ml, 53 mmol) in DMF (50 ml)
Heated to reflux for an hour.

The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane → hexane: ethyl acetate =
4: 1) to give ethyl 3-nitro-4phenylbenzoate (2) (3.0 g, 11 mmol, 60%). 2: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 1.44 (t, J = 7.2 Hz, 3H), 4.45
(Q, J = 7.2 Hz, 2H), 7.31-7.36
(M, 2H), 7.43-7.57 (m, 3H), 7.
54 (d, J = 8 Hz, 1H), 8.27 (dd, J =
8.1, 7 Hz, 1 H), 8.49 (d, J = 1.7 H)
z, 1H).

3) 10% palladium-carbon (0.1 g) was added to a solution of 2 (1.0 g, 3.7 mmol) in ethyl acetate (10.2 ml) and acetic acid (6.8 ml), and the solution was added under hydrogen atmosphere. Stirred at 5 atm for 8 hours. The reaction solution was filtered, water was added, the mixture was extracted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and dried over anhydrous sodium sulfate. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate 4: 1 →
2: 1) and ethyl 3-amino-4-phenyl-benzoate (3) (787 mg, 326 mmol, 88
%). 3: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 1.40 (t, J = 7.1 Hz, 3H), 4.37
(Q, J = 7.1 Hz, 2H), 7.18 (d, J =
7.8 Hz, 1 H), 7.39 to 7.45 (m, 7
H).

4) 3 (787 mg, 3.26 mmol)
A 70% aqueous solution of sodium nitrite (5 ml) was added to a mixture of 24% hydrobromic acid, and copper bromide (1.15 g, 8 mmol) 48
A solution of 5% hydrobromic acid (5 ml) was added and heated at 60 ° C. for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate 8: 1 → 4: 1)
To give ethyl 3-bromo-4-phenylbenzoate (4) (541 mg, 1.7 mmol, 53%). 4: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 1.42 (t, J = 7.0 Hz, 3H), 4.41
(Q, J = 7.0 Hz, 2H), 7.38-7.49
(M, 6H), 8.19 (dd, J = 8.1, 1.6H)
z, 1H), 8.34 (d, J = 1.6 Hz, 1H).

5) 4 (430 mg, 1.42 mmol)
l), triethylsilylacetylene (0.4 ml, 2.
8 mmol), bis- (triphenylphosphine) -palladium (II) chloride (20 mg, 0.029 mm)
ol), triphenylphosphine (10 mg, 0.03
8 mmol), copper (I) iodide (10 mg, 0.053
mmol), triethylamine (1.5 ml, 10.8
mmol) in DMF (1 ml) at 100.degree.
Heated for hours. The reaction solution was extracted with ethyl acetate, washed sequentially with an aqueous ammonium chloride solution and saturated saline, and the solvent was distilled off under reduced pressure. Add 4 (541 mg, 1.77 mmol)
The same operation as in 1) was performed, and the obtained residues were combined to obtain an oily substance (916 mg) containing a coupling product from which a highly polar substance had been removed by a silica gel part (hexane → hexane: ethyl acetate 18: 1).

This was dissolved in THF (10 ml), and 1
M tetra-n-butylammonium fluoride TH
The F solution (3.1 ml, 3.1 mmol) was added and stirred for 30 minutes. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane → hexane:
Ethyl acetate = 40: 1) to give 3-ethynyl-4
-Ethyl phenylbenzoate 3ac (173 mg, 0.6
9 mmol, 22%). 3ac: ¹ H NMR (CDCl ₃ , 250 MHz) δ
ppm: 1.42 (t, J = 7.2 Hz, 3H);
09 (s, 1H), 4.41 (q, J = 7.2 Hz, 2
H), 7.38 to 7.50 (m, 4H), 7.59-
7.64 (m, 2H), 8.06 (dd, J = 8.1,
1.8 Hz, 1 H), 8.29 (d, J = 1.8 Hz,
1H). Synthesis Example 44

[0500]

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According to the above route, 2 was synthesized. Shown below. 1) Ethinyl magnesium (0.5M in THF,
145 ml, 72.5 mmol) in 4-fluorophenylacetone (10 g, 66 mmol) in THF (10 m
l) The solution was added dropwise and then acetic anhydride (7.5 ml, 79
mmol) was added dropwise. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was passed through silica gel (70 g), and the solvent was distilled off under reduced pressure (developing solvent, hexane: ethyl acetate 4: 1). The residue was diluted with ether, and saturated aqueous sodium hydrogen carbonate solution was added.
After washing with saturated saline in order, the solvent was distilled off under reduced pressure, and 1 (1
4.6 g, 66 mmol, quantitative) were obtained.

1: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 1.64 (s, 3H), 2.03
(S, 3H), 2.60 (s, 1H), 3.13 (d,
J = 13.7 Hz, 1H), 3.23 (d, J = 13.
7Hz, 1H), 6.95-7.03 (m, 2H),
7.22-7.29 (m, 2H). 2) Acetate (1) (7.0 g, 31.8 mmol)
And ethyl isonipecotate (12.0 g, 76.4 mm
ol) in THF (70 ml) solution.
2 mg, 2.2 mmol) and 66 ° C. for 2 hours, 8
Heated at 6 ° C. for 10 minutes. The solvent was distilled off under reduced pressure. The residue was extracted with ether (100 ml), and washed with an aqueous ammonia solution and then with a saturated saline solution. After the organic layer was extracted with a 3N aqueous hydrochloric acid solution (160 ml), a 3N aqueous sodium hydroxide solution (150 ml) and a saturated aqueous sodium hydrogen carbonate solution were added to the aqueous layer, and the mixture was extracted with dichloromethane (300 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica 50 g, hexane: ethyl acetate = 4: 1) to obtain the desired product 3ad (8.21).
g, 25.8 mmol, 81%).

3ad: ¹ H NMR (CDCl ₃ , 25
0 MHz) δ ppm: 1.20 (s, 3H), 1.26
(T, J = 7.1 Hz, 3H), 1.67-1.88.
(M, 2H), 1.89-2.05 (m, 2H), 2.
20-2.38 (m, 3H), 2.38 (s, 1H),
2.81 (d, J = 13.4 Hz, 1H), 2.97 −
3.19 (m, 1H), 3.02 (d, J = 13.4H)
z, 1H), 3.20-3.31 (m, 1H), 4.1
4 (q, J = 7.1 Hz, 2H), 6.90-7.0
(M, 2H), 7.22-7.29 (m, 2H). Synthesis Example 45

[0504]

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Phenylacetone (4 g, 29.8 mmol)
l) in THF (10 ml) was added to a 0.5 M ethynylmagnesium chloride THF solution (71 ml, 37 mmo).
l) was added and stirred for 1 hour. A 0.5N hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and propargyl alcohol 3ae (4.36 g,
27.2 mmol, 91%).

3ae: ¹ H NMR (CDCl ₃ , 25
0 MHz) δ ppm: 1.56 (s, 3H), 2.47
(S, 1H), 2.93 (d, J = 13.2 Hz, 1
H), 3.01 (d, J = 13.2 Hz, 1H), 7.
27-7.35 (m, 5H). Synthesis Example 46

[0507]

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4-methylphenol (1.08 g, 10
mmol), propargyl alcohol (840 mg, 1
0 mmol), triphenylphosphine (2.62 g,
10 mmol) in a THF (10 ml) solution while stirring under an aqueous solution of ice with diethyl azodicarboxylate (1.5 ml).
(8 ml, 10 mmol) was added dropwise and left at room temperature for 24 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solution, n-hexane: ethyl acetate 15:
1) Then, the desired ether compound 3af (260 mg,
1.5 mmol, 15% yield). 3af: ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 1.62 (s, 6H), 2.30 (s, 3
H), 2.52 (s, 1H), 7.05-7.15.
(M, 4H). Synthesis Example 47 3ag was synthesized by the following method.

[0509]

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1) 2-Phenylpropionaldehyde (6.7 g, 50 mmol) in dichloromethane (450
ml) solution into triphenylphosphine (52 g, 200 g).
mmol), carbon tetrabromide (33.2 g, 100 mmol
l) was added at 0 ° C and stirred. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography.
(11.2 g, 39 mmol, 77%) were obtained. 2) 1 (11.2 g, 39 mmol) in 40% triton B methanol solution (73 ml), diethylamine (55
ml, 540 mmol) and stirred. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3ag (2.7 g, 13.4 mmol, 35%).

3ag: ¹ H NMR (CDCl ₃ , 30
0 MHz) δ ppm: 1.04 (t, J = 7.2 Hz,
6H), 1.58 (s, 3H), 2.24 (s, 1
H), 2.43 (dt, J = 7.2, 13.8 Hz, 1
H), 2.45 (dt, J = 7.2, 13.8 Hz, 1
H), 2.67 (dt, J = 7.2, 13.8 Hz, 1
H), 2.69 (dt, J = 7.2, 13.8 Hz, 1
H), 7.22-7.33 (m, 5H), 7.71-
7.74 (m, 1H). Synthesis Example 48 3ah was synthesized by the following method.

[0512]

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1) 2-bromo-biphenyl (1 g, 4.
29 mmol) in THF (40 ml) was dissolved in a 1.7 M solution of n-butyllithium in hexane (3 ml, 5.15).
mmol) was added dropwise at -78 ° C. After stirring for 30 minutes, dimethylformamide (0.5 ml, 6.45 mmol)
Was added to room temperature, and then an aqueous ammonium chloride solution was poured. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (hexane: ethyl acetate = 10: 1) to obtain 1 (748 mg, 4.1 mmol, 96%). 2) Triphenylphosphine (4.3 g, 16.4 mmol), carbon tetrabromide (2.7) in a dichloromethane (40 ml) solution of 1 (748 mg, 4.1 mmol) at 0 ° C.
2 g, 8.2 mmol) and stirred for 30 minutes. To this, pentane (160 ml) was added, and the filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane) to give 2 (1.21 g, 3.57 mmol, 8
7%).

3) 2 (2.29 g, 6.77 mmol)
In THF (20 ml) at −78 ° C. at 1.7 M n-butyllithium in hexane (3.98 ml,
(6.77 mmol) was added to room temperature. Water was added to the reaction solution, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (hexane) and 3ah (796 m
g, 4.47 mmol, 66%). 3ah: ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 3.03 (s, 1H), 7.30-7.43
(M, 6H), 7.57-7.60 (m, 3H). Synthesis Example 49

[0515]

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Acetate (1) (1.0 g, 4.54
mmol), diethylamine (1.02 ml, 9.86)
mmol), copper (I) chloride (30.7 mg, 0.31 m
mol) in THF (20 ml) was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, diluted with ether, and extracted with a dilute aqueous hydrochloric acid solution. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and 3ai (296 mg, 1.35 mmol)
I got 3ai: ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 1.11 (t, J = 7.1 Hz, 6H), 1.
23 (s, 3H), 2.29 (s, 1H), 2.74
(D, J = 13.2 Hz, 1H), 2.77 (q, J =
7.1 Hz, 4H), 3.04 (d, J = 13.2H)
z, 1H), 6.80-6.83 (m, 2H), 7.2
2-7.26 (m, 2H). Synthesis Example 50

[0517]

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1) Cyclohexylacetone (2 g, 1
4.3 mmol) in a 0.5 M ethynylmagnesium chloride THF solution (86 ml, 43 mm).
ol) was added dropwise, and the mixture was heated under reflux for 3 hours. Acetic anhydride (4.75 ml, 50.1 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred. Ether was added to the reaction solution, and the mixture was washed successively with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 16: 1),
1 (1.95 g, 9.36 mmol, 65%) was obtained.

2) 1 (1.95 g, 9.36 mmol)
l), diethylamine (2.1 ml, 20.3 mmol)
l), a solution of copper (I) chloride (63 mg, 0.64 mmol) in THF (40 ml) was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, diluted with ether, and extracted with a dilute aqueous hydrochloric acid solution. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, extracted with dichloromethane, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 3aj (8
99 mg, 4.06 mmol, 43%). 3aj: ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 1.06 (t, J = 7.1 Hz, 6H), 1.
12-1.68 (m, 11H), 1.35 (s, 3
H), 1.74-1.78 (m, 1H), 1.88-
1.92 (m, 1H), 2.20 (s, 1H), 2.6
4 (q, J = 7.1 Hz, 4H). Synthesis Example 5 3ak was synthesized by the following method.

[0520]

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1) 2,2-dimethyl-3-phenyl-1
Pyridinium chlorochromate (3.23 g, 15 mmol) was added to a dichloromethane (150 ml) solution of -propanol (1.64 g, 10 mmol) and stirred.
The reaction solution was filtered using celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 1 (1.61 g, 9.96).
mmol, 99.6%).

2) 2,2-dimethyl-3-phenyl-1
-To a solution of propanol (1) (1.94 g, 12 mmol) in dichloromethane (50 ml) was added triphenylphosphine (12.6 g, 48 mmol) and carbon tetrabromide (8.9 g).
(0 g, 24 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 5: 1) to give a residue.
(2.26 g, 7.11 mmol, 59%) was obtained.

3) A 1.6 M solution of normal butyllithium in hexane (9.8 ml, 15.6) was added to a solution of (2.26 g, 7.11 mmol) in THF (50 ml) at -78 ° C.
mmol) was added dropwise. The reaction solution was brought to room temperature, water was added to stop the reaction, and the mixture was extracted with ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with silica gel column chromatography (hexane) and washed with 3ak (1.02g, 6.45).
mmol, 91%). 3ak: ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 1.22 (s, 6H), 2.14 (s, 1
H), 2.72 (s, 2H), 7.26-7.27
(M, 5H). Synthesis Example 52 Compound 4 was synthesized according to the following scheme.

[0524]

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1) 4-methoxyphenylacetone (3.
28 g (20 mmol) was reacted in the same manner as in the synthesis method of Synthesis Example 35-2 to give 1 (7.17 g, 17.9 mmol).
1, 90%). 1 (7.17 g, 17.9 mmo
l) in a THF (100 ml) solution was added to a 1M tetra-n-butylammonium fluoride THF solution (18 m
1, 18 mmol) was added dropwise and stirred. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate =
4: 1) and 2 (3.71 g, 19.5 mmol)
1, 98%).

2) 2 (3.71 g, 19.5 mmol)
1M sodium hexamethyldisilazide in THF (20 ml) at −78 ° C. (21.5 ml,
Acetic anhydride (2.19 g, 21.5 mmol) was added at 0 ° C. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate =
5: 1) and 3 (2.08 g, 8.95 mmol)
1, 46%).

3) 3 (2.08 g, 8.95 mmol)
In a THF (10 ml) solution was added diethylamine (2 m
l) and copper chloride (60 mg, 0.61 mmol) were added and the mixture was heated under reflux. The reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography (hexane: ethyl acetate = 10: 1), and 3al (559 mg, 2.28 mmol, 25
%). 3al: ¹ H NMR (CDCl ₃ , 300 MHz) δ
ppm: 1.20 (t, J = 7.1 Hz, 6H), 1.
24 (s, 3H), 2.28 (s, 1H), 2.70
(D, J = 13.2 Hz, 1H), 2.77 (q, J =
7.1 Hz, 2H), 2.78 (q, J = 7.1 Hz,
2H), 3.03 (d, J = 13.2 Hz, 1H),
3.59 (s, 3H), 6.80-6.83 (m, 2
H), 7.22-7.26 (m, 2H). Synthesis Example 53

[0528]

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Following the above route, pyrimidine derivative 2
p and 2q were synthesized. 1) 4,6-dichloro-5-nitropyrimidine (9.3
g, 48 mmol), according to J. Chem. Soc. 99,
(1951); R. Boon, W.C. C. M. Jon
es and G. R. The reaction was carried out according to the method of Ramage to obtain 4-amino-6-chloro-5-nitropyrimidine (2p) (4.4 g, 25 mmol, 52%).

2) 4-Amino-6-chloro-5-nitropyrimidine 2p (5.0 g, 28 mmol) was obtained according to J. Am. A
m. Chem. Soc. 75 , 263 (1953),
R. K. The reaction was carried out by the method of Robins, et al.
-Diamino-6-chloropyrimidine (1) (2.5 g,
17 mmol, 60%). 3) 4,5-diamino-6-chloropyrimidine (1)
(1.9 g, 13 mmol). Am. Chem. S
oc. , 78, 225 (1956); W. The reaction was carried out according to the method of Dally et al., And 4-chloro-6,7-dimethylpteridine (2q) (1.9 g, 9.8 mmol, 75
%). Synthesis Example 54

[0531]

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Fuming nitric acid (7.5 ml) and concentrated sulfuric acid (38 m
1) Add 2,4-diamino-6- to the mixture at 30-35 ° C.
Chloropyrimidine (7.2 g, 0.05 mol) was added little by little and stirred for 30 minutes. After the reaction solution was poured into ice (250 g) and the pH was adjusted to 9 with an aqueous ammonia solution, the crystals were collected by filtration, dried under reduced pressure, and 2,4-diamino-5-nitro-
6-chloropyrimidine (2r) (4.6 g, 0.026
2 mol, 52%). Synthesis Example 55

[0533]

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Chloroquinazoline (5.0 g, 22.3 mmol) was added to 55-58% hydroiodic acid (50 ml) under ice-cooling.
l) was added little by little and stirred for 2 hours. Water (50 ml) was poured, and yellow crystals were collected by filtration.
1), washed with a 5% aqueous ammonia solution and water in that order, dried over Na ₂ SO ₄ , and the solvent was distilled off (6.0 g, 1 g).
8.9 mmol (yield 85%) with iodoquinazoline (2
s) was obtained. 2s: ¹ H NMR (DMSO-d ₆ , 250 MHz)
δ ppm: 4.0 (s, 3H), 4.01 (s, 3
H), 7.14 (s, 1H), 7.35 (s, 1H),
8.69 (s, 1H). EI-MASS 316 (M ⁺ ), 189 (MI) Synthesis Example 56

[0535]

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According to the above route, 6-iodo-9-methylpurine (2t) was synthesized. Shown below. 1) Sodium hydride (60% oily, 77 mg, 1.9)
mmol) in THF (2 ml), and 6-chloropurine (251 mg, 1.6 mmol) in THF (2 ml).
DMF (2 ml) solution was added. Then, after adding methyl iodide (0.12 ml, 1.9 mmol), water was poured, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (C
HCl ₃ : MeOH = 10: 1) and purified by purification. 6-Chloro-9-methylpurine (1) (167 mg, 1.08)
mmol, 61%), 6-chloro-7-methylpurine (69 mg, 0.41 mmol, 25%).

1: ¹ H NMR (CDCl ₃ , 250M
Hz) δ ppm: 3.95 (s, 3H), 8.12
(S, 1H), 8.78 (s, 1H). 2) 6-chloro-9-methylpurine (1) (175 mg, 1.0 mm) was added to hydroiodic acid (55%, 2 ml) under ice-cooling.
ol) and stirred for 1.5 hours. An aqueous ammonia solution was poured into the reaction solution, and ethyl acetate and chloroform were extracted in this order. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 6-iodo-9-methylpurine (2t) (2t).
33 mg, 0.89 mmol, 89%). 2t; ¹ H NMR (CDCl ₃ , 250 MHz) δp
pm: 3.93 (s, 3H), 8.13 (s, 1H),
8.65 (s, 1H). Example 128

[0538]

Embedded image

Propardylamine 3am (1.00 g,
3.2 mmol) and chloroquinazoline 2j (835 m
g, 3.2 mmol) in the same manner as in Example 7.
The desired product (1.37 g, 2.74 mmol, 86%) was obtained as a reddish brown oily substance. ¹ H NMR (CDCl ₃ , 300 MHz) δ ppm:
1.25 (t, J = 7.0 Hz, 3H), 1.50
(T, J = 7.0 Hz, 3H), 1.56 (t, J =
7.0 Hz, 3H), 1.61 (s, 3H), 1.75
-1.90 (m, 2H), 1.93-2.08 (m, 2
H), 2.13-2.50 (m, 5H), 2.81-
2.92 (m, 2H), 3.13-3.39 (m, 2
H), 4.14 (q, J = 7.0 Hz, 2H), 4.1.
7 (q, J = 7.0 Hz, 2H), 4.28 (q, J =
7.0 Hz, 2H), 7.16-7.32 (m, 6
H), 7.46 (s, 1H), 9.06 (s, 1H). Example 129

[0540]

Embedded image

The ester obtained in Example 128 (1.20
g, 2.26 mmol) was reacted in the same manner as in Example 8 to give the desired product (1.00 g, 1.99 mmol, 88%).
I got White crystal IR (KBr) νcm ^-1 : 3422,2984,293
7, 2808, 2214, 1718, 1612, 157
7,1500,1469,1396,1369,123
6,1043,939,852,825,748,70
0,632. ¹ H NMR (DMSO-d ₆ , 250 MHz) δpp
m: 1.35 (t, J = 6.9 Hz, 3H), 1.41
(T, J = 6.9 Hz, 3H), 1.55 (s, 3
H), 1.57-1.72 (m, 2H), 1.80-
1.95 (m, 2H), 2.04-2.40 (m, 4
H), 2.42-2.50 (m, 1H), 2.70-
2.82 (m, 2H), 3.01-3.24 (m, 2
H), 4.14 (q, J = 6.9 Hz, 2H), 4.2
5 (q, J = 6.9 Hz, 2H), 7.12-7.30
(M, 5H), 7.33 (s, 1H), 7.39 (s,
1H), 8.98 (s, 1H). Example 130

[0542]

Embedded image

Propardylamine 3i (385 mg,
1.29 mmol) and 4-chloro-6-nitroquinazoline 2u (270 mg, 1.29 mmol) were prepared in Example 7
The reaction was carried out in the same manner as described above, and the desired product (578 mg, 1.22 m
mol, 95%) as a red-brown oil. IR (neat) νcm ^-1 : 3379,2932,28
10, 2208, 1728, 1622, 1577, 15
27, 1485, 1439, 1412, 1356, 13
40,1263,1178,1045,962,85
2,806,744,702.

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.26 (t, J = 6.9 Hz, 3
H), 1.56 (s, 3H), 1.75-1.95.
(M, 2H), 2.00-2.13 (m, 2H), 2.
27-2.62 (m, 3H), 3.11 (d, J = 1
3.2 Hz, 1 H), 3.26-3.32 (m, 1
H), 3.29 (d, J = 13.2 Hz, 1H);
45-3.55 (m, 1H), 4.15 (d, J = 6.
9Hz, 2H), 7.21-7.33 (m, 3H),
7.35-7.38 (m, 2H), 8.19 (d, J =
9.2 Hz, 1H), 8.66 (dd, J = 9.2,
2.4 Hz, 1 H), 9.09 (d, J = 2.4 Hz,
1H), 9.42 (s, 1H). Example 131

[0545]

Embedded image

3an (1.0 g, 3.3 mmol) and chloroquinazoline (830 mg, 3.14 mmol) were obtained.
The reaction was carried out in the same manner as in Example 7, and the target product (870 mg,
(1.62 mmol, 52%). ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.34 (t, J = 7.0 Hz, 3H), 1.54
(T, J = 7.0 Hz, 3H), 2.44 (s, 3
H), 3.63 (q, J = 7.0 Hz, 2H), 4.2
5 (q, J = 7.0 Hz, 2H), 7.15 (s, 1
H), 7.24-7.46 (m, 7H), 7.68-
7.71 (m, 1H), 7.70 (d, J = 8.3H)
z, 2H), 7.85 (d, J = 8.3 Hz, 2H),
9.07 (s, 1H). Example 132

[0547]

Embedded image

The tosyl form (140 mg,
0.26 mmol) of ethanol (4 ml), THF
(2 ml), a 1 N aqueous solution of sodium hydroxide (0.5 ml, 0.5 mmol) was added to the mixed solution, and the mixture was stirred for 4.5 hours. A 1N aqueous hydrochloric acid solution (1 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol 30: 1) to obtain the desired product (68 mg, 0.18 mmol, 68%).

Light yellow crystals m. p. 201-204 ° C IR (KBr) νcm ^-1 : 3412,3155,298
4,2910,2361,2341,183,161
2,1572,1531,1502,1458,142
9,1344,1332,1234,1201,114
9,1037,935,852,837,783,75
2,698,630,617,605. ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.34 (t, J = 7.0 Hz, 3H), 1.55
(T, J = 7.0 Hz, 3H), 3.64 (q, J =
7.0 Hz, 2H), 4.26 (q, J = 7.0 Hz,
2H), 6.98-7.02 (m, 1H), 7.24-
7.32 (m, 3H), 7.34-7.43 (m, 3
H), 7.75-7.79 (m, 2H), 8.90-
9.10 (m, 1H), 9.06 (s, 1H). TOF-MS m / z; 384 (M + H). Example 133

[0550]

Embedded image

The substance obtained in Example 132 (50 mg, 0.1 mg) was obtained.
To a solution of 13 mmol) in DMF (2 ml) was added 60% sodium hydride (6.2 g, 0.16 mmol) followed by methyl iodide (8.9 μl, 0.143 mmol). Water was added to the reaction solution, and extracted with chloroform.
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 40: 1), and the obtained crystals were washed with ether to give the desired substance (21 mg, 0.053 mmol).
1, 41%).

Yellow crystals m.p. p. 136-137.5 ° C IR (KBr) νcm ^-1 : 3427,2982,293
4,2361,2341,189,1612,157
0, 1502, 1452, 1417, 1400, 135
9,1342,1232,1201,1155,103
7,900,829,775,742,698,65
3,605,584 ¹ H NMR (CDCl ₃ , 250 MHz) δ ppm:
1.33 (t, J = 7.0 Hz, 3H), 1.55
(T, J = 7.0 Hz, 3H), 3.61 (q, J =
7.0 Hz, 2H), 3.75 (s, 3H), 4.26
(Q, J = 7.0 Hz, 2H), 6.79 (d, J =
2.3 Hz, 1 H), 7.17 (d, J = 2.3 Hz,
1H), 7.23-7.40 (m, 5H), 7.71-
7.75 (m, 2H), 9.05 (s, 1H). TOF-MS m / z; 398 (M + H) Example 134

[0553]

Embedded image

The substance obtained in Example 132 (100 mg,
0.26 mmol) and bromoacetic acid ethyl ester (6
5 mg, 0.39 mmol) was reacted in the same manner as in Example 132 to give the desired product (68 mg, 0.145 mmol, 5
5%). White crystals mp. 174-175 ° C IR (KBr) νcm ^-1 : 3425,2982,295
3,2363,2202,1739,1614,157
0, 1500, 1458, 1444, 1363, 131
3,1232,1205,1161,1035,102
4,850,825,777,740,700,62
8,607,592.

¹ H NMR (CDCl ₃ , 300 MH
z) δ ppm: 1.32 (t, J = 7.0 Hz, 3
H), 1.33 (t, J = 7.0 Hz, 3H), 1.5
4 (t, J = 7.0 Hz, 3H), 3.63 (q, J =
7.0 Hz, 2H), 4.25 (q, J = 7.0 Hz,
3H), 4.28 (q, J = 7.0 Hz, 2H), 4.
68 (s, 2H), 6.84-6.85 (m, 1H),
7.22-7.29 (m, 4H), 7.33-7.39
(M, 2H), 7.73-7.77 (m, 2H), 9.
05 (s, 1H). TOF-MS m / z; 470 (M + H) Example 135

[0556]

Embedded image

The ethyl ester obtained in Example 134 (3
5 mg, 0.0745 mmol) was subjected to a hydrolysis reaction in the same manner as in Example 8 to give the desired product (30 mg, 0.068 mm).
ol, 91%). Yellow crystal 230-244 ° C Thermal decomposition IR (KBr) νcm ^-1 : 3427,3123,298
6,2941,2490,2364,2195,195
7, 1720, 1612, 1574, 1531, 150
0, 1450, 1400, 1363, 1315, 124
2,1159,1035,931,898,785,7
46,698,611 ¹ H NMR (DMSO-d ₆ , 300 MHz) δpp
m: 1.30 (t, J = 6.9 Hz, 3H), 1.42
(T, J = 6.9 Hz, 3H), 3.78 (q, J =
6.9 Hz, 2H), 4.26 (q, J = 6.9 Hz,
2H), 4.89 (s, 2H), 7.24 (d, J =
2.1Hz, 1H), 7.26-7.32 (m, 3
H), 7.38-7.44 (m, 2H), 7.59.
(D, J = 2.1 Hz, 1H), 7.72-7.73
(M, 1H), 7.74-7.75 (m, 1H), 8.
99 (s, 1H), 12.9-13.4 (m, 1H). TOF-MS m / z; 442 (M + H)

[0558]

[Table 174]

[0559]

[Table 175]

[0560]

[Table 176]

[0561]

[Table 177]

[0562]

[Table 178]

[0563]

[Table 179]

[0564]

[Table 180]

[0565]

[Table 181]

[0566]

[Table 182]

[0567]

[Table 183]

Synthesis Example 57 3am was synthesized according to the following route.

[0569]

Embedded image

1) Benzyl acetone (7 g, 47.2 mmol) was added dropwise to a 0.5 M ethynylmagnesium chloride THF solution (104 ml, 52 mmol). Next, acetic anhydride (5.36 ml, 56.5 mm) was added to the reaction solution.
ol) was added dropwise. A 1N HCl aqueous solution (60
ml) and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, an aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 8: 1) to give 1
(9.5 g, 44 mmol, 93%). 1: ¹ H NMR (CDCl ₃ , 250 MHz) δpp
m: 1.74 (s, 3H), 2.03 (s, 3H),
2.09-2.31 (m, 2H), 2.62 (s, 1
H), 2.75-2.90 (m, 2H), 7.16-
7.35 (m, 5H).

2) Acetate (1) (5 g, 23 mmol)
l) in THF (50 ml) was added to copper (I) chloride (161).
mg, 1.6 mmol) and ethyl isonipecotate (8.71 g, 55.4 mmol), and the mixture was heated under reflux for 3 hours. The reaction solution was brought to room temperature, concentrated under reduced pressure, and extracted with ether. This was washed with an aqueous ammonium chloride solution and a saturated saline solution in this order, and then extracted with a 3N aqueous HCl solution. After washing the aqueous layer with ether, a 2N aqueous solution of NaOH and an aqueous solution of sodium hydrogen carbonate were added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4: 1) to give 3am (5.02).
g, 16 mmol, 69%).

3am; ¹ H NMR (CDCl ₃ , 25
0 MHz) δ ppm: 1.25 (t, J = 7.0 Hz,
3H), 1.40 (s, 3H), 1.75-1.85
(M, 2H), 1.90-2.00 (m, 4H), 2.
20-2.30 (m, 3H), 2.33 (s, 1H),
2.70-2.78 (m, 2H), 3.00-3.21
(M, 2H), 4.13 (q, J = 7.0 Hz, 2
H), 7.17-7.21 (m, 2H), 7.25-
7.32 (m, 3H). Synthesis Example 58 3an was synthesized according to the following route.

[0573]

Embedded image

1) Benzyl silicate (1.2 g,
5 mmol) and ether of p-toluenesulfonylmethyl isocyanide (976 mg, 5 mmol) (10 m
1) DMSO (5 ml) mixed solution with NaH (60%,
(240 mg, 6 mmol) in ether (10 ml) was added dropwise and stirred for 15 minutes. Water was poured into the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ether, and 1 (864 mg, 3.
12 mmol, 62%).

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 5.22 (s, 2H), 6.76-6.
79 (m, 1H), 7.23-7.37 (m, 8H),
7.44-7.54 (m, 3H), 8.40-8.60
(M, 1H). 2) 1 (864 mg, 3.12 mmol) of THF (1
0 ml) solution in triethylamine (650 μl, 4.6
6 mmol), dimethylaminopyridine (189 mg,
1.55 mmol) and p-toluenesulfonyl chloride (711 mg, 3.73 mmol) were added, and the mixture was stirred for 3.5 hours. An aqueous ammonium chloride solution was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 2 (1.29 g,
(3.0 mmol, 96%).

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 2.43 (s, 3H), 5.18 (s,
2H), 7.12 (d, J = 2.7 Hz, 1H), 7.
23-7.41 (m, 12H), 7.80-7.84
(M, 2H), 7.85 (d, J = 2.7 Hz, 1
H). 3) 2 (2.76 g, 6.4 mmol) of THF (70
ml) solution with lithium aluminum hydride (291 m
g, 7.7 mmol) and stirred for 40 minutes. Water (0.3 ml), 3N aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml) were added to the reaction solution in that order, and the supernatant was collected by filtration. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
1 → ethyl acetate) to purify 3 (1.94 g, 5.9)
mmol, 92%) as a colorless oil.

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 2.41 (s, 3H), 4.59 (s,
1H), 4.61 (s, 1H), 7.23-7.40.
(M, 7H), 7.43-7.48 (m, 2H), 7.
80 (d, J = 8.4 Hz, 2H). 4) To a solution of 3 (1.94 g, 5.9 mmol) in dichloromethane (100 ml) was added manganese dioxide (7.8 g), and the mixture was stirred for 7 hours. The reaction solution was filtered using Celite-silica gel, and the filtrate was concentrated under reduced pressure to give 4 (1.66 g,
5.1 mmol, 86%).

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 2.44 (s, 3H), 7.23 (d.
J = 2.4 Hz, 1H), 7.33-7.45 (m, 7
H), 7.85 (d, J = 8.5 Hz, 2H), 7.8
6 (d, J = 2.4 Hz, 1H), 9.89 (s, 1
H). 5) Triphenylphosphine (2.6) was added to a solution of 4 (1.66 g, 5.1 mmol) in dichloromethane (50 ml).
8g, 10.2 mmol), and carbon tetrabromide (1.86 g, 5.6 mmol) in dichloromethane (1
5 ml) solution was added dropwise and stirred for 40 minutes. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, silica (10 g) was added, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (hexane:
(Ethyl acetate = 9: 1 → dichloromethane)
(2.33 g, 4.85 mmol, 95%) as white crystals.

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 2.43 (s, 3H), 7.16-7.
17 (m, 2H), 7.26-7.43 (m, 7H),
7.85 (d, J = 8.3 Hz, 2H), 7.90 −
7.91 (m, 1H). 2) 5 (616 mg, 1.28 mmol) in THF (1
Solution at -78 ° C at 1.78 M in normal butyllithium hexane solution (2.78 ml, 4.42 m).
mol) was added dropwise. An aqueous ammonium chloride solution was added to the reaction solution, the mixture was brought to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (hexane → hexane: ethyl acetate 9: 1)
And purified by 3an (163 mg, 0.51 mmol, 4
0%).

¹ H NMR (CDCl ₃ , 250 MH
z) δ ppm: 2.42 (s, 3H), 3.10 (s,
1H), 7.25 (d, J = 2.4 Hz, 1H), 7.
26-7.38 (m, 5H), 7.45 (d, J = 2.
4 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2
H), 7.80 (d, J = 8.4 Hz, 2H). Synthesis Example 59

[0581]

Embedded image

According to the description of JP-A-6-73025, 4-chloro-6-nitroquinazoline 2u
Was synthesized from 5-nitro-anthranisic acid. Test Example 1 <Evaluation of tyrosine kinase inhibitor of the present invention> In order to evaluate the tyrosine kinase inhibitory activity and cancer cell growth inhibitory activity of the tyrosine kinase inhibitor of the present invention,
Partially purified human EGF (epidermal growth factor)
The test was performed in a receptor tyrosine kinase activity measurement system and a cell culture system using human cancer cells. Furthermore, in order to compare and evaluate the strength of the inhibitory activity, among the existing tyrosine kinase inhibitors disclosed in patents or literature, those having relatively high activity were simultaneously tested.

(1) Tyrosine kinase activity inhibitory action (Measurement method) Tyrosine kinase activity inhibitory action was determined by using an EGF receptor partially purified from a human squamous cell carcinoma-derived A431 cell line according to Linda J. et al. Pike et al.'S P
rosedings of the Nationa
l Academy of Sciences of t
he U.S. S. A. 79, 1433 (1982).

The detailed method is as follows. A431
The cells are cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) at 37 ° C. under 5% carbon dioxide, and the cells are cultured at 10 mM N-2-hydroxyethylpiperazino-N ′. -2-ethanesulfonic acid (H
epes) After homogenizing in a solution containing a buffer solution (pH 7.4), 0.25 M saccharose, and 0.1 mM EDTA, centrifuging at 3000 g for 5 minutes, and further centrifuging the supernatant at 100,000 × g for 30 minutes. A431
A cell membrane fraction was obtained, and this was subjected to measurement as a partially purified EGF receptor as an enzyme source.

The A431 cell membrane fraction (10 to 15 μm)
g), 30 mM Hepes buffer (pH 7.7), 2
100 ng of EGF was added to a reaction mixture of a test substance (final concentration 1% DMSO) dissolved in mM MnCl ₂ , 100 μM Na ₃ VO ₄ , and dimethyl sulfoxide (DMSO), and then the synthetic substrate RR-SRC peptide (A
rg-Arg-Leu-Ile-Glu-Asp-Al
a-Glu-Tyr-Ala-Ala-Arg-Gl
y) The reaction was started by adding 75 μg, 10 μM γ- ³² P-adenosine triphosphate (37 Kbp). The volume at this time is 60 μl. In addition, the RR-SRC peptide is
It is a synthetic substrate that serves as a substrate for the tyrosine kinase of the EGF receptor, and has an amino acid sequence containing a tyrosine residue that is phosphorylated in the src gene product.

The reaction was carried out in ice for 30 minutes and 10 mg /
The reaction was stopped by adding 6 μl of ml bovine serum albumin and 25 μl of 20% trichloroacetic acid, and left on ice for 30 minutes. Next, after centrifugation at 5000 × g for 2 minutes, 40 μl of the supernatant was sampled and adsorbed on P81 phosphocellulose paper. This was fixed by immersing it in 30% acetic acid water for 15 minutes, washed by immersing it in 15% acetic acid water for 15 minutes (washing was repeated 4 times), and counted ³² P attached to P81 phosphocellulose paper by a liquid scintillation counter. Was measured, and this value was designated as A. At the same time, the counts of the reaction without the addition of the test substance and the reaction without the addition of both the test substance and EGF were also measured, and were designated as B and C, respectively. From these values, the tyrosine kinase inhibition rate is determined by the following equation.

[0587]

## EQU1 ## Inhibition rate (%) = 100−Δ (AC) / (B−)
C)｝ × 100

The IC ₅₀ value (50% inhibitory concentration) was calculated from the inhibition rate obtained by changing the concentration of the test substance. (2) Cancer cell growth inhibitory effect (Measurement method) KB cells, which are human nasopharyngeal carcinomas, have an excess of EGF receptor on the cell surface. This KB
Using the cells, the effect of the test substance on the growth of cultured cancer cells was examined by the following method.

[0589] KB cells were seeded on a 96-well dish at 2.5 x 10 ³ cells / well, and 10% F
After culturing for 1 day in a DMEM: F12 (1: 1) medium containing BS, 50 U / ml penicillin and 50 μg / ml streptomycin at 37 ° C. and 5% carbon dioxide, DMS was added.
A test substance dissolved in O was added to the medium (final DMSO concentration <0.1%), and the cells were cultured under the above conditions for 3 days. The test substance was replaced together with the medium every 24 hours.

The count of the number of living cells was determined by
C. Alley et al. CancerResearch 4
8,589 (1988) with reference to the MTT method.
(3- [4,5-Dimethylthiazol-2
-Yl] -2,5-diphenetetrazoli
um bromide) reagent at 540 nm and 660
It was determined by colorimetry at two wavelengths of nm, and the value was defined as a.
At the same time, the count of the number of living cells when no test substance was added was also measured, and the value was defined as b. The cell growth inhibition rate is determined by the following equation.

[0591]

## EQU2 ## Inhibition rate (%) = {(ba) / b} × 100

The IC ₅₀ value (50% inhibitory concentration) was calculated from the inhibition rate obtained by changing the concentration of the test substance. The above results are shown in the table. In the table, Enz represents the tyrosine kinase inhibition rate, and Cell represents the cell growth inhibition rate.

[0593]

[Table 184]

[0594]

[Table 185]

[0595]

[Table 186]

[0596]

[Table 187]

[0597]

[Table 188]

[0598]

[Table 189]

[0599]

[Table 190]

[0600]

[Table 191]

[0601]

[Table 192]

[0602]

[Table 193]

[0603]

[Table 194]

[0604]

[Table 195]

[0605]

[Table 196]

[0606]

[Table 197]

[0607]

[Table 198]

[0608]

[Table 199]

[0609]

[Table 200]

[0610]

[Table 201]

[0611]

[Table 202]

[0612]

[Table 203]

[0613]

[Table 204]

[0614]

[Table 205]

[0615]

[Table 206]

[0616]

The ethynylpyrimidine derivative of the present invention is
Since it has strong tyrosine kinase inhibitory activity and cancer cell growth inhibitory activity, it is useful as an anticancer agent, an immunosuppressant, a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, or a cancer cell growth inhibitor.

[Table 207]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/52 ACB A61K 31/52 ACB 31/535 ABC 31/535 ABC C07D 239/42 C07D 239/42 Z 239/62 239 / 62 239/78 239/78 401/06 239 401/06 239 403/06 207 403/06 207 405/12 239 405/12 239 405/14 211 405/14 211 417/06 239 417/06 239 471/04 108 471/04 108Z 117 117Z 473/00 473/00 475/00 475/00 487/04 144 487/04 144 148 148 491/048 491/048 491/056 491/056 (72) Inventor Takeshi Suzuki Kanagawa Prefecture 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Jun Atsushi Oya 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Yokohama Research Laboratory (72) Inventor Hiroto Hara 2-5-2-2 Marunouchi, Chiyoda-ku, Tokyo Mitsubishi Chemical Corporation Pharmaceutical Company

Claims (5)

[Claims] 1. A compound represented by the following general formula (I) [However, in the above general formula (I), A and B are each independently a (1) nitro group; (2)-(CH ₂ ) _{n ′} NR ³ R ⁴
(In the formula, n ′ represents 0 or 1, and R ³ and R ⁴ each independently represent (a) a hydrogen atom; or (b) a carboxyl group or a C ₁ -C ₅ alkoxycarbonyl group. also represents an alkyl group optionally C ₁ -C _5); or a, B together form a ring, (3) ## STR2 ## [Wherein, X ^{1 to} X ⁴ each independently represent (a) a hydrogen atom, (b) a halogen atom, (c) a nitro group, (d) —O
R '(wherein, R' is (cycloalkyl group i) an oxygen atom optionally one comprise C ₃ -C ₈ or (ii) C _1,
Alkoxy group -C _5, amino optionally substituted by a group or a morpholino group represents an alkyl group which may _{C 1 ~C 5), (e} ) C 1 ~C 5 alkyl amino which may be substituted with a group Or (f) adjacent substituents together form a ring and represent a C ₁ -C ₅ oxyalkylene group); (Wherein, X ^{5 to} X ⁷ each independently represent a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group or an amino group optionally substituted with a C ₁ -C ₅ alkyl group);
(5) (Wherein X ^{8 to} X ¹⁰ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group, or a C ₁ -C 5
₅ represents an amino group which may be substituted by an alkyl group); (6) (Wherein X ¹¹ and X ¹² are hydrogen atoms; or C ₁ -C
₅ represents an alkyl group); (7) [Wherein, W represents a nitrogen atom or C—X ¹⁵ (in the formula, X ¹⁵ represents a hydrogen atom or a C ₁ -C ₅ alkyl group);
X ¹³ and X ¹⁴ represent a hydrogen atom or a C ₁ -C ₅ alkyl group]; (8) (Wherein X ¹⁶ and X ¹⁷ represent a hydrogen atom or a C ₁ -C ₅ alkyl group), and R ¹ is (1) a hydrogen atom; (2) a halogen atom; An optionally substituted phenyl group; (4)
Alkyl group optionally C ₁ -C ₅ substituted phenyl group; (5) a carboxyl group or a C ₁ -C ₅ alkoxycarbonyl C ₁ -C optionally substituted with a group ₅
(6) hydroxyl group; or (7)
C ₁ -C alkyl group or a C ₁ -C ₅ alkanoyl group which may be substituted an amino group of _5, R ² is (1) embedded image Wherein R ³ and R ⁴ are each independently substituted with (a) a hydrogen atom; (b) a halogen atom, a pyridyl group, a pyridazinyl group, or a C _{3 to} C ₈ cycloalkyl group. alkyl _{C 1 ~C 5; (c)} -COR
^{6 wherein} R ⁶ is (i) a hydroxyl group; (ii) C _1-
An alkoxy group having _{C 5; (iii) C 1} ~C 5 amino group which may be substituted by an alkyl group; or (iv) a halogen atom or a C ₁ -C ₅ phenyl which may be substituted with an alkoxy group (D) represents the group: (In the formula, j represents 0, ¹ , 2 or 3, and Z ¹ , Z ² ,
Z ³ is each independently: (i) a hydrogen atom; (ii) a halogen atom; (iii) a hydroxyl group; (iv) a C ₁ -C ₅ alkoxy group; or (v) a C ₁ -C ₅ alkoxycarbonyl Or (e) (i) a C ₁ -C ₅ alkyl group, or (ii) — (CH ₂ ) _n ″ R ²⁰ (wherein R ³ and R ⁴ form a ring with each other). , N ″ represents 0, 1 or 2, and R ²⁰ represents a carboxyl group, or a C ₃ -C ₈ cycloalkyl group optionally substituted with a carboxyl group or a C ₁ -C ₅ alkoxycarbonyl group. An amino group optionally substituted with: (f) (Wherein R ²¹ represents a carboxyl group or a C ₁ -C ₅ alkoxycarbonyl group); (g) (Where k represents 1, 2, 3 or 4; R ⁷ represents (i)
Hydroxyl group; (ii) hydroxyl group or C _1-
(H) an amino group optionally substituted with a C ₅ alkyl group; or (iii) a C ₁ -C ₅ alkoxy group); (I) (J) Or (k) Represents R ⁵ is (a) a hydroxyl group; (b) C ₁ -C
Alkoxycarbonyl group _{(c) C 1 ~C 5;} ; 5 alkyl group (d) alkanoyloxy group C ₁ -C _5;
(E) carboxyl group; (f) [Wherein, m represents 0 or 1, n represents 0, 1, 2, or 3, E represents (i) an oxygen atom; (ii) -NHSO
₂ -; (iii) -NHCO-; or (iv) -NR ⁷ -
(Wherein R ⁷ is 1) a hydrogen atom; 2) a C ₁ -C ₅ alkyl group; or 3) a hydroxyl group, a carboxyl group,
Or a C ₁ -C ₅ alkyl group which may be substituted with a C ₁ -C ₅ alkoxycarbonyl group), wherein Y ¹ , Y ² and Y ³ each independently represent (i) a hydrogen atom (Ii) a halogen atom; (iii) a hydroxyl group;
(Iv) an alkyl group of C ₁ -C _5; or (v) C ₁ ~C
₅ represents an alkoxy group]; (g) —O— (CO) _p −
G-COR ^{8 wherein} p represents 0 or 1, and G represents (i) a C ₁ -C ₅ alkylene group optionally substituted with a hydroxyl group or an acetoxy group; or (ii) Wherein R ⁸ is (i) a hydroxyl group; (ii) C ₁ -C
₅ alkoxy group; or (iii) represents a C ₁ -C ₅ alkyl amino group which may be substituted with a group of]; (h) -
NR ⁹ R ¹⁰ } wherein R ⁹ and R ¹⁰ are each independently
Alkyl group _{(ii) C 1 ~C 5;} ; (i) a hydrogen atom (ii
i) a cycloalkyl group of C ₁ -C ₅ alkoxy optionally substituted by a carbonyl group C ₃ -C _8; or (iv)
-(CO) _q -L- (CO) _r R ¹¹ [wherein q and r
Represents 0 or 1, L represents 1) a C ₁ -C ₅ alkylene group which may be substituted by a hydroxyl group or an acetoxy group and may be via an oxygen atom;
Represents a cycloalkylene group _{3 ~C 8,} R ¹¹ is 1) hydroxyl groups; 2) alkoxy C ₁ -C _20; 3) pivaloyloxymethoxy group; or 4) -NR ¹² R ¹³ (wherein , R ¹² is a) a hydrogen atom; an alkyl group or _{c) C 1 ~C 5, R} 13 is a) a hydrogen atom;; b) hydroxyl groups b) a phenyl group, substituted with a carboxyl group or hydroxyl group alkyl group which may C ₁ -C ₅ and; c) an alkoxycarbonyl group having C ₁ ~C _7; d) cyano group; e) phenyl or C ₁ -C ₅ alkyl carbamoyl optionally substituted by group F) a phenyl group or a sulfonyl group optionally substituted with a C ₁ -C ₅ alkyl group; or g) a C ₁ -C ₅ alkanoyl group)] or R ⁹ , R ¹⁰ Together form a ring, (v [Of 18] [Wherein, t and u represent 0, 1 or 2, and R ¹⁴ represents 1) a hydroxyl group; 2) a C ₁ -C ₂₀ alkoxy group;
3) pivaloyloxymethoxy group; 4) —NR ¹⁵ R
¹⁶ wherein R ¹⁵ is a) a hydrogen atom; b) a hydroxyl group;
Or c) represents a C ₁ -C ₅ alkyl group, wherein R ¹⁶ is a)
Hydrogen atoms; b) phenyl group, a carboxyl group and / or hydroxyl groups C ₁ may be substituted with -C ₅
(Vi) a cyano group)]; (vi) Wherein s represents 0, 1, or 2, and R ¹⁷ represents 1) a hydroxyl group; 2) a C ₁ -C ₂₀ alkoxy group; 3) a pivaloyloxymethoxy group; ₁ -C be substituted by ₅ alkyl groups representing also represents an amino group] represents a} or represents>, or,
(2) (In the formula, CyA represents a benzene ring, a pyridine ring, or a pyrrole ring, Q represents a phenyl group optionally substituted with a halogen atom, V is (1) a hydrogen atom, (2) C ₁
Alkoxycarbonyl group -C _5, (3) a carboxyl group, or (4) C ₁ ~C ₅ alkoxycarbonyl groups or optionally C ₁ ~ optionally substituted by carboxyl group
Ethynyl pyrimidine derivatives and their hydrates represented by representing the representative) an alkyl group having C _5], pharmacologically acceptable salts, optically active forms, racemates and diastereomeric mixtures. 2. The ethynylpyrimidine derivative according to claim 1, wherein A and B together form a ring in the general formula [I], and hydrates and pharmacology thereof. Salts, optically active isomers, racemates, and diastereomeric mixtures. 3. A pharmaceutical composition comprising the compound according to claim 1 and a pharmacologically acceptable carrier. 4. The pharmaceutical composition according to claim 3, which is used as a prophylactic and / or therapeutic agent for a disease caused by enhanced tyrosine kinase activity. 5. The pharmaceutical composition according to claim 3, which is used as an anticancer agent, an immunosuppressant, a platelet aggregation inhibitor, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, or a cancer cell growth inhibitor.