ES2366887T3 - NEW DERIVATIVES OF AMIDA AND ITS THERAPEUTIC USE. - Google Patents

Abstract

An amide derivative represented by the formula (1) wherein R1, R2 and R3 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents , cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylalkyl group, group acyloxy which optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group which optionally has substituents , alc group Oxycarbonyl, carboxyl group, acylamino group, sulfamoyl group which optionally has substituents or haloalkyl group or any two of R1, R2 and R3 in combination with the adjacent carbon atom can form a ring, a, b, c, d and each are each atom carbon or 1 or 2 of a, b, c, d and d are nitrogen atoms (as long as the nitrogen atom here can be attached with oxygen atom of amine oxide and the rest are carbon atoms, R4, R5 and R6 are the same or different and each one is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally it has substituents, arylalkyl group which optionally has substituents, heteroarylalkyl group which optionally has substituents, alco group xi which optionally has substituents, aryloxy group, arylalkyloxy group, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group that optionally has substituents, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoyl group that optionally has substituents, haloalkyl group or haloalkyloxy group, A is cycloalkyl group that optionally has substituents, aryl group that optionally has substituents or heteroaryl group that optionally has substituents, W1 and W2 are the same or different and each is a bond or alkylene (Cn) that optionally has substituents, wherein n is an integer from 1 to 3, X is an oxygen atom or sulfur atom, Y is a bond, oxygen atom, -CO-, -N (R7) -, where R7 is the atom of hi halogen or alkyl group that optionally has substituents, -SOm-, wherein m is an integer from 0 to 2, -CON (R8) -, where R8 is hydrogen atom or alkyl group that optionally have substituents or -N ( R9) CO-, wherein R9 is hydrogen atom or alkyl group that optionally has substituents), Z is alkylene group which optionally has substituents and optional substituents are selected from alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group , arylalkyl group, heteroaryl group, heteroarylalkyl group, alkoxy group, aryloxy group, arylalkyl group, acyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoyl group, haloalkyl group, haloalkyloxy group, oxo group (yes undertake that, when replacing a divalent nitrogen atom, form amine oxide), tetrahydropyran-2-yloxy, R13O (CH2) jO (CH2) kO (CH2) lO-, R13O (CH2) jO (CH2) kO-, R13O (CH2) jO-, R13O (CH2) jO (CH2) kO (CH2) l-, R13O (CH2) jO (CH2) k-, R13O (CH2) j-, where j, kyl are each, so independent, an integer from 2 to 10, R13 is hydrogen atom, alkyl group, cycloalkyl group, aryl group, heteroaryl group, arylalkyl group, heteroarylalkyl group or haloalkyl group, one of its optically active forms or one of its pharmaceutically acceptable salts .

Description

Technical field

The present invention relates to an amide derivative that shows an antagonistic action of the C5a receptor and is useful for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like, sepsis, respiratory distress syndrome in adults , chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease or severe organic injury (eg, pneumonia, nephritis, hepatitis and pancreatitis and the like) due to the activation of leukocytes caused by reperfusion due to ischemia, trauma, burn, surgical invasion and the like, one of its optically active forms, one of its pharmaceutically acceptable salts and its pharmaceutical use.

Prior art

When the complement system is activated, the protein of the complement system is enzymolyzed and fragments that have various physiological activities are produced. One of the fragments, component of complement C5a, is a glycoprotein that has a molecular weight of approximately 11,000, consists of 74 amino acids and has a strong action that induces inflammation. C5a has a wide range of actions such as soft muscle contraction, promotion of blood vessel permeability, leukocyte migration, leukocyte degranulation, production of reactive oxygen species, reinforcement of antibody production, production induction of cytokines, TNF (tumor necrosis factor) and leukotrienes, and the like and is said to be a substance causing diseases such as autoimmune diseases (eg rheumatism and systemic lupus erythematosus and the like), sepsis, respiratory distress syndrome in adults , chronic obstructive pulmonary disease, allergic diseases (for example, asthma and the like), atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease, severe organic lesions (for example, pneumonia, nephritis, hepatitis, pancreatitis and the like) due to leukocyte activation caused by reperfusion due to ischemia, trauma, burn, inv surgical asion and the like, and others [Annu. Rev. Immunol., Vol. 12, pp. 775-808 (1994), Immunopharmacology, vol. 38, pp. 3–15 (1997), Curr. Pharm Des., Vol. 5, pp. 737–755 (1999) and IDrugs, vol. 2, pp. 686–693 (1999)].

Accordingly, a small non-peptide molecular compound having an antagonistic action of the C5a receptor is expected to be a novel non-steroidal anti-inflammatory drug. In addition, it can be expected to be a preventive or therapeutic drug for infectious diseases caused by bacteria or viruses that invade through a C5a receptor.

As for the C5a antagonist, for example, the following patent applications have been published. JP-A-10-182648 discloses compounds related to TAN-2474 that have an antagonistic action of C5a. In addition, the specification of WO-A-94/07815 discloses peptide derivatives having an antagonistic action of the C5a receptor, the specification of WO-A-99/00406 discloses cyclic peptide derivatives having an antagonistic action of the C5a receptor . US-A-5,491,152 discloses bicyclic amide derivatives that are useful in the treatment of atherosclerosis.

Until now, however, a pharmaceutical drug that prevents or treat diseases or syndromes due to inflammation caused by C5a by inhibiting the action of C5a has not been developed.

Description of the invention

In view of the aforementioned situation, the present inventors conducted intensive studies in order to find a non-peptide compound having an antagonistic action of the C5a receptor. As a result, they found that an amide derivative according to the present invention shows an antagonistic action of the C5a receptor, which resulted in the culmination of the present invention.

Accordingly, the present invention provides the following.

1. An amide derivative represented by formula (1) wherein

image 1

R1, R2 and R3 are the same or different and each is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylalkyl group, acyloxy group that optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group which optionally has substituents, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoi group which optionally has substituents or haloalkyl group or any two of R1, R2 and R3 in combination with the adjacent carbon atom can form a ring,

a, b, c, d and e are each carbon atom or 1 or 2 of a, b, c, d and e are nitrogen atoms (provided that the nitrogen atom here can be attached with amine oxide oxygen atom and the rest they are carbon atoms,

R4, R5 and R6 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylalkyl group, acyloxy group that optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group which optionally has substituents, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoi group which optionally has substituents, haloalkyl group or haloalkyloxy group,

A is cycloalkyl group that optionally has substituents, aryl group that optionally has substituents or heteroaryl group that optionally has substituents,

W1 and W2 are the same or different and each is a bond or alkylene (Cn) that optionally has substituents, where n is an integer from 1 to 3,

X is an oxygen atom or sulfur atom,

Y is a bond, oxygen atom, –CO–, –N (R7) -, where R7 is hydrogen atom or alkyl group that optionally has substituents, –SOm–, where m is an integer from 0 to 2 , –CON (R8) -, where R8 is hydrogen atom or alkyl group that optionally have substituents or –N (R9) CO–, where R9 is hydrogen atom or alkyl group that optionally has substituents),

Z is alkylene group that optionally has substituents and

Optional substituents are selected from alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, alkoxy group, aryloxy group, arylalkyl group, acyloxy group, halogen atom, hydroxyl group, group nitro, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoyl group, haloalkyl group, haloalkyloxy group , oxo group (provided that, when replacing a divalent nitrogen atom, it forms amine oxide), tetrahydropyran-2-yloxy, R13O (CH2) jO (CH2) kO (CH2) 10-, R13O (CH2) jO (CH2) kO–, R13O (CH2) jO–, R13O (CH2) jO (CH2) kO (CH2) l–, R13O (CH2) jO (CH2) k–, R13O (CH2) j–, where j, kyl are each one, independently, an integer from 2 to 10, R13 is hydrogen atom, alkyl group, g rupo cycloalkyl, aryl group, heteroaryl group, arylalkyl group, heteroarylalkyl group or haloalkyl group, one of its optically active forms or one of its pharmaceutically acceptable salts.

2. The above amide derivative, where, in formula (1),

R1, R2 and R3 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, group carboxyl, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl group,

a, b, c, dya are each carbon atom or 1 or 2 of a, b, c, dye are nitrogen atoms and the rest are carbon atoms, R4, R5 and R6 are the same or different and each is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group that optionally has substituents, halogen atom, hydroxyl group, group nitro, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or hahoalkyl group ,

A is cycloalkyl group, aryl group that optionally has substituents or heteroaryl group that optionally has substituents,

W1 and W2 are the same or different and each is a bond or alkylene (Cn) that optionally has substituents, where n is an integer from 1 to 3,

X is an oxygen atom or sulfur atom,

Y is a bond, oxygen atom, –CO–, –N (R7) -, where R7 is hydrogen atom or alkyl group that optionally has substituents, –SOm–, where m is an integer from 0 to 2 , -CON (R8) -, where R8 is hydrogen atom or alkyl group that optionally has substituents or -N (R9) CO-, where R9 is hydrogen atom or alkyl group that optionally has substituents,

Z is an alkylene group that optionally has substituents, one of its optically active forms or one of its pharmaceutically acceptable salts and the optional substituents are defined as in item 1 above.

3.

 The amide derivative of the preceding point 2, wherein a, b, c, d and c in the formula (1) are all carbon atoms, one of its optically active forms or one of its pharmaceutically acceptable salts.

Four.

 The amide derivative of item 1 above, wherein R1, R2 and R3 in the formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group, one of its optically active forms or one of its pharmaceutically acceptable salts.

5.

 The amide derivative of item 1 above, wherein R1, R2 and R3 in formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group having 2 at 4 carbon atoms, one of its optically active forms or one of its pharmaceutically acceptable salts.

6.

 The amide derivative of item 1 above, wherein R1, R2 and R3 in formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or a methoxy group, one of its optically active forms or one of its pharmaceutically acceptable salts.

7.

 The amide derivative of item 1 above, wherein R4, R5 and R6 in formula (1) are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group, haloalkyl group or haloalkyloxy group and wherein the optional substituents are defined as in item 1 above, one of its optically active forms or one of its pharmaceutically acceptable salts.

8.

 The amide derivative of item 1 above, wherein R4, R5 and R6 in formula (1) are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group or haloalkyl group and wherein the optional substituents are defined as in item 1 above, one of its optically forms active or one of its pharmaceutically acceptable salts.

9.

 The amide derivative of item 1 above, where Z of the formula (1) is –CH2–,

one of its optically active forms or one of its pharmaceutically acceptable salts.

10.

 The amide derivative of item 1 above, wherein A of the formula (1) is aryl group that optionally has substituents or heteroaryl group that optionally has substituents and where optional substituents are defined as in item 1 above, one of its optically active forms or a pharmaceutically acceptable salt thereof.

eleven.

 The amide derivative of item 1 above, wherein A of the formula (1) is phenyl group that optionally has substituents, pyridyl group that optionally has substituents, pyrazolyl group that optionally has substituents, thiazolyl group that optionally has substituents, oxazolyl group that optionally it has substituents or thienyl group which optionally has substituents and wherein the optional substituents are defined as in item 1 above, one of its optically active forms or one of its pharmaceutically acceptable salts.

12.

 The amide derivative of item 1 above, wherein A of the formula (1) is a phenyl group that optionally has substituents or a nitrogen-containing heterocyclic group selected from the group consisting of the following formulas (Aa) - (Ac)

image 1

Wherein R 10 is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group that optionally has substituents, halogen atom , hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group,

10 carboxyl group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl group and wherein the optional substituents are defined as in item 1 above, one of its optically active forms or one of its pharmaceutically acceptable salts.

13. The amide derivative of item 1 above, wherein X of the formula (1) is an oxygen atom, one of its optically active forms or one of its pharmaceutically acceptable salts.

14. The amide derivative of item 1 above, wherein –W1 – Y – W2– of the formula (1) is - (CH2) 2–, - (CH2) 3– or - (CH2) 2O,

one of its optically active forms or one of its pharmaceutically acceptable salts.

15. The amide derivative of item 1 above, wherein R1, R2 and R3 of the formula (1) are the same or different and each

one is hydrogen atom, alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms,

a, b, c, d and e are each carbon atom or b or d is a nitrogen atom and the rest are carbon atoms,

R4, R5 and R6 are the same or different and each one is hydrogen atom, methoxy group, halogen atom or hydroxyl group,

Z is –CH2–,

A is a phenyl group that optionally has substituents or nitrogen-containing heterocyclic group selected from the group consisting of the following formulas (Aa ') - (Ae')

image 1

wherein R10a, R11 and R12 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents; heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylakyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, alkylthio group, amino group, alkylamino group, dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) lO–, where j, kyl are each, independently, a number integer from 2 to 10, R13 is hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally it has substituents or haloalkyl group or R13O (CH2) jO (CH2) kO–, where j , k and R13 are as defined above, R10b is a hydrogen atom,

Alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, haloalkyl group, haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) l–, where j, k, l and R13 are as previously defined or R13O (CH2) O (CH2) k–, where j, k and R13 are as defined before

X is an oxygen atom,

–W1 – Y – W2– is - (CH2) 2 - or - (CH2) 3

and where the optional substituents are defined as in point 1 above,

one of its optically active forms or one of its pharmaceutically acceptable salts.

16.

 The amide derivative according to any of items 1 to 15 above, wherein the amide derivative is selected from the group consisting of N - [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) -1, 2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) indan-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N– ( 4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4- tetrahydronaphthalen – 1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) chroman – 4-carboxamide, N - [(4-dimethylaminophenyl) methyl] –5 – hydroxy-N– (4– isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -6-methoxyindan-1-carboxamide, N - [(1– ethylpyrazole – 4-yl) methyl] –N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -6-methoxychroman-4-carboxamide, N - [(1,3-dioxaindan-5-yl) methyl] -N- (4 -Isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -4-hydroxy-N- (4-isopropylphenyl) indan-1-carboxamide, N - [(1-ethylpyrazol-4-yl) methyl) -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide and

N - ((1-ethylpyrazol-4-yl) methyl) -4-hydroxy-N- (4-isopropylphenyl) indan-1-carboxamide, one of its optically active forms or one of its pharmaceutically acceptable salts.

17.

 The amide derivative of item 1 above, wherein the amide derivative is N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1.2 , 3,4-tetrahydronaphthalen-1-carboxamide, one of its optically active forms or one of its pharmaceutically acceptable salts.

18.

 The amide derivative according to any of items 1 to 15 above, wherein the amide derivative is selected from the group consisting of N - [(2,6-dimethoxypyridin-3-yl) methyl] –5-hydroxy– N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (4-isopropylphenyl) –N - [(6-phenoxypyridin-3-yl) methyl) –1 , 2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(6-dimethylaminopyridin-3-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen- 1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-ethoxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(5-ethylthiophene-2 –Il) methyl] –N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-fluoro-N– (4-isopropylphenyl) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide, N– (4-bromophenyl) –N - [(4-dimethylaminophenyl) methyl] –7 – fluoro – 1, 2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -8-fluoro-5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1 –Carboxamide, N - [(2,6-dimethoxypyridin-3-yl) methyl] –5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - [(6-methoxypyridin-3-yl) -methyl-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2 , 4-dimethylthiazol-5-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-butylphenyl) - N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-methoxy-N- (4-methoxyphenyl ) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide, N– (4-chlorophenyl) –N - [(4-dimethylaminophenyl) methyl] –7-methoxy – 1,2,3,4-tetrahydronaphthalen – 1 –Carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-methoxy-N– (4-methylphenyl)] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl ] –N– (4-ethoxyphenyl) –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-bromophenyl) –N - [(4-dimethylaminophenyl) methyl] –7-methoxy –1,2,3,4 – tetrahydronaft alen-1-carboxamide, N– (4-isopropylphenyl) -7-methoxy-N - [(4-methylaminophenyl) methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl ) methyl] –5-hydroxy-N– (4-methoxyphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4-isopropylphenyl) –N - [(2-methylthiazole– 4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-bromophenyl) -N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-1,2,3, 4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N- (2-tolylmethyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,4– dichlorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4-nitrophenyl ) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(3-tolyl) methyl] –1,2,3,4-tetrahydronaphthalen –1 – carboxamide, N– (4 isopropylphenyl) –7-methoxy-N - [(4-tolyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-fluorophenyl) methyl] –N– (4-isopropylphenyl) –7 – methoxy – 1,2,3,4-tetrahydronaphthalen – 1-carboxamide, N - [(4-fluorophenyl) methyl] –N– (4-isopropylphenyl) –7 – methoxy – 1,2,3,4– tetrahydronaphthalen-1-carboxamide, N - [(2,4-dimethylphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4– isopropylphenyl) –7-methoxy-N - [(2-methoxyphenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-chlorophenyl) methyl] -N- (4-isopropylphenyl) –7 – methoxy – 1,2,3,4-tetrahydronaphthalen – 1-carboxamide, N - [(2,4-difluorophenyl) methyl] –N– (4-isopropylphenyl) –7-methoxy – 1,2,3, 4-tetrahydronaphthalen-1-carboxamide, N - [(2,6-difluorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- [ (4 – ethoxyphenyl) methyl] –N– (4 – isopr opylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4-oxacroman-6-yl) methyl] –1, 2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,3-dimethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide , N - [(2,4-dimethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7- methoxy-N - [(2-trifluoromethylphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4-trifluoromethylphenyl) methyl] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-bromophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide , N– (4-isopropylphenyl) -7-methoxy-N - [(2,3,4-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4 –Isopropylphenyl) –N - {[1– ( 2-pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(1-benzylpyrazol-4-yl) methyl] -5-hydroxy-N- (6 –Isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) –N - {[1– (2-pyridylmethyl) pyrazole –4 – il] methyl} –1,2,3,4 – tetrahydronaphthalen – 1–

carboxamide,

N - ({1 - [(4-fluorophenyl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, N - ({1 - [(4-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen – 1–

carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen -

1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methoxyphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4 –Tetrahydronaphthalen – 1– carboxamide,

N - ({1 - [(4-bromophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 -

carboxamide, N - ({1 - [(3-chlorophenyl) methyl] pyrazol-4-yl) methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen –1– carboxamide,

N - ({1 - [(2-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 -

carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen –1– carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(5-methylpyridin-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [( 5-

methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N- ( {1 - [(6-methylpyridine-2-yl) methyl-1-yl] -pyrazol-4-yl) -methyl) -1,2,3,4- tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridine-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4 -

tetrahydronaphthalen-1-carboxamide, 8-fluoro-5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1- (2-pyridylmethyl) pyrazol-4-yl] methyl} –1,2, 3,4-tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylpyridin-2-yl) methyl] pyrazole-4-yl} methyl) –1,2,3,4 -

tetrahydronaphthalen-1-carboxamide, N - ({1 - [(6-dimethylaminopyridin-2-yl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1 , 2,3,4– tetrahydronaphthalen-1-carboxamide,

N - ({1– [3– (dimethylaminophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4–

tetrahydronaphthalen-1-carboxamide, N - [(2-ethyl-4-trifluoromethylthiazol-5-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen –1– carboxamide,

5-benzyloxy-N– (4-isopropylphenyl) -N - [(1-isopropylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4– isopropylphenyl) –N - [(1-methylpyrazol-4-methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-benzyloxy-N- (4-isopropylphenyl) –N - [(1-propylpyrazole– 4-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (4-isopropylphenyl) –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide, 5-hydroxy-N– (4-isopropylphenyl) –N - {(1– (3-thienylmethyl) pyrazol-4-yl] methyl) –1.2 , 3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (4-fluorobenzyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (4-methoxyphenyl) –1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide, N - [(1-ethylpyrazol-4-yl) methyl] –5-hydroxy-N– (4-methoxyphenyl) –1,2,3,4-tetrahydronaphthalen – 1 – carboxamide, N– {(1– (cyclohexylmethyl) pyrazol-4-yl] met il) -5-hydroxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1 - (2-piperidinoethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1–

carboxamide,

N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N– [(1-Heptylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- ( 6 – isopropylpyridin-3-yl) –N - {[1– (3-thienylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(2-methylthiazol-4-yl) methyl] pyrazol-4-yl} methyl) –1,2,3 , 4-tetrahydronaphthalen-1-carboxamide,

N - [(1-Butylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (3-methylbutyl) pyrazol-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N - [(1-benzylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-methoxypyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1– [2– (2-pyridyl) ethyl] pyrazol-4-yl} methyl – 1,2,3,4-tetrahydronaphthalen– one-

carboxamide, N - [(1-dodecylpyrazi-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - [(1-nonylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (2-Butoxyethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1– [2– (2-methoxyethoxy) ethyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen -one- carboxamide, 5-hydroxy-N– (4-isopropylphenyl) -N - [(6-morpholinopyridin-3-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (4-isopropylphenyl) -N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl) methyl) –1,2,3,4-tetrahydronaphthalen – 1 -

carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(6-morpholinopyridin-2-yl) methyl] pyrazol-4-yl) methyl) –1,2,3,4 - tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {(1 - [(6-methoxypyridin-2-yl) methyl] -pyrazol-4-yl) methyl} –1,2,3, 4-

tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N - [(1-isopropylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (6-isopropylpyridin-3-yl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (2-thienylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide,

N - ({1 - [(5-chlorothiophene-2-yl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4 –Tetrahidronaftalen– 1-carboxamide, 5-benzyloxy-N - ({1– [2– (2-butoxyethoxy) ethyl] pyrazol-4-yl) methyl) –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen -one-

carboxamide,

N - ({1– [2– (2-Butoxyethoxy) ethyl] pyrazol-4-yl) methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen -one- carboxamide and N - ({1– [2– (2-ethoxyethoxy) ethyl] pyrazol-4-yl} methyl) -N– (6-isopropylpyridin-3-yl) –5-hydroxy – 1,2,3,4-tetrahydronaphthalen -one-

carboxamide, one of its optically active forms or one of its pharmaceutically acceptable salts.

19.

 A pharmaceutical composition comprising the amide derivative or any of items 1 to 18 above, one of its optically active forms or one of its pharmaceutically acceptable salts and a pharmaceutically acceptable additive.

twenty.

 A drug comprising the amide derivative of any of items 1 to 18 above, one of its optically active forms or one of its pharmaceutically acceptable salts as an active ingredient for use in the prevention and therapy of a disease selected from a disease autoimmune, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease or severe organic injury due to leukocyte activation caused by reperfusion due to ischemia, trauma , burn or surgical invasion.

twenty-one.

 The drug of item 20 above, where the autoimmune disease is rheumatism or systemic lupus erythematosus.

22

 A C5a receptor antagonist comprising the amide derivative according to any of items 1 to 18 above, one of its optically active forms or one of its pharmaceutically acceptable salts in the form of an active ingredient.

2. 3.

 The C5a receptor antagonist of item 22 above, which is used in combination with an agent for the prevention or treatment of an autoimmune disease, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis, infarction cardiac, cerebral infarction, psoriasis, Alzheimer's disease or severe organic injury due to leukocyte activation caused by reperfusion due to ischemia, trauma, burn or surgical invasion.

24.

 A drug combined with an agent for the prevention or treatment of an autoimmune disease, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease or organic injury severe due to leukocyte activation caused by reperfusion due to ischemia, trauma, burn or surgical invasion, which comprises the amide derivative of any of items 1 to 18 above, one of its optically active forms or one of its pharmaceutically acceptable salts in form of an active ingredient.

The "C5a receptor antagonist action" implies an action that inhibits a reaction that causes some physiological changes (eg, increase in intracellular Ca2 +, and the like) by binding, by means of a C5a receptor, of "substances that bind with a C5a receptor ”with cells expressing the C5a receptor.

In the present specification, each symbol is as defined below.

In R1-R13, R10a and R10b, the alkyl group is straight or branched chain alkyl having 1 to 18, preferably 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl , tertiary butyl, isopentyl, pentyl, 3-methylbutyl, neopentyl, 1-ethylpentyl, hexyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, dodecyl, hexadecyl, octadecyl and the like.

In R1-R6 and R10, the alkenyl group is straight or branched chain alkenyl having 2 to 18, preferably 2 to 12, more preferably, 2 to 8 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 5-hexenyl, 4-methyl-3-pentenyl, 2-octenyl, 2-dodecenyl, and the like.

In R1-R6 and R10, the alkynyl group is straight or branched chain alkynyl having 2 to 18, preferably 2 to 12, more preferably, 2 to 5, carbon atoms, such as ethynyl, 2-propynyl, 2 -Butynyl, 5-pentinyl, 2-octinyl, 2-dodecinyl and the like.

In R1-R6, R10-R13, R10a-R10b and A, the cycloalkyl group, for example, is cycloalkyl having preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

In R1-R6, R10-R12 and R10a, the alkoxy group is, for example, straight or branched chain alkoxy having preferably 1 to 18 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, 3-methylbutoxy, neopentyloxy, hexyloxy, heptyloxy, octyloxy, decyloxy, hexadecyloxy, octadecyloxy and the like, and others.

In R1-R6 and R10, the acyloxy group is, for example, alkanoyloxy having 2 to 9 carbon atoms, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy, 2-methylbutyryloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyryloxy , valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy and the like, cycloalkylcarbonyloxy having 4 to 8 carbon atoms, such as cyclopentylcarbonyloxy, cyclohexylcarbonyloxy and the like, arylcarbonyloxy having 7 to 11 carbon atoms, such as benzoyloxy and naphthoxy, naphthoxy, and the like , and others.

In R1-R6, R10-R12 and R10a, the halogen atom is chlorine, bromine, fluorine or iodine.

In R1-R6 and R10, the acyl group is, for example, alkanoyl having 1 to 8, preferably 2 to 8, carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, octanoyl and the like, cycloalkylcarbonyl having 4 to 8 carbon atoms (cycloalkyl moiety is the same as the aforementioned cycloalkyl), such as cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like, aroyl having 7 to 11 carbon atoms, such as benzoyl, toluoyl, naphthoyl and the like, heteroarylcarbonyl such as nicotinoyl, tenoyl, furoyl and the like, and others.

In R1-R6, R10-R12 and R10a, the alkylthio group is straight or branched chain alkylthio having 1 to 18, preferably 1 to 12, carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio , secondary butylthio, tertiary butylthio, pentylthio, 3-methylbutylthio, neopentylthio, 1-ethylpentylthio, hexylthio, 2-ethylbutylthio, heptylthio, octylthio, decylthio, hexadecylthio, octadecylthio and the like.

In R1-R6 and R10, the alkylsulfonyl group is alkylsulfonyl group, wherein the alkyl moiety is as defined in the "alkyl group" mentioned above (straight or branched chain alkyl having 1 to 18, preferably 1 to 12 carbon atoms). Examples include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, and the like.

In R1-R6, R10-R12 and R10a, the alkylamino group is an alkylamino group wherein the alkyl moiety is as defined for the "alkyl group" mentioned above. Examples include methylamino group, ethylamino group, propylamino group, isopropylamino group and the like.

In R1-R6, R10-R12 and R10a, the dialkylamino group is one in which each alkyl moiety is as defined for the "alkyl group" mentioned above and the respective alkyl may be the same or different. Examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, ethylmethylamino group, butylmethylamino group and the like.

The cyclic amino group in R1-R6, R10-R12, R10a and A is a saturated 3- to 8-membered cyclic amino group that may contain one or more oxygen atoms and sulfur atoms as ring constituent atoms, in addition to the atom of carbon and nitrogen atom. Examples include aziridinyl, azetidinyl, pyrrolizinyl, piperidino, piperidyl, piperazino, piperazinyl, azepinyl, morpholino, morpholinyl, thiomorpholinyl, imidazolidinyl, heptamethyleneimino and the like.

In R1-R6, the sulfamoyl group is optionally mono- or disubstituted sulfamoyl group with lower alkyl having 1 to 3 carbon atoms. Examples include sulfamoyl, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl and the like.

In R1-R6, R10-R13, R10a and R10b, the haloalkyl group is alkyl substituted with one or more halogen atoms which is the "halogen atom" mentioned above, wherein the alkyl moiety is as defined for the "group alkyl ”mentioned above. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl and trichloromethyl and the like;

In the haloalkyloxy group for R4-R6, R11, R12, R10a and R10b, "haloalkyl" is as defined for the aforementioned haloalkyl. Examples of the haloalkyloxy group include trifluoromethyloxy, 2,2,2-trifluoroethyloxy and the like.

In R1-R6, R11-R13, R10a, R10b and A, the aryl group is, for example, aryl having 6 to 14 carbon atoms such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2– Antrilo and the like. The aryl may have one or more substituents where the substitution position is not particularly limited. The substituents may form a ring, may be condensed with aryl and may be partially reduced.

In R1-R6, R11-R13, R10a, R10b and A, the heteroaryl is a 5- to 14-membered ring group containing one or more heteroatoms such as nitrogen atom, oxygen atom, sulfur atom and the like as atoms Ring constituents, in addition to carbon atom, may be monocyclic or polycyclic and may be partially reduced. Examples include pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, benzoxazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzxazololyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzoxidazolyl, benzxaidazolyl, benzxaidazolyl, benzxaidazolyl, benzoxidazolyl, benzxaidazolyl, benzxazololyl, benzxazolol , quinoxalinyl, quinazolinyl, phenazinyl, tetrazolyl, oxadlazolyl, imidazothienyl, 1,3-dioxaindanyl, 4-oxacromanyl and the like. These heteroaryl groups optionally have one or more substituents, where the substitution position is not particularly limited. In the case of a polycycle, any ring may be substituted. The link may be present in any ring, if possible.

When any two of R1, R2 and R3 in combination with the adjacent carbon atom form a ring, it may be fused to aryl (the "aryl" here is as defined above); or partially reduced. In addition, the ring may contain one or more heteroatoms such as nitrogen atom, oxygen atom, sulfur atom and the like to form heteroaryl (the "heteroaryl" here is as defined above) and a ring where the heteroaryl is partially reduced is also included.

In R1-R6 and R10, the alkoxycarbonyl group is one in which the alkoxy moiety is as defined for the "alkoxy group" mentioned above. The alkoxycarbonyl group is exemplified by means of methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tertiary butoxycarbonyl group, and the like.

In R1-R6, the acylamino group is one in which the acyl group is as defined for the "acyl" mentioned above. In addition, alkylsulfonylamino and arylsulfonylamino are also comprised of acylamino, wherein "alkyl" and "aryl" herein are as defined above. Examples of the acylamino group include acetamide, benzamide and the like.

In W1, W2 and Z, the alkylene group is alkylene having 1 to 10, preferably 1 or 2 carbon atoms. Examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octamethylene, nonamethylene, decamethylene, and the like.

In R1-R6, R11, R12, R10a, R10b and R13, the arylalkyl is one in which the aryl moiety is as defined for the aforementioned "aryl group" and the alkyl moiety is straight or branched chain alkyl having 1 to 12, preferably 1 to 3 carbon atoms. Examples of arylalkyl include benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2– (1-naphthyl) ethyl, 2-naphthylmethyl, 2– (2-naphthyl) ethyl and the like. The aryl aryl alkyl moiety may have one or more substituents, where the substitution position is not particularly limited.

In R1-R6, R11, R12, R10a, R10b and R13, the heteroarylalkyl group is one in which the heteroaryl moiety is as defined for the "heteroaryl group" mentioned above and the alkyl moiety is straight or branched chain alkyl which it has 1 to 12, preferably 1 to 3 carbon atoms. Examples of heteroarylalkyl include 2-pyridylmethyl, 3-pyridylmethyl, pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 3-pyrazolylmethyl, 4-pyrazolylmethyl, 5-pyrazolylmethyl 2-imidazolylmethyl, 4-imidazolylmethyl, 5-imidazolylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl, 5-oxazolylmethyl, 3-isoxazolylmethyl, 4-isoxazolylmethyl, 5-isoxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl-3-thiazolylmethyl isothiazolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl, 2– (2-pyridyl) ethyl, 2– (3-pyridyl) ethyl, 2– (4-pyridyl) ethyl, 2– (2-thienyl) ethyl, 2– (3 -Thienyl) ethyl, 2– (2-thiazolyl) ethyl, (4-thiazolyl) ethyl, 2– (5-thiazolyl) ethyl and the like. The heteroaryl group of the heteroarylalkyl group may have one or more substituents, where the substitution position is not particularly limited.

In R1-R6, the carbamoyl group that optionally has substituents is an optionally mono carbamoyl group

or disubstituted by lower alkyl having 1 to 3 carbon atoms. Examples include carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and the like.

In R1-R6, R11, R12 and R10a, the aryloxy group is one in which the aryl moiety is as defined for the aforementioned "aryl group". Examples of the aryloxy group include phenoxy and the like.

In R1-R6, R11, R12 and R10a, the arylalkyloxy group is one in which the arylalkyl moiety is as defined for the aforementioned "arylalkyl." Examples of arylalkyloxy group include benzyloxy and the like.

In the present invention, the substituent of the "optionally having substituents" is selected from the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, alkoxy group, aryloxy group, arylalkyl group, acyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoyl group, haloalkyl group, haloalkyloxy group, oxo group (provided that, when it substitutes a divalent nitrogen atom, it forms amine oxide), tetrahydropyran-2-yloxy, R13O (CH2) jO (CH2) kO (CH2) lO–, where j, k, l and R13 are as defined above, R13O (CH2) jO (CH2) kO–, where j, k and R13 are as previously defined, R13O (CH2) jO–, in where j and R13 are as defined above, R13O (CH2) jO (CH2) kO (CH2) l–, where j, k, l and R13 are as previously defined, R13O (CH2) jO (CH2) k–, where j, k and R13 are as defined above, R13O (CH2) j–, where j and R13 are as previously defined), which are as previously defined. These substituents may be optionally substituted with the substituents mentioned herein. In addition, the substituted substituents are optionally also substituted by the substituents mentioned herein.

As the amide derivative (1), one of its optically active forms or one of its pharmaceutically acceptable salts of the present invention, it is preferred, for example, amide derivative (1), wherein R1, R2 and R3 are the same or different and each one is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group that optionally has substituents, halogen atom , hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group, oxadiazolyl group , sulfamoyl group or haloalkyl group,

a, b, c, d and e are each carbon atom or one or two of a, b, c, d and e are nitrogen atoms and the rest are carbon atoms,

R4, R5 and R6 are the same or different and each is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, group carboxyl, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl group,

A is hydrogen atom, cycloalkyl group, aryl group that optionally has substituents, heteroaryl group that optionally has substituents or cyclic amino group,

W1 and W2 are the same or different and each is a bond or alkylene (Cn) that optionally has substituents, where n is an integer from 1 to 3,

X is an oxygen atom or sulfur atom,

Y is a bond, oxygen atom, –CO and –N (R7) -, where R7 is a hydrogen atom or alkyl group that optionally has substituents, –SOm–, where m is an integer from 0 to 2, -CON (R8), where R8 is hydrogen atom or alkyl group that optionally has substituents or -N (R9) CO-, where R9 is hydrogen atom or alkyl group that optionally has substituents and

Z is an alkylene bond or group that optionally has substituents, one of its optically active forms or one of its pharmaceutically acceptable salts. At this time, a, b, c, d and e are preferably all carbon atoms.

R1, R2 and R3 of the formula (1) are preferably the same or different and each is a hydrogen atom, group

5 alkyl having 2 to 4 carbon atoms or alkoxy group, more preferably, hydrogen atom, alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms, more preferably still, atom of hydrogen, alkyl group having 2 to 4 carbon atoms or methoxy group.

As R1, alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms is preferred. As R2 and R3, hydrogen atom is preferred.

As R4, R5 and R6 of the formula (1), they are preferably the same or different and each is hydrogen atom, alkyl group that optionally has substituents, alkoxy group that optionally has substituents, acyloxy group that optionally has substituents, atom of halogen, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group, haloalkyl group or haloalkyloxy group, more preferably, hydrogen atom, alkyl group which optionally has substituents, alkoxy group which

It optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group or haloalkyl group.

As A of the formula (1), aryl group is preferred which optionally has substituents or heteroaryl group which optionally has substituents, more preferably, phenyl group which optionally has substituents, group

Pyridyl which optionally has substituents, pyrazolyl group that optionally has substituents, thiazolyl group that optionally has substituents, oxazolyl group that optionally has substituents or thienyl group that optionally has substituents, more preferably still, phenyl group that optionally has substituents or heterocyclic group that contains nitrogen selected from the group consisting of the following formulations (Aa) - (Ac),

image 1

25

wherein R 10 is a hydrogen atom, an alkyl group that optionally has substituents, an alkenyl group that optionally has substituents, an alkynyl group that optionally has substituents, a cycloalkyl group, an alkoxy group that optionally has substituents, an acyloxy group that optionally has substituents, a halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group,

Amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl group or phenyl group optionally having substituents or a nitrogen-containing heterocyclic group selected from group consisting of (Aa ') - (Ae')

image 1

Wherein R10a, R11 and R12 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group which optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group which optionally has substituents, aryloxy group, arylalkyl group, halogen atom, hydroxyl group, nitro group,

40 cyano group, alkylthio group, amino group, alkylamino group, dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) lO–, where j, k, l and R13 are as defined above or R13O (CH2) jO (CH2) kO–, where j, k and R13 are as defined above, R10b is hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has

45 substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, haloalkyl group, R13O (CH2) jO (CH2) kO (CH2) l–, where j, k, l and R13 are as defined above or R13O (CH2) jO (CH2) k–, where j, k and R13 are as defined above.

As –W1 – Y – W2 of the formula (1), - (CH2) 2–, - (CH2) 3– or - (CH2) 2O– are preferred.

It is preferable that a, b, c, d and e of the formula (1) is preferably all carbon atoms, or that b (or d) is a nitrogen atom and the rest are carbon atoms. The case in which R1, R2 and R3 of the formula (1) are the same or different and each is a hydrogen atom,

5 prefers the alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms, a, b, c, d and e are each carbon atom obod is a nitrogen atom and the rest are carbon atoms , R4, R5 and R6 are the same or different and each is hydrogen atom, methoxy group, halogen atom or group

hydroxyl, Z is –CH2–,

A is a phenyl group that optionally has substituents or a nitrogen-containing heterocyclic group selected from the group consisting of the following formulas (Aa ') - (Ae')

image 1

wherein R10a, R11 and R12 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that

It optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylalkyl-xyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, alkylthio group, amino group, alkylamino group, dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) 10-, where j, k, l and R13 are as defined above or R13O (CH2) jO (CH2) kO– , where j, k and R13 are as defined above,

R10b

20 is a hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, haloalkyl group , haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) l–, where j, k, l and R13 are as defined above or R13O (CH2) jO (CH2) k–, where j, ky R13 are as it is

25 defined previously, X is an oxygen atom and –W1 – Y – W2 is - (CH2) 2– or - (CH2) 3–. As X of the formula (1), oxygen atom is preferred. As –W1 –Y – W2 - of the formula (1), - (CH2) 2– or - (CH2) 3 is preferred.

As Z of the formula (1), -CH2- is preferred. Preferred examples of the amide derivative (1) are the following: N - [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- [ (4-dimethylaminophenyl) methyl] –N– (4-ethylphenyl) indan – 1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) –1,2,3,4 – tetrahydronaphthalen– 1-carboxamide,

35 N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N - (4-Isopropylphenyl) chroman-4-carboxamide, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) –6-methoxyindan-1-carboxamide, N - [(1-ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) –1 , 2,3,4-tetrahydronaphthalen-1-carboxamide,

40 N - [(4-dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) –6-methoxychroman-4-carboxamide, N - [(1,3-dioxaindan-5-yl) methyl] –N– (4– isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -4-hydroxy-N- (4-isopropylphenyl) indan-1-carboxamide, N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide and N - [(1-ethylpyrazole-4– il) methyl] –4-hydroxy-N– (4-isopropylphenyl) indan-1-carboxamide, furthermore, N - [(1-ethylpyrazol-4-yl) methyl] –5-hydroxy-N– (6-isopropylpyridine –3 – il) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide, and,

in addition, N - [(2,6-dimethoxypyridin-3-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N - (4-Isopropylphenyl) –N - [(6-phenoxypyridin-3-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(6-dimethylaminopyridin-3-yl) methyl] –5 – hydroxy-N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-ethoxy-N– (4-isopropylphenyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(5-ethylthiophe-2-yl) methyl] -N- (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide , N - [(4-dimethylaminophenyl) methyl] -7-fluoro-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-bromophenyl) -N - [( 4-dimethylaminophenyl) methyl] –7-fluoro-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –8-fluoro-5-hydroxy-N– (4-isopropylphenyl ) –1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide, N - [(2,6-dimethoxypyridin-3-yl) methyl] –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4 – tetrahydronaphthalen– 1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N - (6-isopropylpyridin-3-yl) -N - [(6-methoxypyridinyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,4-dimethylthiazol-5-yl) methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-butylphenyl) –N - [(4-dimethylaminophenyl) methyl ] –5 – hydroxy – 1,2,3,4-tetrahydronaphthalen – 1-carboxamide, N - [(4-dimethylaminbphenyl) methyl] –7-methoxy-N– (4-methoxyphenyl) –1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide, N– (4-chlorophenyl) –N - [(4-dimethylaminophenyl) methyl] –7 – methoxy – 1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide, N - [(4– dimethylaminophen il) methyl] –7-methoxy-N– (4-methylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N– (4-ethoxyphenyl) - 7 – methoxy – N– (4 – bromophenyl) –N - [(4-dimethylaminophenyl) methyl] –7–

methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4-methylaminophenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1 -Carboxamide, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4-isopropylphenyl) ) –N - [(2-methylthiazol-4-yl) methyl] –1,2,3,4– hydronaphthalen-1-carboxamide, N– (4-bromophenyl) –N - [(dimethylaminophenyl) methyl] –5– hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N- (2-tolylmethyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,4-dichlorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy –N - [(4-nitrophenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) –7-methoxy-N - [(3-tolyl) methyl] –1 , 2,3,4 – tetrahydronaphthalen– 1-carboxamide, N– (4-isopropylphenyl) –7-methoxy-N - [(4-tolyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-fluorophenyl) methyl ] –N– (4-isopropylphenyl) –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-fluorophenyl) methyl] –N– (4-isopropylphenyl) –7-methoxy –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide, N - [(2,4-dimethylphenyl) methyl] –N– (4-isopropylphenyl) –7-methoxy 1,2,3,4-tetrahydronaphthalen – 1 –Carboxamide, N– (4-isopropylphenyl) –7-methoxy-N - [(2-methoxyphenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-chlorophenyl) methyl] –N– (4-isopropylphenyl) –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,4-difluorophenyl) methyl] –N– (4-isopropylphenyl) –7– methoxy] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,6-difluorophenyl) methyl] -N- (4-isopropylphenyl) –7-methoxy – 1,2,3,4– tetrahydronaphthalen – 1 – carboxamide, N - [(4 – ethoxyphene il) methyl) -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4-oxacroman –6 – yl) methyl] –1,2,3,4-tetrahydronaphthalene – 1-carboxamide, N - [(2,3-dimethoxyphenyl) methyl] –N– (4-isopropylphenyl) –7 – methoxy – 1,2 , 3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,4-dimethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N– (4-isopropylphenyl) –7-methoxy-N - [(2-trifluoromethylphenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N– (4-isopropylphenyl) –7-methoxy-N - [(4-oxacroman-6-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-bromophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide, N– (4-isopropylphenyl) –7-methoxy-N - [(2,3,4-trimethoxyphenyl) methyl] –1,2,3,4– tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4-iso propylphenyl) –N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(1-benzylpyrazol-4-yl) methyl ] –5 – hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) –N– {[1– (2-Pyridylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide,

N - ({1 - [(4-fluorophenyl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, N - ({1 - [(4-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen – 1–

carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen– 1 –Carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) –N - ({1 - [(4-methoxyphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4– tetrahydronaphthalen – 1–

carboxamide,

N - ({1 - [(4-bromophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, N - ({1 - [(3-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen – 1–

carboxamide,

N - ({1 - [(2-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4– tetrahydronaphthalen – 1–

carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(5-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4 –Tetrahydronaphthalen– 1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) –N - ({1 - [(5-methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) - 1,2,3,4–

tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(6-methylpyridine-2-yl) methyl] pyrazol-4-yl) methyl) –1,2,3,4 - tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridine-2-yl) methyl] pyrazol-4-yl) methyl) - 1,2,3,4–

tetrahydronaphthalen-1-carboxamide, 8-fluoro-5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1- (2-pyridylmethyl) pyrazol-4-yl] methyl} –1,2, 3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4–

tetrahydronaphthalen-1-carboxamide, N - ({1 - [(6-dimethylaminopyridin-2-yl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1 , 2,3,4– tetrahydronaphthalen-1-carboxamide,

N - ({1– [3– (dimethylaminophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4–

tetrahydronaphthalen-1-carboxamide, N - [(2-ethyl-4-trifluoromethylthiazol-5-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen –1– carboxamide,

5-benzyloxy-N– (4-isopropylphenyl) -N - [(1-isopropylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4– isopropylphenyl) –N - [(1-methylpyrazol-4-yl) methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-benzyloxy-N- (4-isopropylphenyl) –N - [(1– propylpyrazol-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (4-isopropylphenyl ) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4-isopropylphenyl) -N - {[1– (3-thienylmethyl) pyrazol-4-yl] methyl} –1, 2,3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (4-fluorobenzyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (4-methoxyphenyl) –1,2,3, 4-tetrahydronaphthalen-1-carboxamide, N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-methoxyphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (cyclohexylmethyl) pyrazol-4-yl] met il} -5-hydroxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1 - (2-piperidinoethyl) pyrazol-4-ylmethyl] –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide,

N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N– [(1-Heptylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- ( 6 – isopropylpyridin-3-yl) –N - {[1– (3-thienylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(2-methylthiazol-4-yl) methyl] pyrazol-4-yl) methyl) –1,2,3,4 –Tetrahydronaphthalen– 1 – carboxamide, N - [(1-butylpyrazol-4-yl) methyl] –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (3-methylbutyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalene – 1–

carboxamide, N - [(1-benzylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-methoxypyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy –N– (6-isopropylpyridin-3-yl) –N - ({1– [2– (2-pyridyl) ethyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide, N - [(1-dodecylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy –N– (6-isopropylpyridin-3-yl) –N - [(1-nonylpyrazol-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen – 1-carboxamide, N - {(1– (2 –Butoxyethyl) pyrazol – 4-yl] methyl} –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1– [2– (2-methoxyethoxy) ethyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen –1– carboxamide, 5-hydroxy-N– (4-isopropylphenyl) –N - [(6-morpholinopyridin-3-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy– N– (4-isopropylphenyl) –N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen – 1–

carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(6-morpholinopyridin-2-yl) methyl] pyrazole-4-yl} methyl) –1,2,3 , 4– tetrahydronaphthalen-1-carboxamide,

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5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(6-methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4 - tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N - [(1-isopropylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide,

N - [(4-dimethylaminophenyl) methyl) -N- (6-isopropylpyridin-3-yl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide,

5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (2-thienylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide,

N - ({1 - [(5-chlorothiophene-2-yl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4 –Tetrahydronaphthalen– 1 – carboxamide,

5-benzyloxy-N - ({1– [2– (2-butoxyethoxy) -ethyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen - 1-carboxamide,

N - ({1– [2– (2-Butoxyethoxy) ethyl] pyrazol-4-yl) methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen –1– carboxamide,

N - ({1– [2– (2-ethoxyethoxy) ethyl] pyrazol-4-yl} methyl) -N– (6-isopropylpyridin-3-yl) –5-hydroxy – 1,2,3,4-tetrahydronaphthalen –1– carboxamide.

The pharmaceutically acceptable salt of the compound of the formula (1) is preferably exemplified by means of a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, a salt with organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, and the like, a salt with an alkali metal (lithium, sodium, potassium and the like), a salt with alkaline earth metal (calcium, magnesium and the like), a salt with metal such as aluminum and the like, organic based salt such as piperidine, piperazine, morpholine , diethanolamine, ethylenediamine and the like.

The present invention comprises solvates (for example, hydrate) of the compound of the aforementioned formula (1)

or one of its salts.

The compound of the present invention also comprises any form of an optically pure enantiomer, a diastereomer and a mixture thereof.

Since the compound of the present invention can be produced by the following methods, the production method is not limited thereto. The methods exemplified herein can be used alone or in combination and a conventional method can also be combined. If necessary, each compound is protected or deprotected by a conventional method.

The compound (1a), wherein X of the formula (1) is an oxygen atom, can be produced by the following methods 1-3.

Method 1: production method 1 of the compound (1a)

image 1

where R1, R2, R3, R4, R5 and Z are as defined above.

For step 1, a known amidation method or peptide synthesis method and the like can be used. For example, the reaction is carried out in the presence of a condensing agent (for example, carbodiimide (N, N- dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and the like), diphenylphosphorylazide, carbonyldiimidazole, hexafluorophosphate of 1-benzotriazolyloxytris (dimethylamino) phosphonium (Bop reagent), 2-chloro-N-methylpyridinium-tributylamine (Mukaiyama method), N-cyclohexylcarbodiimide-N'-methylpolystyrene iodide system and the like, in an inert solvent or solvent preferably from -20 ° C to 80 ° C. In step 1, an acid neutralizing agent may be present [eg, organic base (for example, triethylamine, N-methylmorpholine, pyridine, dimethylaniline and the like), inorganic base ( for example, hydrogen-sodium carbonate, potassium carbonate, sodium hydroxide and the like)] and others In general, the reaction of step 1 is completed within 24 h.

The compound (la) in step 1 can also be produced by converting the compound (3) into a different reactive derivative. When the reactive derivative of the compound (3) is acid halide (for example, acid chloride, bromide

5 of acid and the like) or acid anhydride (for example, symmetric acid anhydride, lower alkyl mixed acid anhydride, carbonate, alkyl phosphate mixed acid anhydride and the like), the reaction with compound (2) is carried out generally carried out in an inert solvent or without solvent from –20 ° C to 80 ° C.

On the other hand, when the so-called active ester is used (4-nitrophenyl ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, pentafluorophenyl ester, succinimide ester, benzotriazole ester, 4-dimethylsulfonium phenyl ester

10 and the like) as the reactive derivative of the compound (3), the reaction is generally carried out in an inert solvent or without solvent at a temperature of -20 ° C at the reflux temperature of the solvent.

The inert solvent for use in the aforementioned amidation is exemplified by hydrocarbons such as hexane, benzene, toluene, xylene and the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and the like, ethers such as tetrahydrofuran (hereinafter, abbreviated as THF),

Dioxane and the like, esters such as ethyl acetate and the like, ketones such as acetone, methyl ethyl ketone and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, amides such as N, N-dimethylformamide (hereinafter abbreviated as DMF), dimethylacetamide (hereinafter more abbreviated as DMA) and the like, acetonitrile, dimethylsulfoxide, water and a mixed solvent and the like.

Method 2: production method 2 of the compound (1a):

image2

wherein R1, R2, R3, R4, R5, R6, a, b, c, d, e, A, W1, W2, Y and Z are as defined above and L is a leaving group such as halogen atom , methanesulfonyloxy or para-toluenesulfonyloxy and the like.

The compound (1a) can be produced by reacting the compound (4) with the compound (5).

In step 2, the reaction is carried out in a solvent that does not inhibit the reaction, in the presence of an agent.

Acid neutralizer [for example, organic base (for example, triethylamine, N-methylmorpholine, pyridine, dimethylaniline and the like), inorganic base (for example, sodium hydride, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide and the like)) and the like at –20 ° C at the reflux temperature of the solvent. The solvent for use in step 2 is exemplified by hydrocarbons such as hexane, benzene, toluene and the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and the like, ethers such

Such as THF, dioxane and the like, esters such as acetic acid ester and the like, ketones such as acetone, methyl ethyl ketone and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, amides such as DMF, DMA and the like, acetonitrile, DMSO, water or a mixed solvent and the like.

Method 3: production method 3 of the compound (1a)

image 1

Where R1, R2, R3, R4, R5, R6, a, b, c, d, e, A, W1, W2, Y and Z are as defined above and Hal is iodine atom, bromine atom or chlorine atom.

By reacting the compound (7) with the compound (6), the compound (1a) can be produced.

Step 3 is carried out in a solvent that does not inhibit the reaction in the presence of an acid neutralizing agent such as an organic base (for example, triethylamine, N-methylmorpholine, pyridine, dimethylaniline and the like)

or an inorganic base (for example, sodium hydride, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide and the like) and, if necessary, a catalyst such as copper, copper iodide and the like at a temperature of 20 ° C at the reflux temperature of the solvent. The solvent for use in step 3 is exemplified by hydrocarbons such as hexane, benzene, toluene and the like, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and the like, ethers such as THF, dioxane and the like, esters such as ester of acetic acid and the like, ketones such as acetone, methyl ethyl ketone and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, amides such as DMF, DMA and the like, nitrobenzene,

10 acetonitrile, DMSO, water or a mixed solvent and the like.

Method 4: production method of the compound (1b), wherein X of the formula (1) is sulfur atom

image 1

where R1, R2, R3, R4, R5, R6, a, b, c, d, e, A, W1, W2, Y and Z are as defined above.

The compound (1b) can be produced from the compound (1a) by means of the aforementioned routes (step 4).

Step 4 is carried out in a solvent that does not inhibit the reaction in the presence of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphene-2,4-disulfide (reagent Lawesson), diphosphorus pentasulfide and the like.

The solvent to be used in step 4 is exemplified by benzene, toluene, xylene, THF, pyridine and the like. The reaction is carried out at a general temperature of 0 ° C at the reflux temperature of the solvent. As the reaction time varies according to the reaction temperature, it is generally from 1 h - 24 h.

Method 5: production method of compound (9), wherein R4 of the formula (1) is hydroxyl group and R5 and R6 are hydrogen atoms

image 1

wherein R1, R2, R3, a, b, c, d, e, A, W1, W2, X, Y and Z are as defined above and M is a hydroxyl protecting group. The compound (9) can be produced by eliminating the group M of the compound (8) 8-stage 5).

The protecting group M is exemplified by methyl, benzyl, substituted benzyl, benzyloxycarbonyl and the like. The protecting group can be removed by means of a conventional method such as hydrolysis, treatment with acid, hydrogenolysis with the metal catalyst (palladium on carbon, Raney nickel and the like), depending on the type of protective group and the like.

30 Method of synthesis of the starting material compound

The compound (2) to be the starting material of method 1 can be produced by means of the following Methods 6-8. Method 6: compound production method (2)

image 1

wherein T is an amino protecting group such as acetyl, t-butoxycarbonyl and the like and R1, R2, R3, a, b, c, d, e, A, Z and L are as defined above.

The compound (10) and the compound (5) are reacted in an appropriate solvent in the presence of a base 5 to give the compound (11), and then a protective group is removed to give the compound (2) (steps 6 and 7).

The solvent to be used in step 6 is exemplified by methanol, ethanol, propanol, isopropyl alcohol, methylene chloride, chloroform, THF, dioxane, benzene, toluene, xylene, DMF, DMSO and the like. The base to be used is exemplified by means of sodium hydride, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and the like. As the

The reaction temperature varies according to the solvent, it is generally 0 ° C - 140 ° C and as the reaction time varies according to the reaction temperature, it is generally from 1 h to 24 h.

This reaction can also be carried out without the protective group T (when T is a hydrogen atom), the compound (2) can be produced.

In step 7, the protecting group can be removed by means of a conventional method such as hydrolysis, acid treatment and the like according to a conventional method, depending on the type of protecting group.

Method 7: production method of compound (15) wherein, in compound (2), -Z-A is -CH (R11) -U-A (U is alkylene which optionally has substituents, R11 is hydrogen atom, alkyl which optionally has substituents, aryl or heteroaryl and A is as defined above:

image 1

20 wherein R1, R2, R3, a, b, c, d, e, A, R11 and U are as defined above.

The compound (12) and the compound (13) are subjected to condensation with dehydration without solvent or in an appropriate solvent to give the compound (14), which compound is then reduced in an appropriate solvent, and the compound (15) can be produced ( stages 8 and 9).

The condensation reaction with dehydration of the compound (12) and the compound (13) in step 8 can be

25 Perform in the presence of a dehydration agent or by removing all water from the reaction system with a Dean-Stark trap.

As the dehydration agent to be used for this reaction, a conventional dehydration agent can be used. Examples of the dehydration agent include anhydrous magnesium sulfate, molecular sieves and the like. The solvent to be used for the reaction can be, for example, methylene chloride, chloroform, benzene,

30 toluene, xylene and the like. As the reaction temperature varies according to the solvent, it is in general from 0 ° C to 150 ° C and as the reaction time varies according to the reaction temperature, it is generally from 1 h - 24 h.

The reducing agent to be used for step 9 is exemplified by means of sodium borhydride, sodium triacetoxyborohydride, sodium cyanoborhydride, formic acid, sodium formate and the like. When sodium triacetoxyborohydride or sodium cyanoborhydride is used as the reducing agent, water removal can be omitted using the

35 dehydration agent or Dean – Stark trap in stage 8.

The solvent to be used for the reaction includes, for example, water, methanol, ethanol, propanol, THF, dioxane, 1,2-dichloroethane, acetic acid and the like and a mixed solvent can be used. As the reaction temperature varies according to the solvent, it is in general from 0 ° C to 80 ° C and as the reaction time varies according to the reaction temperature, it is generally from 1 h to 24 h.

Method 8: method of production of compound (18), where, in compound (2), –Z – A is –CH2 – U – A, where A and U are as defined above

image 1

where R1, R2, R3, a, b, c, d, e, A and U are as defined above.

The compound (12) or one of its salts and the compound (16) or one of its reactive derivatives are reacted without

10 solvent or in a suitable solvent to give the compound (17), whose compound is then reacted with a reducing agent in an appropriate solvent, the compound (18) being able to be produced (steps 10 and 11).

The reaction of the compound (12) or one of its salts with the compound (16) in step 10 can be carried out in the same manner as in step 1.

The reducing agent to be used for the reduction in step 11 is exemplified by means of lithium hydride and

15 aluminum, borane and the like. The solvent to be used for the reduction is, for example, THF, diethyl ether, hexane and the like; or a mixed solvent of them. As the reaction temperature varies according to the solvent, it is generally from 0 ° C to 65 ° C and as the reaction time varies according to the reaction temperature, it is generally from 1 h to 24 h.

The compound (3) to be the starting material can be produced by means of the following methods 9-10.

Method 9: production method 1 of the compound (3)

image 1

The compound (3) to be used in Method 1 can be produced from the compound (19) wherein R4, R5, R6, W1, W2 and Y are as defined above according to the method described in a reference ( Synthetic Communications, 12 (10), 763-770, 1982) (step 12).

Method 10: production method 2 of compound (3) wherein R4, R5, R6, W1, W2, Y and L are as defined above.

image 1

The compound (3) can be produced from the compound (19) by means of steps 13-16.

The reducing agent for the reduction in step 13 is, for example, lithium aluminum hydride,

5 sodium, lithium borhydride, diborane and the like. The solvent to be used in step 13 is, for example, water, methanol, ethanol, propanol, ether, THF, dioxane, acetic acid and the like or one of its mixed solvents. As the reaction temperature varies according to the solvent, it is in general from 0 ° C to 80 ° C and as the reaction time varies according to the reaction temperature, it is generally from 1 h to 24 h.

When L of the compound (21) in step 14 is chlorine atom, the reaction is generally carried out in a

10 inert solvent or without solvent in the presence of thionyl chloride, methanesulfonyl chloride, para-toluenesulfonyl chloride or triphenylphosphine, if necessary, in co-presence of an organic base such as triethylamine and the like, from -20 ° C to 80 ° C . The solvent to be used is then, for example, methylene chloride, chloroform, carbon tetrachloride, ether, DMF and the like; or a mixed solvent thereof, and the like.

When L of the compound (21) is methanesulfonyloxy or paratoluenesulfonyloxy, the reaction is generally carried out in

15 an inert solvent or without solvent in the presence of methanesulfonyl chloride or para-toluenesulfonyl chloride in co-presence of an organic base such as triethylamine and the like from -20 ° C to 80 ° C. The solvent for use herein is, for example, methylene chloride, chloroform, ether, DMF or a mixed solvent thereof, and the like.

Step 15 is carried out in a solvent that does not inhibit the reaction in the presence of sodium cyanide, potassium cyanide, tetraethylammonium cyanide and the like at a temperature of -20 ° C at the reflux temperature of the

20 solvent. The solvent to be used in the step includes water, methanol, ethanol, propanol, ether, DMF, DMSO, acetone, acetonitrile and a mixed solvent and the like.

Step 16 is carried out in a solvent that does not inhibit the reaction in the presence of an inorganic base (for example, sodium hydroxide, potassium hydroxide, barium hydroxide, and the like) or an acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like) at a temperature of - 20 ° C at reflux temperature

25 of the solvent. The solvent to be used in step 16 is, for example, water, methanol, ethanol, propanol, ethylene glycol, ethylene glycol monomethyl ether, DME, acetic acid, formic acid; or a mixed solvent thereof, and the like.

Method 11: production method of compound (4), which is a starting material of Method 2

image 1

wherein R1, R2, R3, R4, R5 are as defined above. The compound (4) can be produced from the compound (12) and the compound (3).

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That is, the compound (4) can be produced by reacting the compound (12) or a salt thereof with the compound (3) or one of its reactive derivatives without solvent or in an appropriate solvent (step 17).

The reaction of the compound (3) with the compound (12) or one of its salts in step 17 can be carried out in the same manner as in step 1.

Method 12: production method of compound (7), which is a starting material of method 3

image 1

where R4, R5, R6, A, W1, WZ, Y and Z are as defined above.

The compound (7) can be produced by reacting the compound (3) with the compound (23) or one of its salts (step 18).

That is, by reacting the compound (23) or one of its salts and the compound (3) or one of its reactive derivatives without solvent or in an appropriate solvent, the compound (7) can be produced.

The reaction of the compound (3) and the compound (23) or one of its salts in step 18 can be carried out in the same manner as in step 1.

The product obtained in each of the above-mentioned steps can be isolated and purified by a conventional method.

A part of the compounds of the formula (1) in the present invention can be converted into a salt as necessary by treatment in a suitable solvent (methanol, and ethanol and the like), with an acid (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, methane sulfuric acid, ethanesulfuric acid, fumaric acid, maleic acid, benzoic acid, citric acid, malic acid, mandelic acid, paratoluenesulfonic acid, acetic acid, succinic acid, malonic acid, acid lactic acid, salicylic acid, gallic acid, picric acid, carbonic acid, ascorbic acid, trifluoroacetic acid, tartaric acid and the like) and alkali metal (lithium, sodium, potassium and the like), alkaline earth metal (calcium, magnesium and the like), metal such as aluminum and the like, or an organic base (piperidine, piperazine, morpholine, diethanolamine, ethylenediamine, and the like).

When the crystal of the compound obtained from the present invention is not a solvate and the like, it is possible to convert the compound of the present invention into a solvate for which the compound is treated with water, with a solvent containing water or another solvent.

The compound of the formula (1) of the present invention, one of its pharmaceutically acceptable salts and one of its solvates show an antagonistic action of the C5a receptor and are useful as a preventive or therapeutic drug for diseases in which it is involved in C5a, for example, diseases or syndromes due to inflammation caused by C5a (for example, autoimmune diseases such as rheumatism and systemic lupus erythematosus and the like; sepsis; respiratory distress syndrome in adults; chronic obstructive pulmonary disease, allergic diseases such as asthma and the like ; atherosclerosis; heart infarction, cerebral infarction; psoriasis; Alzheimer's disease; severe organic injury (e.g. pneumonia, nephritis, hepatitis and pancreatitis and the like) due to leukocyte activation caused by ischemic reperfusion, trauma, burns, surgical invasion and the like.They are also useful as a preventive drug or therap utico of infectious diseases caused by bacteria or viruses that invade C5a receptor.

When the compound of the present invention of the formula (1), its pharmaceutically acceptable salts and its solvates are used for the prevention or treatment mentioned above, it is generally administered systematically or topically and orally or parenterally. The dose for patients varies depending on age, body weight, sex, general health conditions, effect of treatment, diet, time of administration, method of administration, speed of elimination, combination of drugs, the condition of the disease under treatment. and the like It is generally desirable to use a range of 0.1 mg to 500 mg per dose for an adult by oral administration one to several times per day, or in the range of 0.01 mg to 200 mg for an adult for parenteral administration ( preferably intravenous administration) one to several times per day.

Since the dose may vary depending on various factors such as those mentioned above, although a dose below the above-mentioned range may be sufficient, a dose outside the mentioned range may be necessary.

The compound of the formula (1) of the present invention, one of its pharmaceutically acceptable salts and one of its solvates can be used orally or parenterally, for example by inhalation, rectal administration, topical administration and the like in the form of a pharmaceutical composition or preparation. (for example, powder, granule, tablet, pill, capsule, syrup, elixir, suspension, solution and the like), wherein at least one compound of the present invention can be used alone or used in the form of a joint mixture with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrector, emulsifier, diluent and / or dissolution aids, and the like).

It is possible to prepare a pharmaceutical composition according to a general method. In the present specification, parenteral expression designates subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip, and the like. An injection composition, such as a sterile injection suspension and an oil suspension, can be prepared by a suitable dispersing agent, wetting agent, suspending agent, according to a method known in the art.

As an example of a solid composition for oral administration, a tablet, pill, capsule, powder, granule and the like are indicated. In the above-mentioned solid composition, it is possible to mix one or more active compounds with at least one additive such as sucrose, lactose, mannitol, maltitol, glucose, corn starch, talc, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate magnesium, dextran, starches, polyvinylpyrrolidone, magnesium aluminosilicate, dextran, starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, acacia, gelatins, collagens, casein, albumin, polymers or synthetic or semi-synthetic glycerides.

In addition, the aforementioned composition may comprise other additives such as lubricating agents (for example magnesium stearate, etc.), preservatives (for example, parabens, sorbines, etc.), antioxidant agents (for example ascorbic acid, α– tocopherol, cysteine, etc.), disintegrating agents (for example, calcium croscarmellose, etc.), stabilizing agents (for example lactose, etc.), dissolving agents (for example glutamic acid, aspartic acid, etc.) , binders, thickeners, sweeteners, flavorings, perfumes and the like.

When necessary, the tablet and the pill may be coated with a gastric or enteric coating film such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and the like, or it is possible to coat them with two or more layers. In addition, they can include a capsule of absorbable material such as gelatin.

The liquid composition for oral administration includes a pharmaceutically acceptable solution, suspension, syrup, elixir, and the like, and may contain a commonly used inactive diluent (purified water, ethanol). This composition may contain, in addition to the inactive diluent, auxiliary agents such as wetting agent, suspending agent, sweetener, flavoring, perfume and preservative. Other compositions for oral administration are for example a spraying agent containing one or more active substances and formulated by a method known per se.

The injection composition for parenteral administration may include a sterile, aqueous or non-aqueous solution, suspension and emulsion. Examples of aqueous solution and suspension include distilled water for injections and physiological saline solutions. Examples of the water insoluble solution and suspension include propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 and the like. The composition mentioned above may also contain auxiliary agents such as preservatives, humectants, emulsifiers, dispersants, stabilizers (for example, lactose and the like) and dissolution aids (for example, amino acids such as arginine, glutamic acid, aspartic acid, and the like) . They can be sterilized for example by filtration through a filter that retains bacteria, by the addition of a microbicide or irradiation.

The composition for injections can be used by producing a solid sterile composition, and the lyophilized product being dissolved for example in sterile water or in a sterile solvent for injection before use.

Other compositions for parenteral administration include external solutions, ointments, liniments, suppositories and the like, which contain one or more active substances and formulated by a conventional method.

The suppository for rectal administration can be produced by mixing the drug with a suitable non-irritating vehicle, which is a solid substance at room temperature but liquid at the temperature of the intestine and melts in the rectum so as to release the drug, such as butter Cocoa and polyethylene glycols.

The amide derivative (1), an optically active form thereof or a pharmaceutically acceptable salt thereof of the present invention are useful as an active ingredient of a C5a receptor antagonist, whose C5a receptor antagonist can be used for prevention. or the treatment of infectious diseases caused by bacteria and viruses that invade through a C5a receptor, and can be used in combination with one or more preventive or therapeutic drugs for autoimmune diseases, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease , allergic disease, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease, or severe organic injury due to leukocyte activation caused by ischemic reperfusion, external lesions, burns or surgical invasion.

It is envisioned that the compound of the formula (1) of the present invention, the optically active form thereof or a pharmaceutically acceptable salt thereof will show a treatment with a superior effect by the combined use with an agent for disease prevention or treatment. autoimmune such as rheumatism, systemic lupus erythematosus and the like, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease, or organic lesions severe (for example, pneumonia, nephritis, hepatitis, pancreatitis and the like) due to the activation of leukocytes caused by ischemic reperfusion, trauma, burns, surgical invasion and the like. As used herein, the term "combined use" refers to a combined composition of the compound of the present invention or a pharmaceutically acceptable salt thereof with an agent for the prevention or treatment of autoimmune diseases such as: rheumatism. , systemic lupus erythematosus and the like; sepsis; respiratory distress syndrome in adults; chronic obstructive pulmonary disease; allergic diseases such as asthma and the like; atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease, or serious organic lesions (e.g. pneumonia, nephritis, hepatitis, pancreatitis and the like) due to the activation of leukocytes caused by ischemic reperfusion, trauma, burns, surgical invasion and the like, and its use as an enhancer for the action of an agent for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like; sepsis, respiratory distress syndrome in adults; chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, heart attack, cerebral infarction, psoriasis, basal disease or serious organic lesions (for example, pneumonia, nephritis, hepatitis pancreatitis and the like) due to leukocyte activation caused by Ischemic reperfusion, trauma, burn, surgical invasion and the like, which includes combined use and simultaneous use, in which two or more active ingredient compounds are used simultaneously or used in a staggered manner with or without mixing. The pharmaceutical drug of the present invention characterized by the combined use of the compound represented by the aforementioned formula (1), its optically active form or a pharmaceutically acceptable salt thereof and an agent for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like; sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease or serious organic lesions (e.g. pneumonia, nephritis, hepatitis, pancreatitis and the like) due to the activation of leukocytes caused by ischemic reperfusion, trauma, burn, surgical invasion and the like, it is not particularly limited in terms of how they are used as long as the compound represented by the formula (1), its optically active form or a pharmaceutically acceptable salt thereof and an agent for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like; sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease; allergic diseases such as asthma and the like; atherosclerosis; heart attack, cerebral infarction; psoriasis, Alzheimer's disease or serious organic lesions (for example, pneumonia, hepatitis pancreatitis nephritis and the like due to the activation of leukocytes caused by reperfusion of ischemia, trauma, burns, surgical invasion and the like, are combined together. For example, (A), the compound represented by the formula (1), its optically active form or its pharmaceutically acceptable salt, and (B) an agent for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like; sepsis , adult respiratory distress syndrome; chronic obstructive pulmonary disease; allergic diseases such as asthma and the like; atherosclerosis, heart attack, cerebral infarction; psoriasis, Alzheimer's disease or severe organic lesions (e.g. pneumonia pneumonia, nephritis, hepatitis, pancreatitis and the like) due to leukocyte activation caused by ischemic reperfusion , trauma, burn, surgical invasion and the like, can be formulated in the form of preparations to be administered in general terms or a composition in which they may have been combined beforehand. The combined pharmaceutical drug of the present invention can be for example a simple agent obtained by mixing the compound represented by the formula (1), its optically active form or a pharmaceutically acceptable salt thereof and an agent for the prevention or treatment of autoimmune diseases such such as rheumatism, systemic lupus erythematosus and the like; sepsis, adult respiratory distress syndrome; chronic obstructive pulmonary disease, allergic diseases such as asthma and the like; atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease or severe organic injury (e.g. pneumonia, nephritis, hepatitis, pancreatitis and the like) due to leukocyte activation caused by ischemic reperfusion, trauma, surgical invasion burn and the like of according to known production methods for pharmaceutical preparations for which they use, when desired a pharmaceutically acceptable diluent, excipient or similar, or preparation thereof obtained using, when desired, a pharmaceutically acceptable diluent or excipient or similar, or a preparation combined in a container that includes its respective preparation (set, kit, package). For example, the combined pharmaceutical drug of the present invention can be used as a combination preparation package with the same preparations or different preparations of a preparation containing the compound represented by the formula (1), or its optically acceptable active form or a of its pharmaceutically acceptable salts, and an agent for the prevention or treatment of autoimmune diseases such as rheumatism, lupus erythematosus and the like; sepsis; respiratory distress syndrome in adults; chronic obstructive pulmonary disease; allergic diseases such as asthma and the like; atherosclerosis; heart attack; cerebral stroke; psoriasis; Alzheimer's disease, or serious organic lesions (e.g. pneumonia, nephritis, hepatitis, pancreatitis and the like) due to the activation of leukocytes caused by ischemic reperfusion, trauma, burns, surgical invasion and the like, or as a composition containing the compound represented by the formula (1) or its optically active form or one of its pharmaceutically acceptable salts and an agent for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like; sepsis; adult respiratory distress syndrome, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like; atherosclerosis; heart attack, cerebral infarction; psoriasis, Alzheimer's disease, serious organic lesions (for example, pneumonia, nephritis, hepatitis pancreatitis and the like due to the activation of leukocytes caused by ischemic reperfusion, trauma, surgical invasion burns and the like.

When the compound of the present invention, its optically active form or a pharmaceutically acceptable salt thereof is used as a combination composition, the ratio of the composition is optional, and the amount of the compound of the present invention or one of its salts Pharmaceutically acceptable for mixing can be determined based on the type of the various pharmaceutical agents to be mixed for combination, and factors such as titration and the like. When used as a combined drug, the dose of the composition of the present invention or of a pharmaceutically acceptable salt thereof and the pharmaceutical agent to be combined with them can be determined as appropriate from the generally used range. It is preferable to administer in a smaller dose than the dose for individual use of each pharmaceutical agent, in order to obtain a synergistic effect.

Examples of agent for the prevention or treatment of autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like; atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease, or serious organic lesions (e.g. pneumonia, nephritis, hepatitis, pancreatitis and the like) due to the activation of leukocytes caused by ischemic reperfusion, trauma, burns, surgical invasion and the like include antirheumatic agents (composed of gold, penicillamine, bucrylamine, lobenzarite, actarite, salazosulfapyridine, etc.); immunosuppressive agents (azathioprine, cyclophosphamide, methotrexate, brequinar sodium, deoxyspergualine, mozoribine, 2-morpholinoethylmicophenolate, cyclosporine, rapamycin, tacrolimus hydrate, leflunide, OKT-3, anti-TNF-α antibody, interleukin-6 antibody FTY720 (EP627406 – B1), etc.); steroid drugs (prednizolone, methylprednizolone, dexamethasone, hydrocortizona, etc.) or non-steroidal anti-inflammatory agents (aspirin, indomethacin, indomethacin farnesylate, diclofenac sodium, alclofenac, sodium ampheenac, ibuprofen, ketoprofeno, naproprenophene, zaphenophene , flufenamic acid, tolfenamic acid, phenylbutazone, ketophenylbutazone, piroxicam, tenoxicam, ampiroxicam, etc.), bactericides (gentamicin, tobramycin, cefotaxime, ceftazidime, vancomycin, erythromycin, imipenem, metronidazole, etc.); Enhancers of cerebral circulation metabolism (meclofenoxate, idebenone, nicergoline, propentophilin, cytochrome C, citicoline, ifenprodil, benzyllane, cinepazide, ozagrel, nozophenone, ibidilast, pentoxifylline, propentophilin, vincopocetin, movinopyrinine, movinopyrinine, movinopyrinine, movinopyrinine, movinopyrazine, ciproxinine , flunarizine, nilvadipine, etc.), inhibitors of antiplatelet aggregation (ticlopidine, aspirin, beraprost, dipyridamole, cilostazol, ozagrel, sarpogrelate, etc.), anticoagulants (heparin, warfarin, etc.), thrombolytic agents (urokinase, plasminogen activator tissue, etc.), antiallergic agents (chromoglylic acid, pranlukast, ozagrel, seratrodast, tranilast, amlexanox, repirinast, tazanolast, pemirolast, ibudilast, supratast, cetotifen, azelastin, oxatomide, terfenadine, mequitazin, asynastinol, zainzastinol, epinastinol, astrozine, zygastinol, zygastinol, zygastinol, zygastinase etc.), proteolytic enzyme inhibitors (gabexate, nafamosutat, aprotinin, etc.), acet inhibitors ilcolinesterase (aricept, etc.), and the like.

Examples

The present invention is specifically explained below with reference to the Preparation Examples, Examples, Formulation Examples and Test Examples, which are not constructed as limiting.

1 H-NMR was measured at 300 MHz. The chemical shift of 1 H NMR was measured using tetramethylsilane (TMS) as an internal standard and expressed as a relative delta value (δ) in parts per million (ppm). For the coupling constant, an obvious multiplicity is shown using s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m. (multiplet), dd (double doublet), brs (broad singlet) and the like in hertz (Hz). Thin layer chromatography was manufactured by Merck and column chromatography was performed using silica gel manufactured by Fuji silysia chemical;

Preparation Example 1

To a solution of 4-dimethylaminobenzaldehyde (11 g) in toluene (200 mL) 4-isopropylaniline (10 g) and 4A molecular sieves (20 g) were added under ice cooling and the mixture was stirred at room temperature for one day. Molecular sieves 4A were filtered from the reaction mixture and the filtrate obtained was concentrated under reduced pressure. The residue was dissolved in methanol (2.00 mL) and sodium borhydride (2.3 g) was added under ice cooling. The mixture was stirred at room temperature for 5 h. After distilling the methanol, water was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give (4-dimethylaminophenylmethyl) (4-isopropylphenyl) amine (13.6 g).

Melting point: 71–73 ° C

Preparation Example 2

5 By reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10.0 g) and 4-methoxyaniline (8.25 g) as starting material, (4– dimethylaminophenylmethyl) (4-methoxyphenyl) amine (5 g).

Melting point: 92–94 ° C

Preparation Example 3

To a solution of 1-ethylpyrazol-4-carboxylic acid (2.34 g) in 1,2-dichloroethane (50 mL), thionyl chloride (1.83 mL) and several drops of DMF were added and the mixture was stirred at 70 ° C for 1.5 h. The reaction mixture was concentrated under reduced pressure and methylene chloride (20 mL) was added to the residue. To this solution was added a solution of 4-isopropylaniline (2.29 mL) in methylene chloride (20 mL) under ice cooling. The temperature of the mixture was raised to room temperature and stirred at the same temperature for 1 h. The mixture of

The reaction was added to saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium anhydrous sulfate. The solvent was evaporated and ether and hexane were added to the residue. The precipitated solid was collected by filtration to give N- (4-isopropylphenyl) -lethylpyrazole-4-carboxamide (3.76 g) (melting point: 141.0 ° C). To this compound (3.75 g) borane-THF complex / 1 mol / L-THF solution (BH3 • THF complex / 1 M THF solution) (29 mL) was added and the mixture was heated at reflux for

20 4 h. After cooling the reaction mixture, 1 mol / L hydrochloric acid (60 mL) was added and the mixture was stirred at room temperature for one day. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (1.95 g).

25 1H – NMR (CDCl3) δ: 1.21 (6H, d, J = 6.9Hz), 1.47 (3H, t, J = 7.3Hz), 2.81 (1H, sept, 6.9Hz ), 3.57-3.78 (1H, brs), 4.14 (2H, q, J = 7.3Hz), 4.15 (2H, s), 6.62 (2H, d, J = 8 , 4Hz), 7.06 (2H, d, J = 8.4Hz), 7.36 (1H, s), 7.47 (1H, s).

Preparation Example 4

6-Chloronicotinic acid (3.15 g), 4-isopropylaniline (2.73 mL) and triethylamine (5.6 mL) were dissolved in DMF (150 mL). 1 – Hydroxybenzotriazole monohydrate (now abbreviated as HOBt • H2O) (3.22 g) and 1-ethyl hydrochloride–

30 3– (3-Dimethylaminopropyl) carbodiimide (hereafter more abbreviated as WSCI · HCl) (4.03 g) was added under ice cooling. The mixture was stirred at room temperature for one day and the reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and ether was added to the residue. The precipitated solid was collected by filtration to give N- (4-isopropylphenyl) -6-chloropyridin-3-carboxamide (4.72 g).

35 1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 2.91 (1H, sept, 6.9Hz), 7.24 (2H, d, J = 8.4Hz ), 7.45 (2H, d, J = 8.4Hz), 7.52 (2H, d, J = 8.4Hz), 7.72–7.87 (1H, m), 8.15 (1H , dd, J = 2.4, 8.4Hz), 8.84 (1H, d, J = 2.4Hz).

N– (4-Isopropylphenyl) -6-chloropyridin-3-carboxamide (1.00 g) was dissolved in THF (10 mL) and sodium methoxide (0.21 g) was added. The mixture was stirred at 50 ° C for one day. After cooling, the reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.

40 anhydrous The solvent was evaporated and the residue was purified by silica gel column chromatography to give N- (4-isopropylphenyl) -6-methoxypyridin-3-carboxamide (0.76 g).

A complex of BH3-THF / 1M solution of THF (6.3 mL) was added to N- (4-isopropylphenyl) -6-methoxypyridin-3-carboxamide (0.76 g) and the mixture was heated at reflux for 4 h. After cooling the reaction mixture, 1 mol / L hydrochloric acid (15 mL) was added and the mixture was stirred at room temperature for one day. Mix

The reaction was poured into saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give (4-isopropylphenyl) [(6-methoxypyridin-3-yl) methyl] amine (0.62 g).

1H-NMR (CDCl3) δ: 1.20 (6H, d, J = 6.9Hz), 2.80 (1H, sept, 6.9Hz), 3.73-3.87 (1H, m), 3 , 93 (3H, s), 4.22 (2H, s),

50 6.59 (2H, d, J = 8.4Hz), 6.72 (1H, d, J = 8.4Hz), 7.04 (2H, d, J = 8.4Hz), 7.59 ( 1H, dd, J = 2.4, 8.4Hz), 8.14 (1H, d, J = 2.4Hz).

Preparation Example 5

To a solution of 7-methoxytetralone (22.3 g) in nitromethane (5 mL) was added zinc iodide (0.65 g). While stirring the mixture, trimethylsilyl cyanide (50 mL) was added under ice cooling. The mixture was stirred at room temperature for 1 h and the reaction mixture was divided into water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in a mixed solvent of acetic acid (200 mL) and concentrated hydrochloric acid (200 mL). To this was added tin chloride (106 g) and the mixture was heated at reflux for one day. After cooling, the reaction mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and ether was added to the residue. The precipitated solid was collected by filtration to give 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (8.1 g). Melting point: 126-127 ° C.

Preparation Example 6

By reaction and treatment in the same manner as in Preparation Example 5 using 5-hydroxy-1-tetralone (20 g) as a starting material, 5-hydroxy-1,2,3,4 acid was obtained. –Tetrahydronaphthalen – 1– carboxylic (18.5 g). This compound (18.5 g) was dissolved in a mixed solvent of DMF (105 mL) and toluene (42 mL). To this, benzyl bromide (25.8 mL) and potassium carbonate (54 g) were added and the mixture was stirred at 50-60 ° C for 8 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and methanol (100 mL), 1,4-dioxane (100 mL) and 1 mol / L of aqueous sodium hydroxide solution (116 mL) were added to the residue. The mixture was stirred at 50 ° C for 5 h. The reaction mixture was divided into water and ethyl acetate and the aqueous layer was acidified with concentrated hydrochloric acid. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (20.4 g). Melting point: 145-146 ° C.

Preparation Example 7

By means of the reaction and the treatment in the same manner as in Preparation Example 5 using 4-chromanone (5.1 g) as a starting material, chroman-4-carboxylic acid (4.1 g) was obtained. Melting point: 94.3 ° C

Preparation Example 8

By reaction and treatment in the same manner as in Preparation Example 5 using 6-methoxy-4-chromanone (6.1 g) as a starting material, 6-methoxychroman-4 acid was obtained. carboxylic (1.2 g). Melting point: 97.4 ° C.

Preparation Example 9

By reaction and treatment in the same manner as in Preparation Example 5 using 6-methoxy-1-indanone (5.6 g) as a starting material, 6-methoxyindan-1-carboxylic acid (2 , 6 g). Melting point: 101.1 ° C.

Preparation Example 10

By means of the reaction and treatment in the same manner as in Preparation Example 6 using 4-hydroxy-1-indanone (5 g) as a starting material, 4-benzyloxyindan-1-carboxylic acid ( 1.4 g) Melting point: 133.4 ° C.

Preparation Example 11

To a solution of 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (2 g) in methylene chloride (10 mL), thionyl chloride (1 mL) was added and the mixture was heated at reflux with stirring for 3 h. The reaction mixture was concentrated under reduced pressure and THF (5 mL) was added to the residue. This solution was added to a solution of 4-isopropylaniline (1.53 g) and triethylamine (4.6 mL) in THF (10 mL) under ice cooling. The temperature was raised to room temperature and the mixture was stirred at the same temperature for 1 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and hexane was added to the residue. The precipitated solid was collected by filtration to give N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.78 g). Melting point: 163.1 ° C.

Preparation Example 12

7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.62 g), 4-isopropylaniline (0.41 g) and triethylamine (0.84 mL) were dissolved in DMF (20 mL) and HOBt • H2O (0.48 g) and WSCI • HCl (0.61 g) were added under ice cooling. The mixture was stirred at room temperature for one day and the reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the ether was added to the residue. The precipitated solid was collected by filtration to give N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.70 g). Melting point: 168-169 ° C.

Preparation Example 13

To a solution of ethyl pyrazole-4-carboxylate (13.0 g), 4-dimethylaminopyridine (0.57 g) and triethylamine (15.5 mL) in tetrahydrofuran (80 mL) was added a solution of di- dicarbonate tert-butyl (24.3 g) in tetrahydrofuran (20 mL) at room temperature. The mixture was stirred at the same temperature for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give ethyl 1- (tert-butyloxycarbonyl) pyrazol-4-carboxylate (22.1 g).

1H – NMR (CDCl3) δ: 1.37 (3H, t, J = 7.1Hz), 1.67 (9H, s), 4.33 (2H, q, J = 7.1Hz), 8.06 (1H, s), 8.56 (1H, s).

(1-tert-Butyloxycarbonyl) pyrazol-4-ethyl carboxylate (17.0 g) was dissolved in anhydrous tetrahydrofuran (150 mL), and 1 mol / L of diisobutylaluminum / toluene hydride solution (142 mL) was added to –78 ° C for 40 min. The reaction temperature was raised to 0 ° C for 1.5 h, and methanol-ether (1: 9) (100 mL), saturated aqueous sodium potassium tartrate solution tetrahydrate (Rochelle salt) (70) were added successively mL), water (330 mL) and ether (1 L) successively to the reaction mixture at the same temperature. The mixture was stirred for another hour. The reaction mixture was passed through Celite and the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 1- (tert-butoxycarbonyl) -4- (hydroxymethyl) pyrazole (5.92 g).

1H-NMR (CDCl3) δ: 1.64 (9H, s), 4.61 (2H, s), 7.69 (1H, s), 8.03 (1H, s).

Preparation Example 14

By reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (5.48 g) and 4-isopropylaniline (3 , 90 mL) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (5.94 g) was obtained. Melting point: 170.4 ° C.

Preparation Example 15

By reaction and treatment in the same manner as in Preparation Example 11 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.51 g) and 5-amino-2-isopropylpyridine (1 , 17 g) as starting materials, N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.18 g) was obtained. Melting point: 155.7 ° C.

Preparation Example 16

By reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.06 g) and 5-amino-2 -Isopropylpyridine (0.50 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.08 g) was obtained . Melting point: 157.4 ° C.

Preparation Example 17

By reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (2.30 g) and 5 -Amino-2-isopropylpyridine (1.04 g) as starting materials, 5-benzyloxy-8 fluoro-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1– was obtained carboxamide (2.83 g). Melting point: 184.0 ° C.

Preparation Example 18

To a solution of 8-nitrochroman-4-carboxylic acid (3.0 g) and 4-isopropylaniline (2.0 g) in dimethylformamide (30 mL) were added N-hydroxybenzotriazole hydrate (2.0 g) and hydrochloride of 1-ethyl-3– (3'-dimethylaminopropyl) carbodiimide (2.8 g) and the mixture was stirred at room temperature. After completing the reaction, the reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N- (4-isopropylphenyl) -8-nitrochroman-4-carboxamide (4.1 g).

1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 6.9Hz), 2.20-2.40 (1H, m), 2.50-2.70 (1H, m), 2 , 80–3.00 (1H, m), 3.80–3.95 (1H, m), 4.30–4.60 (2H, m), 6.90–7.60 (7H, m) , 7.75-7.90 (1H, m).

Preparation Example 19

By reaction and treatment in the same manner as in Preparation Example 18 using 4-benzyloxyindan-1-carboxylic acid (0.8 g) and 2,4-dimethoxyaniline (0.5 g) as starting materials , 4-benzyloxy-N- (2,4-dimethoxyphenyl) indan-1-carboxamide (0.96 g) was obtained. Melting point: 129.7 ° C.

1H-NMR (CDCl3) δ: 2.40-2.60 (2H, m), 2.90-3.20 (2H, m), 3.75 (3H, s), 3.78 (3H, s ), 4.00–4.20 (1H, m), 5.12 (2H, s), 6.40–6.50 (2H, m), 6.82 (1H, d, J = 8.0Hz ), 7.01 (1H, d, J = 7.5Hz), 7.10-7.60 (6H, m), 7.73 (1H, brs), 8.24 (1H, d, J = 8 , 6Hz).

Preparation Example 20 By reaction and treatment in the same manner as in Preparation Example 18 using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.34 g) and 5-amino-2-isopropylpyridine (0.62 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -8-methyl-1,2,3,4 –Tetrahydronaphthalen – 1– carboxamide (1.75 g).

1H-NMR (CDCl3) δ: 1.26 (6H, d, J = 6.9Hz), 1.55-1.80 (1H, m), 1.85-2.00 (2H, m), 2 , 20 (3H, s), 2.40–2.55 (1H, m), 2.55–2.75 (1H, m), 2.95–3.10 (2H, m), 3.80 –3.90 (1H, m), 5.10 (2H, s), 6.83 (1H, d, J = 8.1Hz), 7.00–7.50 (8H, m), 7.95 –8.10 (1H, m), 8.27 (1H, d, J = 2.4H).

Preparation Example 21 By reaction and treatment in the same manner as in Preparation Example 18 using acid 5–

benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (20.0 g) and 5-amino-2-methoxypyridine (8.72 g) as materials of Starting, 5-benzyloxy-N- (6-methoxypyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (23.9 g) was obtained. 1H-NMR (DMSO-d6): 1.62-1.69 (1H, m), 1.96-2.05 (3H, m), 2.64-2.69 (2H, m), 3, 82 (3H, s), 3.81-3.85 (1H, m),

5.11 (2H, s), 6.71–6.89 (3H, m), 7.05–7.10 (1H, m), 7.30–7.49 (5H, m), 7, 92–7.96 (1H, m), 8.39–8.40 (1H, m), 10.20 (1H, s).

Preparation Example 22 7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (5.0 g) and (R) - (+) - 1-phenethylamine (3.13 mL) were dissolved in methanol (50 mL) and the solvent was evaporated under reduced pressure to give crude crystals (7.33 g). This was recrystallized from a mixed solvent of methanol and isopropyl ether. The crystals obtained were divided into ethyl acetate and 1 mol / L hydrochloric acid. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give (R) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.65 g).

Optical purity> 99.9% e.e. Analysis conditions Column: CHIRALCEL OD (DAICEL) Development solvent: hexane / isopropanol / acetic acid = 97/3/3 Flow rate: 0.5 mL / min UV detection: 254 nm Retention time: 21.5 min Example Preparation 23 7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (5.0 g) and (S) - (-) - 1-phenethylamine (3.2 mL) were dissolved in

methanol (50 mL) and the solvent was evaporated under reduced pressure to give crude crystals (7.33 g). This was recrystallized from a mixed solvent of methanol and isopropyl ether. The crystals obtained were divided into ethyl acetate and 1 mol / L hydrochloric acid. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give (S) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.96 g).

Optical purity> 99.9% e. and. Analysis conditions Column: CHIRALCEL OD (DAICEL) Development solvent: hexane / isopropanol / acetic acid = 97/3/3 Flow rate: 0.5 mL / min UV detection: 254 nm Retention time: 26 min Preparation example 24 By reaction and treatment in the same manner as in Preparation Example 11 using acid 5–

benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic (2.82 g) and 2-amino-5-methylpyridine (1.08 g) as starting materials, 5-benzyloxy-N- (5 –Methylpyridin – 2-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.00 g).

MS (ESI) m / z: 373 [MH] + Example 1

image 1

To a solution of 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) in methylene chloride (10 mL) was added

5 thionyl chloride (0.68 mL) and the mixture was heated at reflux with stirring for 3 h. The reaction mixture was concentrated under reduced pressure and THF (6 mL) was added to the residue. This solution was added to a solution of [(4-dimethylaminophenyl) methyl] (4-ethylphenyl) amine (1.2 g) and triethylamine (2 mL) in THF (6 mL) under ice cooling. The mixture was allowed to warm to room temperature and stirred at the same temperature for one day. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over

10 anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography. The crystals obtained were recrystallized from a mixed solvent of ethyl acetate and hexane to give N- [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.28 g). Melting point: 109–110 ° C

Example 2

image3

By reaction and treatment in the same manner as in Example 1 using indan-1-carboxylic acid (0.46 g) and [(4-dimethylaminophenyl) methyl] (4-ethylphenyl) amine (0.6 g ) As starting materials, N- [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) indan-1-carboxamide (0.15 g) was obtained.

1H-NMR (CDCl3) δ: 1.22 (3H, t, J = 7.3Hz), 2.00-2.20 (1H, m), 2.25-2.63 (2H, q, J = 7.3Hz), 2.65-2.85 (1H, m), 2.93

20 (6H, s), 3.00–3.15 (1H, m), 3.96 (1H, t, J = 7.9Hz), 4.73 (1H, d, J = 13.9Hz), 4.94 (1H, d, J = 13.9Hz), 6.64 (2H, d, J = 8.6Hz), 6.97 (2H, d, J = 7.9Hz), 7.00–7 , 20 (8H, m).

Example 3 By reaction and treatment in the same manner as in Example 1 using 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-carboxylic acid (0.54g) and [(4-dimethylaminophenyl] ) methyl] (4-ethylphenyl) amine (0.6 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-ethiiphenyl) -6,7,8,9-tetrahydro was obtained –5H – benzocyclohepten – 5– carboxamide (0.2 g).

image 1

1H-NMR (CDCl3) δ: 1.17 (3H, t, J = 7.3Hz), 1.20-2.05 (6H, m), 2.10-2.30 (1H, m), 2 , 56 (3H, q, J = 7.3Hz), 2.92 (6H, s), 3.69 (1H, d, J = 7.9Hz), 4.78 (1H, d, J = 13, 9Hz), 4.90 (1H, d, J = 13.9Hz), 6.55-6.65 (4H, m), 6.90-7.30 (8H, m).

Example 4

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To a solution of 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (3.3 g) in 1,2-dichloroethane (20 mL) was added thionyl chloride (2.1 mL) and the mixture was heated to reflux with stirring for 3 h. The reaction mixture was concentrated under reduced pressure and methylene chloride (10 mL) was added to the residue. This solution was added to a solution of [(4-dimethylaminophenyl) methyl) (4-isopropylphenyl) amine (5.1 g) in methylene chloride (10 mL) under ice cooling. The reaction mixture was heated to room temperature and stirred thereto.

15 temperature for one day. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography. The crystals obtained were recrystallized from isopropyl ether to give N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (4.38 g). Melting Point: 121 ° C

Example 5 To a solution of 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.24 g) in methylene chloride (3 mL) thionyl chloride (0.15 mL) was added and the mixture was heated to reflux with stirring for 3 h. The reaction mixture was concentrated under reduced pressure and THF (2 mL) the residue was added. This solution was added to a solution of (5-bromo-2-isobutoxyphenyl) [(4-dimethylaminophenyl) methyl] amine (0.5 g) and sodium hydride (0.07 g) in THF (3 mL). The

image 1

The reaction mixture was heated to room temperature and stirred at the same temperature for one day. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography. The crystals obtained were recrystallized from ethyl acetate to give N- (5-bromo-2-isobutoxyphenyl) -N - [(4-dimethylaminophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 3 g) Melting point: 176–178 ° C.

10 Example 6

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N- (4-Isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.5 g) and butyl bromide (0.22 mL) was dissolved in DMF (3 mL) and hydride was added. sodium (0.08 g) under ice cooling. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 h. The reaction mixture was divided into water and

15 ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-butyl-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.53 g) .

1H – NMR (CDCl3) δ: 0.91 (3H, t, J = 7.3Hz), 1.26 (6H, d, J = 6.6Hz), 1.20–1.65 (5H, m) , 1.80–2.10 (3H, m), 2.63 (1H, dt, J = 16.5Hz, 4.6Hz), 2.75–3.00 (2H, m), 3.65– 3.80 (3H, m), 6.95–7.30 (8H, m).

20 Example 7

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By reaction and treatment in the same manner as in Example 6 using N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.5 g) and 2– chloride Morpholino-2-oxoethyl (0.33 g) as starting materials, N- (4-isopropylphenyl) -N- (2-morpholino-2-oxoethyl) -1,2,3,4-tetrahydronaphthalen-1- was obtained carboxamide (0.43

25 g) Melting point: 180 ° C.

Example 8 By reaction and treatment in the same manner as in Example 6 using N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.75 g) and bromide 3- (tetrahydropyran-2-yloxy) propyl (0.52 mL) as starting materials, N- (4-isopropylphenyl) -N- [3- (tetrahydropyran-2-yloxy) propyl) -1,2, 3,4- tetrahydronaphthalen-1-carboxamide (0.9 g).

image 1

1H-NMR (CDCl3) δ: 1.26 (6H, d, J = 7.3Hz), 1.40-2.10 (13H, m), 2.63 (1H, dt, J = 16.5Hz, 4.6Hz), 2.75-3.05 (2H, m), 3.35-3.50 (2H, m), 3.70-4.00 (4H, m), 4.12 (1H, dd, J = 14.5Hz, 7.3Hz), 6.95-7.30 (8H, m).

Example 9

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10 N– (4-Isopropylphenyl) –N– [3– (tetrahydropyran-2-yloxy) propyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.24 g) was dissolved in a mixed solvent (7 mL) acetic acid: THF: water (4: 2: 1) and stirred at room temperature for 2 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N- (3-hydroxypropyl) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-

15 carboxamide (0.12 g).

1H-NMR (CDCl3) δ: 1.27 (6H, d, J = 6.6Hz), 1.40-2.10 (6H, m), 2.65 (1H, dt, J = 16.5Hz, 4.6Hz), 2.75–3.05 (2H, m), 3.60–3.90 (4H, m, 3.95–4.15 (4H, m), 6.95–7.30 (8H, m).

Example 10

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By reaction and treatment in the same manner as in Example 1 using thiochroman-4-carboxylic acid (0.55 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0.63 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) thiochroman-4-carboxamide (0.3 g) was obtained. Melting point: 118 ° C.

Example 11

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By reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.56 g) and (3-cyanopropyl) (4 -Isopropylphenyl) amine (1.79 20 g) as starting materials, N- (3-cyanopropyl) -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1- was obtained carboxamide (1.56 g). Melting point: 74–75 ° C.

Example 12

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To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) in 1,2-dichloroethane (20 mL),

10 thionyl chloride (2.1 mL) was added and the mixture was refluxed with stirring for 3 h. The reaction mixture was concentrated under reduced pressure and methylene chloride (10 mL) was added to the residue. This solution was added to a solution of [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (1.3 g) in methylene chloride (10 mL) under ice cooling. The reaction mixture was heated to room temperature and stirred at the same temperature for one day. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed

15 with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.7.3 g).

1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 7.3Hz), 1.43-1.45 (1H, m), 1.86-2.01 (2H, m), 2 , 25 (3H, s), 2.54-2.79 (1H, m), 2.70-3.00 (2H, m), 2.93 (6H, s), 3.68 (1H, t , J = 8.6Hz), 3.68 (3H, s), 4.59 (1H, d, J = 14Hz), 6.51 (1H, d, J = 2.5Hz),

20 6.66 (2H, dd, J = 2.6, 8.5Hz), 6.91-6.99 (2H, m), 7.17 (2H, dd, J = 8.7, 14Hz).

Example 13 By reaction and treatment in the same manner as in Example 1 using chroman-4-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl) methyl) (4-isopropylphenyl) amine (0, 63 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (0.25 g) was obtained. Melting point: 110– 112 ° C.

image 1

Example 14

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By means of the reaction and treatment in the same manner as in Example 1 using 1,1-dioxothiochroman-4-carboxylic acid (0.26 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine ( 0.31 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,1-dioxothiochroman-4-carboxamide (0.07

10 g) Melting point: 185-187 ° C.

Example 15

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By reaction and treatment in the same manner as in Example 12 using 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (2.0 g) and [(4-dimethylaminophenyl) methyl ] (4-isopropylphenyl) amine (1.91 g) as materials

Starting, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -5-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.48 g) was obtained.

1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 7.3Hz), 1.43-1.45 (1H, m), 1.86-2.01 (2H, m), 2 , 25 (3H, s), 2.63 (1H, t, 5.9Hz), 2.80–2.99 (1H, m), 2.70–3.00 (2H, m), 2.94 (6H, s) 3.68 (1H, t, J = 8.6Hz), 3.77 (3H, s), 4.73 (1H, d, J = 14Hz), 4.95 (1H, d, J = 14Hz), 6.66 (2H, d, J = 8.0Hz), 6.68 (2H, s), 6.97 (2H, d, J = 8.0Hz), 7.04–7, 30 (5H, m)

Example 16 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (2.0 g) and [(4– dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (1.91 g) as starting materials, 5-benzyloxy-N - ((4-dimethylaminophenyl) methyl) -N- (4-isopropylphenyl) -1,2, 3,4- tetrahydronaphthalen-1-carboxamide (0.76 g).

image 1

1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 7.3Hz), 1.39-1.53 (1H, m), 1.79-2.08 (3H, m), 2 , 68-2.78 (2H, m) 2.83-2.92 (1H, m), 2.94 (6H, s), 3.73 (1H, t, J = 8.6Hz), 4, 72 (1H, d, J = 14Hz), 4.93 (1H, d, J = 14Hz), 5.03 (2H, s), 6.61–6.74 (4H, m), 6.94– 7.20 (7H, m), 7.28-7.44 (5H, m).

Example 17

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10 5-Benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.75 g) was dissolved in methanol (60 mL ) and 10% palladium formate (1.5 g) was added. The reaction mixture was filtered and the filtrate was concentrated. Water was added to the residue and the precipitated crude crystals were recrystallized from ethyl acetate to give N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen –1– carboxamide (0.5 g), Melting point: 200–202 ° C.

15 Example 18

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By reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.1 g) and (4-isopropylphenyl) [6– (tetrahydropyran– 2-yloxy) hexyl] amine (2.0 g) as starting materials, N- (4-isopropylphenyl) -N- [6- (tetrahydropyran-2-yloxy) hexyl] -1,2,3,4 was obtained -

Tetrahydronaphthalene-1-carboxamide (1.0 g). Through the reaction and treatment of this compound in the same manner as in Example 9, N- (6-hydroxyhexyl) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1 was obtained - carboxamide (0.64 g).

1H-NMR (CDCl3) δ: 1.26 (6H, d, J = 7.3Hz), 1.20-2.10 (13H, m), 2.63 (1H, dt, J = 16.5Hz, 4.6H, z), 2.75-3.05 (2H, m), 3.59 (2H, t, J = 5.9Hz), 3.65-3.80 (3H, m), 6, 95–7.30 (8H, m).

Example 19 By reaction and treatment in the same manner as in Example 1 using 2-oxo-1,2,3,4-tetrahydroquinolin-4-carboxylic acid (0.5 g) and [(4– dimethylarylphenyl) methyl] (4-isopropylphenyl) amine (0.7 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -2-oxo-1,2, 3,4-tetrahydroquinolin-4-carboxamide (0.6 g). Melting point: 170 ° C.

image 1

Example 20

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N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (3.2 g) was dissolved in methylene chloride (60 mL ) and boron tribromide (0.72 mL) was added under ice cooling. The mixture was stirred at room temperature for one day. The reaction mixture was divided into hydrogen carbonate

10 saturated aqueous sodium and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N - [(4-dimethylaminophenyl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.36 g). Melting point: 214-217 ° C.

Example 21

image3

By reaction and treatment in the same manner as in Example 12 using 6-methoxyindan-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0, 7 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -6-methoxyindan-1-carboxamide (0.53 g) was obtained.

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.6Hz), 2.00-2.20 (1H, m), 2.30-2.50 (1H, m), 2 , 60–2.75 (1H, m), 2.80–3.10 (2H,

20 m), 2.93 (6H, s), 3.74 (3H, s), 3.93 (1H, t, J = 7.9Hz), 4.68 (1H, d, J = 13.9Hz ), 4.98 (1H, d, J = 13.9Hz), 6.60–6.75 (4H, m), 6.90–7.20 (7H, m).

Example 22 By reaction and treatment in the same manner as in Example 1 using 7-isopropyl-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl] ) methyl] (4-isopropylphenyl) amine (1.07 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -7-isopropyl-N- (4-isopropylphenyl) -1,2,3 , 4– tetrahydronaphthalen-1-carboxamide (0.53 g). Melting point: 123-125 ° C.

image 1

Example 23

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By reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.5 g) and [(1-ethylpyrazol-4-yl) methyl ] (4-Isopropylphenyl) amine (0.57 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3 was obtained, 4-tetrahydronaphthalen-1-carboxamide (0.12 g). Melting point: 75–76 ° C.

Example 24

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By reaction and treatment in the same manner as in Example 12 using 6-methoxy-1,2,3,4–

Tetrahydronaphthalen-1-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0.7 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] was obtained. –N– (4-isopropylphenyl) -6-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.36 g).

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.6Hz), 1.35-1.55 (1H, m), 1.75-2.10 (3H, m), 2 , 55–2.70 (1H, m), 2.75–3.00 (2H, m), 2.94 (6H, s), 3.60–3.70 (1H, m), 3.74 (3H, s), 4.70 (1H, d, J = 13.9Hz), 4.93 (1H, d, J = 13.9Hz), 6.50–6.75 (4H,

20 m), 6.90–7.20 (7H, m).

Example 25 By reaction and treatment in the same manner as in Example 1 using 6-methoxychroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine ( 0.7 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -6-methoxychroman-4-carboxamide (0.3 g) was obtained. Melting point: 82–84 ° C.

image 1

Example 26

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By reaction and treatment in the same manner as in Example 12 using 7-methyl-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl) methyl ] (4-isopropylphenyl) amine (1.40 g) as materials

10 Starting, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methyl- 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.53 g) was obtained.

1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 7.3Hz), 1.43-1.45 (1H, m), 1.86-2.01 (2H, m), 2 , 25 (3H, s), 2.54–2.79 (1H, m), 2.70–3.00 (2H, m), 2.93 (6H, s), 3.69 (1H, t , J = 8.6Hz), 4.70 (1H, d, J = 14Hz), 4.98 (1H, d, J = 14Hz), 6.65 (2H, d, J = 8.5Hz), 6 , 80 (1H, s), 6.91 (2H, s), 6.96 (2H, d, J = 7.9Hz), 7.15 (4H, dd, J = 6.6, 8.6Hz) .

15 Example 27

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By reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) and [(, 4-chlorophenyl) methyl] (4 -Isopropylphenyl) amine (1.3 g) as starting materials, N - [(4-chlorophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.1 g).

20 Melting point: 122–123 ° C.

Example 28 By reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) and [(4-chlorophenyl ) methyl] (4-isopropylphenyl) amine (1.5 g) as starting materials, N - [(4-chlorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.58 g). Melting point: 87–88 ° C.

image 1

Example 29

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By reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.5 g) and [(4-bromophenyl) methyl ] (4-Isopropylphenyl) amine (2.21 g) as starting materials, N - [(4-bromophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.526 g). Melting point: 85 ° C.

Example 30

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Through reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4–

Tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(1,3-dioxoindan-5-yl) methyl] (4-isopropylphenyl) amine (1.3 g) as starting materials, N - [( 1,3-dioxaindan-5-yl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.3 g). Melting point: 97–98 ° C.

Example 31 By reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.63 g) and [(4-cyanophenyl] ) methyl] (4-isopropylphenyl) amine (0.83 g) as starting materials, N - [(4-cyanophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.63 g). Melting point: 137–138 ° C.

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Example 32

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By means of the reaction and treatment in the same manner as in Example 1 using 6-fluorochroman-4-carboxylic acid (1.96 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (2, 68 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -6-fluoro-N- (4-isopropylphenyl) chroman-4-carboxamide (2.89 g) was obtained. Melting point: 95–98 ° C.

Example 33

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By reaction and treatment in the same manner as in Example 4 using 1,2,3,4– acid

Tetrahydronaphthalen-1-carboxylic acid (0.5 g) and [(1-ethyl-3,5-dimethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.65 g) as starting materials, was obtained N - [(1-eti1-3,5-dimethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.31 g). Oxalic acid was added to this compound. By recrystallization from ethyl acetate, N - [(1-ethyl-3,5-dimethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1– was obtained carboxamide 1/2 oxalate 1/2 hydrate (0.03 g), Melting point: 142-143 ° C.

Example 34 By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.5 g) and (4-isopropylphenyl) ) [(4-methylthiophenyl) methyl] amine (2.0 g) as starting materials, N- (4-isopropylphenyl) -7-methoxy-N - [(4-methylthiophenyl) methyl] -1,2, 3,4-tetrahydronaphthalen-1-carboxamide (1.4 g).

image 1

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 7.3Hz), 1.43-1.45 (1H, m), 1.86-2.01 (3H, m), 2 , 25 (3H, s), 2.47 (3H, s), 2.53-2.61 (1H, m), 2.71-2.97 (2H, m), 3.70 (3H, s ), 3.72 (1H, t, J = 8.6Hz), 4.70 (1H, d, J = 14Hz), 5.04 (1H, d, J = 14Hz), 6.65 (1H, d , J = 2.7Hz), 6.67 (1H, dd, J = 2.7, 8.6Hz), 6.93-6.99 (3H, m), 7.16-7.22 (6H, m).

Example 35

image4

N- (4-isopropylphenyl) -7-methoxy-N - [(4-methylthiophenyl) methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.0 g) was dissolved in acetic acid (10 mL) and 3.0% aqueous hydrogen peroxide (5.5 mL) was added at room temperature. The mixture was stirred with heating at 100 ° C for 3 h. Water was added to the reaction mixture and the precipitated solid was purified by silica gel column chromatography to give crude crystals. The crystals are

15 recrystallized from ethyl acetate to give N- (4-isopropylphenyl) -N - [(4-methylsulfonylphenyl) methyl] -7-methoxy-1,2,3,4- tetrahydronaphthalen-1-carboxamide (0.61 g) . Melting point: 131–132 ° C.

Example 36

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Through reaction and treatment in the same manner as in Example 1 using 6-benzyloxy acid–

1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.1 g) and [(4-dimethylaminophenyl) methyl) (4-isopropylphenyl) amine (1.05 g) as starting materials, 6– was obtained benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.23 g). Melting point: 107-109 ° C.

Example 37 To a solution of 6-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.75 g) in methanol (8.6 mL) 10% palladium on carbon (0.09 g) and ammonium formate (0.44 g) were added and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and the solvent evaporated. The obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to give N - [(4-dimethylaminophenyl) methyl] -6-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen –1 – carboxamide (0.23 g). Melting point: 169–171 ° C.

image 1

Example 38

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By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.45 g) and (4-butylphenyl) [(4-dimethylaminophenyl) ) -Methyl] amine (0.6 g) as starting materials, N- (4-butylphenyl) N - [(4-dimethylaminophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.35 g).

1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.3Hz), 1.20-1.70 (5H, m), 1.80-2.10 (3H, m), 2 , 58 (2H, t, J = 7.3Hz), 2.50-2.70 (1H, m), 2.75-3.00 (1H, m), 2.94 (6H, s), 3 , 70–3.80 (1H, m), 4.72 (1H, d, J = 13.9Hz), 4.93 (1H, d, J = 13.9Hz), 6.64

15 (2H, d, J = 8.6Hz), 6.90–7.20 (10H, m).

Example 39

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.75 g) and [(1,3-dioxaindan –5 – yl) methyl] (4-methoxyphenyl) amine (0.93 g) as materials

Starting 20, N - [(1,3-dioxaindan-5-yl) methyl] -N- (4-methoxyphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0 , 15 g).

1H-NMR (CDCl3) δ: 1.43-1.45 (1H, m), 1.86-2.01 (3H, m), 2.52-2.63 (1H, m), 2.70 –2.90 (2H, m), 3.73 (3H, s), 3.79 (3H, s), 3.72 (1H, t, J = 8.6Hz) 4.63 (1H, d, J = 14Hz), 5.00 (1H, d, J = 14Hz), 5.93 (2H, s), 6.50 (1H, d, J = 2.0Hz), 6.61–6.99 ( 9H, m).

Example 40 By reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.5, g) and [(4 -Methoxyphenyl) methyl] (4-methoxyphenyl) amine (0.88 g) as starting materials, N - [(4-methoxyphenyl) methyl] -N- (4-methoxyphenyl) -7-methoxy-1,2 , 3,4-tetrahydronaphthalen-1-carboxamide (0.72 g). Melting point: 89–90 ° C.

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Example 41

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By reaction and treatment in the same manner as in Example 12 using 6-chlorochroman-4-carboxylic acid (0.66 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0, 83 g) as starting materials,

10 obtained 6-chloro-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (0.36 g). 1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.80-2.00 (1H, m), 2.10-2.20 (1H, m), 2 , 80–3.00 (1H, m), 2.94 (6H, s), 3.65–3.75 (1H, m), 3.90–4.05 (1H, m), 4.40 –4.50 (1H, m), 4.73 (1H, d, J = 13.8Hz), 4.88 (1H, d, J = 13.8Hz), 6.60–7.30 (11H, m).

Example 42

image3

By reaction and treatment in the same manner as in Example 12 using 6-bromochroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl) methyl) (4-isopropylphenyl) amine (0, 57 g) as starting materials, 6-bromo-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (0.52 g) was obtained.

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.81-1.95 (1H, m) 2.07-2.23 (1H, m), 2, 81-2.98 (1H, m), 2.93 (6H, s),

20 3.71 (1H, t, J = 6.2Hz), 3.91-4.03 (1H, m), 4.38-4.50 (1H, m), 4.71 (1H, d, J = 13.9Hz), 4.89 (1H, d, J = 13.9Hz), 6.60–6.72 (3H, m) 6.91–7.25 (8H, m).

Example 43

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.31 g) and (4-isopropylphenyl) [( 6-isopropylpyridin-3-yl) methyl] amine (0.46 g) as 5 starting materials, N- (4-isopropylphenyl) -N - [(6-isopropylpyridin-3-yl) methyl] -7- methoxy – 1,2,3,4– tetrahydronaphthalen – 1-carboxamide (0.12 g).

1H-NMR (CDCl3) δ: 1.19 (6H, d, J = 6.9Hz), 1.37 (6H, d, J = 6.9Hz) 1.28-1.45 (1H, m), 1.78-1.97 (3H, m), 2.47-2.71 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.50 (1H, sept, J = 6.9Hz), 3.70 (3H, s), 3.61-3.75 (1H, m), 5.02 (1H, d, J = 13.9Hz), 5.13 (1H, d , J = 13.9Hz), 6.46 (1H, d, J = 2.4Hz), 6.71 (1H, dd, J = 2.4, 8.4Hz), 6.96 (1H, d, J = 8.4Hz),

10 7.28–7.41 (4H, m), 8.01 (1H, dd, J = 3.6, 8.1Hz), 8.40 (1H, dd, J = 1.8, 8.4Hz ), 8.61 (1H, d, J = 1.5Hz).

Example 44

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By reaction and treatment in the same manner as in Example 12 using 8-methoxychroman-4-carboxylic acid (0.64 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0, 83 g) as starting materials,

15 obtained N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -8-methoxychroman-4-carboxamide (0.69 g).

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.90-2.00 (1H, m), 2.15-2.30 (1H, m), 2 , 80–3.00 (1H, m), 2.94 (6H, s), 3.77 (1H, t, J = 6.3Hz), 3.84 (3H, s), 4.00–4 , 20 (1H, m), 4.50-4.65 (1H, m), 4.71 (1H, d, J = 13.9Hz), 4.91 (1H, d, J = 13.9Hz) , 6.55–7.25 (11H, m).

Example 45

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By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.70 g) and [(4-methoxyphenyl) methyl] (4– Methoxyphenyl) amine (0.97 g) as starting materials, N - [(4-methoxyphenyl) methyl] -N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1 , 33 g).

1H-NMR (CDCl3) δ: 1.47-1.52 (1H, m), 1.86-2.03 (3H, m), 3.78 (3H, s), 3.80 (3H, s ), 4.76 (1H, d, J = 13.9Hz), 4.94 (1H, d, J = 13.9Hz), 6.80–7.16 (12H, m).

Example 46

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5 By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.50 g) and (4-isopropylphenyl) [ (6-methoxypyridin-3-yl) methyl] amine (0.62 g) as starting materials, N- (4-isopropylphenyl) -N - [(6-methoxypyridin-3-yl) methyl] -7- methoxy – 1,2,3,4– tetrahydronaphthalen – 1-carboxamide. This was dissolved in ether and 4 N hydrochloric acid / dioxane was added. The precipitated solid was collected by filtration to give N- (4-isopropylphenyl) -N- [(6-methoxypyridin-3– monohydrochloride)

10 il) methyl] –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.47 g). Melting point: 114–117 ° C

Example 47

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By reaction and treatment in the same manner as in Example 12 using 4-methoxyindan-1-carboxylic acid (0.20 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0, 27 g) as starting materials,

15 obtained N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -4-methoxyindan-1-carboxamide (0.24 g).

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 2.08-2.09 (1H, m), 2.31-2.38 (1H, m), 2 , 63–2.72 (1H, m), 2.86–2.92 (1H, m), 2.94 (6H, s), 3.79 (3H, s), 3.94–4.00 (1H, m), 4.71 (1H, d, J = 13.9Hz), 4.93 (1H, d, J = 13.9Hz), 6.63-6.68 (3H, m), 6 , 75 (1H, d, J = 7.5Hz), 6.95-6.98 (3H, m), 7.01-7.18 (4H, m).

Example 48

image2

By reaction and treatment in the same manner as in Example 12 using 5-methoxyindan-1-carboxylic acid (0.50 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0, 80 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -5-methoxyindan-1-carboxamide (1.00 g) was obtained.

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9), 2.08-2.09 (1H, m), 2.31-2.38 (1H, m), 2 , 63-2.77 (1H, m), 2.86-2.93 (1H, m), 2.93 (6H, s), 3.76 (3H, s), 3.90 (1H, t , J = 8.6Hz), 4.71 (1H, d, J = 13.9Hz), 4.92 (1H, d, J = 13.9Hz), 6.63–6.73 (4H, m) 6.95–7.02 (3H, m), 7.01 (2H, d, J = 8.7Hz), 7.17 (2H, d, J = 8.3Hz).

Example 49

image5

By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.5 g) and ((1-benzylpyrazole-4 -Yl) methyl] (4-isopropylphenyl) amine (2.22 g) as starting materials, N - [(1-benzylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -7-methoxy was obtained –1,2,3,4– tetrahydronaphthalen – 1 – carboxamide (1.64 g).

10 1H-NMR (CDCl3) δ: 1.27 (6H, d, J = 6.9Hz), 1.37-1.53 (1H, m), 2.07 (3H, m), 2.52– 2.66 (1H, m), 2.69-2.83 (1H, m), 2.91 (1H, sept, J = 6.9Hz), 3.60-3.73 (1H, m), 3.65 (3H, s), 4.58 (1H, d, J = 13.9Hz), 4.85 (1H, d, J = 13.9Hz), 5.24 (2H, s), 6, 45 (1H, d, J = 2.4Hz), 6.67 (1H, dd, J = 2.4, 8.4Hz), 6.95 (1H, d, J = 8.4Hz), 7.03 (2H, d, J = 8.4Hz), 7.13-7.45 (9H, m).

Example 50

image3

By reaction and treatment in the same manner as in Example 4 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.31 g) and (4-isopropylphenyl) [( 4-methoxyphenyl) methyl] amine (0.38, g) as starting materials, N- (4-isopropylphenyl) -N - [(4-methoxyphenyl) methyl] -7-methoxy-1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.37 g). Melting point: 83–85 ° C.

20 Example 51

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.58 g) and [(6-ethylpyridine-3 -Yl) methyl] (4-isopropylphenyl) amine (0.71 g) as materials

Starting, N - [(6-ethylpyridin-3-yl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g) was obtained.

1H – NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.28 (3H, t, J = 7.7Hz), 1.40–1.57 (1H, m) , 1.70-2.05 (3H, m), 2.50-2.64 (1H, m), 2.71-2.95 (4H, m), 3.70 (3H, s), 3 , 64–3.79 (1H, m), 4.80 (1H, d, J = 13.9Hz), 4.96 (1H, d, J = 13.9Hz), 6.47 (1H, d, J = 2.4Hz), 6.67 (1H, dd, J = 2.4, 8.4Hz), 6.96 (1H, d, J = 8.4Hz), 7.00 (2H, d, J = 8.4Hz), 7.12 (1H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz), 7.68 (1H, dd, J = 2.4, 8.4Hz), 8.29 (1H, d, J = 2.4Hz).

Example 52

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Through reaction and treatment in the same manner as in Example 12 using 4-benzyloxyindan acid–

10 1-carboxylic (0.7 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0.7 g) as starting materials, 4-benzyloxy-N - [(4-dimethylaminophenyl) was obtained methyl] -N- (4-isopropylphenyl) indan-1-carboxamide (1.5 g).

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 2.00-2.20 (1H, m), 2.30-2.45 (1H, m), 2 , 65-22.80 (1H, m), 2.85-3.00 (1H, m), 2.94 (6H, s), 3.05-3.20 (1H, m), 3.95 –4.05 (1H, m), 4.72 (1H, d, J = 13.8Hz), 4.94 (1H, d, J = 13.8Hz), 5.06 (2H, s), 6 , 60–6.80 (4H, m), 6.90–7.45 (12H, m).

15 Example 53

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By reaction and treatment in the same manner as in Example 37 using 4-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) indan-1-carboxamide (1.19 g ) As a starting material, N- [(4-dimethylaminophenyl) methyl] -4-hydroxy-N- (4-isopropylphenyl) indan-1-carboxamide (0.57 g) was obtained. Melting point: 158–

20 160 ° C.

Example 54 To a solution of N - [(4.-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.79 g) in toluene (10 mL ) Lawesson reagent (0.9 g) was added and the mixture was heated at reflux for 5 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography.

image 1

5 of silica gel to give N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carbothioamide (0.19 g). Melting point: 123-125 ° C.

Example 55

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4–

Tetrahydronaphthalen-1-carboxylic acid (0.31 g) and [(6-dimethylaminopyridin-3-yl) methyl] (4-isopropylphenyl) amine (0.24 g) as starting materials, N - [(6– dimethylaminopyridin-3-yl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide. This was dissolved in ether and 4 mol / L-hydrochloric acid / dioxane (0.30 mL) was added. The solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give N - [(6-dimethylaminopyridin-3-yl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4 hydrochloride –Tetrahidronaftalen – 1–

15 carboxamide 1/2 hydrate (0.43 g). Melting point: 158-160 ° C.

Example 56

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.31 g) and (4-isopropylphenyl) [( 5-methoxypyridin-2-yl) methyl] amine (0.38 g) as

20 starting materials, N- (4-isopropylphenyl) -N- ((5-methoxypyridin-2-yl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide was obtained. dissolved in ether and 4 moles / L-hydrochloric acid / dioxane (0.40 mL) were added.The solvent was evaporated and the ether was added to the residue.The precipitated crystals were collected by filtration to give N- hydrochloride (4– isopropylphenyl) -N - [(5-methoxypyridin-2-yl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide 1/2 hydrate (0.54g). Melting point: 108-110 ° C.

Example 57 By reaction and treatment in the same manner as in Example 4 using 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.31 g) and [(1– ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methylj-N- (4-isopropylphenyl) -6 was obtained –Methoxy – 1,2,3,4 – tetrahydronaphthalen – 1– carboxamide (0.45 g). Melting point: 111–113 ° C

image 1

Example 58

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.31 g) and [(2-dimethylaminopyridine-3 -Yl) methyl] (4-isopropylphenyl) amine (0.40 g) as

10 starting materials, N - [(2-dimethylaminopyridin-3-yl) methyl) -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 58 g).

1H-NMR (CDCl3) δ: 1.17 (6H, d, J = 6.9Hz), 1.31-1.48 (1H, m), 1.70-2.05 (3H, m), 2 , 48–2.68 (2H, m), 2.89 (1H, sept, J = 6.9Hz) 3.04 (6H, s), 3.60–3.76 (4H, m), 4, 93 (1H, d, J = 13.9Hz), 5.12 (1H, d, J = 13.9Hz), 6.49 (1H, d, J = 2.4Hz), 6.72 (1H, dd , J = 2.4, 8.4Hz), 6.97 (1H, d, J = 8.4Hz), 7.14 (1H, dd, J = 6.0, 7.3Hz), 7.32 ( 2H, d, J = 8.4Hz), 7.38 (2H,

15 d, J = 8.4Hz), 7.95 (1H, d, J = 7.4H2), 8.07 (1H, dd, J = 1.3, 5.8Hz).

Example 59

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By reaction and treatment in the same manner as in Example 122 using 5-methoxy– 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.31 g) and [(1-ethylpyrazole-4 -Yl) methyl] (4-isopropylphenyl) amine (0.37 g) as

20 starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -5-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 52 g)

1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.37-1.52 (1H, m), 1.45 (3H, t, J = 7.3Hz) , 1.67-2.05 (3H, m), 2.57-2.71 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.70 (1H, t, J = 6.2Hz), 3.77 (3H, s), 4.11 (2H, q, J = 7.3Hz), 4.58 (1H, d, J = 13.9Hz), 4.84 ( 1H, d, J = 13.9Hz), 6.54 (1H, d, J = 7.7Hz), 6.65 (1H, d, J = 7.7Hz), 6.98–7.10 (3H , m), 7.22 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.41 (1H, s).

Example 60

image 1

5 By reaction and treatment in the same manner as in Example 12 using 6-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) ) amine (0.37 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -6-methoxyindan-1-carboxamide (0.35 g) was obtained ).

1H – NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 2.03-2.15 (1H, m) , 2.26-2.39 (1H, m), 2.61-2.73 (1H, m), 2.87-3.03 (2H, m), 3.74 (3H, s), 3 , 93 (1H, t, J = 8.1Hz), 4.12 (2H, q, J = 7.3Hz), 4.66 (1H, d, J = 13.9Hz),

10 4.79 (1H, d, J = 13.9Hz), 6.68 (1H, d, J = 2.4Hz), 6.69 (1H, dd, J = 2.4, 8.4Hz), 7.00–7.10 (3H, m), 7.23 (2H, d, J = 8.4Hz), 7.32 (1H, s), 7.40 (1H, s).

Example 61

image 1

Through reaction and treatment in the same manner as in Example 12 using 5-benzyloxy acid–

1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.56 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.49 g) as starting materials, 5-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) was obtained.

1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.39-1.55 (1H, m), 1.45 (3H, t, J = 7.3Hz) , 1.78-2.09 (3H, m), 2.68-2.80 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.72 (1H, t, J = 6.2Hz), 4.13 (2H, q, J = 7.3Hz), 4.58 (1H, d, J = 13.9Hz), 4.84 (1H,

20 d, J = 13.9Hz), 5.03 (2H, s), 6.56 (1H, d, J = 7.7Hz), 6.70 (1H, d, J = 7.7Hz), 6 , 98–7.12 (3H, m), 7.20–7.42 (9H, m).

By reaction and treatment in the same manner as in Example 37 using 5-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.72 g), N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) –1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.33 g). Melting point: 212– 215 ° C.

Example 62 By reaction and treatment in the same manner as in Example 6 using N- (4-isopropylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-2– (4-methoxyphenyl) ethane (0.38 g) as starting materials, N- (4-isopropylphenyl) -N- [2– (4-methoxyphenyl) ethyl] -7 was obtained –Methoxy – 1,2,3,4– tetrahydronaphthalenecarboxamide (0.15 g).

image 1

1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.78-2.09 (3H, m), 2 , 51-2.63 (1H, m) 2.69-2.97 (4H, m), 3.65-4.15 (9H, m), 6.51 (1H, d, J = 2.4Hz ), 6.67 (1H, dd, J = 2.4, 8.4Hz), 6.75–6.88 (2H, m), 6.96 (1H, d, J = 8.4Hz), 7 , 06–7.29 (6H, m).

Example 63

image4

By reaction and treatment in the same manner as in Example 6 using N- (4-isopropylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-3– (4-methoxyphenyl) propane (0.40 g) as starting materials, N- (4-isopropylphenyl) -N- [3– (4-methoxyphenyl) propyl] -7-methoxy- was obtained 1,2,3,4- tetrahydronaphthalene-1-carboxamide (0.41 g).

1 H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.40-1.53 (1H, m), 1.81-2.09 (5H, m), 2.51-2.64 (3H, m), 2.70-2.85 (1H, m), 2.93 (1H, sept, J = 6.9Hz), 3.68-3.87 (9H , m), 6.57 (1H, d, J = 2.4Hz), 6.67 (1H, dd, J = 2.4, 8.4Hz), 6.80 (2H, d, J = 8, 4Hz), 6.95 (1H, d, J = 8.4Hz), 7.08 (2H, d, J = 8.4Hz), 7.14–7.33 (4H, m).

Example 64

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By reaction and treatment in the same manner as in Example 6 using N- (4-isopropylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-4– (4-methoxyphenyl) butane (0.43 g) as starting materials, N- (4-isopropylphenyl) -N- [4– (4-methoxyphenyl) butyl] -7-methoxy was obtained –1,2,3,4– tetrahydronaphthalen – 1 – carboxamide (0.25 g).

1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.40-1.68 (5H, m) 1.80-2.05 (3H, m), 2, 50–2.62 (3H, m), 2.71–2.83 (1H, m), 2.93 (1H, sept, J = 6.9Hz), 3.64–3.88 (9H, m ), 6.56 (1H, d, J = 2.4Hz), 6.67 (1H, dd, J = 2.4, 8.4Hz), 6.80 (2H, d, J = 8.4Hz) , 6.95 (1H, d, J = 8.4Hz), 7.05 (2H, d, J = 8.4Hz), 7.13 (2H, d, J = 8.4Hz), 7.24 ( 2H, d, J = 8.4Hz).

Example 65

image5

By reaction and treatment in the same manner as in Example 4 using 7-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.56 g) and [(1-ethylpyrazole-4 -Yl) methyl] (4-isopropylphenyl) amine (0.49 g) as starting materials, 7-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) was obtained amine (0.61 g). Melting point: 100–101 ° C.

10 Example 66

image 1

By reaction and treatment in the same manner as in Example 4 using 4-benzyloxyindan-1-carboxylic acid (0.54 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) Amine (0.49 g) as starting materials, 4-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) indan-1-carboxamide (0.79 g) was obtained ).

1 H NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 2.04-2.18 (1H, m ), 2.24–2.39 (1H, m), 2.65–2.80 (1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.06–3.20 (1H, m), 3.98 (1H, t, J = 6.2Hz), 4.12 (2H, q, J = 7.3Hz), 4.65 (1H, d, J = 13.9Hz) , 4.79 (1H, d, J = 13.9Hz), 5.06 (2H, s), 6.67 (1H, d, J = 7.7Hz), 6.70 (1H, d, J = 7.7Hz), 7.00–7.10 (3H, m), 7.20–7.43 (9H, m).

Example 67

image2

By reaction and treatment in the same manner as in Example 4 using indan-1-carboxylic acid (0.24 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine ( 0.37 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) indan-1-carboxamide (0.23 g)) was obtained. Melting point: 83–84 ° C.

Example 68

image 1

By reaction and treatment in the same manner as in Example 4 using 6-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.56 g) and [(1-ethylpyrazole-4 -Yl) methyl] (4-isopropylphenyl) amine (0.49 g) as starting materials, 6-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) was obtained –1,2,3,4– tetrahydronaphthalene – 1 – carboxamide (0.65 g). Melting point: 122–124 ° C

Example 69

image 1

By reaction and treatment in the same manner as in Example 12 using 6-fluorochroman acid–

10 4-carboxylic (0.29 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazole) was obtained 4-yl) methyl] -6-fluoro-N- (4-isopropylphenyl) chroman-4-carboxamide (0.42 g).

1H-NMR (CDCl3) δ: 1.27 (6H, d, J = 6.9Hz), 1.46 (3H, t, J = 7.3Hz), 1.84-1.97 (1H, m) , 2.08-2.20 (1H, m), 2.94 (1H, sept, J = 6.9Hz), 3.72 (1H, t, J = 6.2Hz), 3.89-4, 00 (1H, m), 4.12 (2H, q, J = 7.3Hz), 4.35-4.45 (1H, m), 4.62 (1H, d, J = 13.9Hz), 4.79 (1H, d, J = 13.9Hz), 6.55 (1H, dd, J = 2.4, 8.4Hz), 6.69-6.83 (2H, m), 7.04 (2H, d, J = 8.4Hz), 7.21–

15 7.31 (3H, s), 7.40 (1H, s).

Example 70

image 1

By reaction and treatment in the same manner as in Example 12 using 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-carboxylic acid (0.29 g) and [(1-ethylpyrazole-4 -Yl) methyl] (4-isopropylphenyl) amine (0.37 g)

20 As starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -6,7,8,9-tetrahydro-5H- benzocyclohepten-5-carboxamide (0 , 36 g).

1H – NMR (CDCl3) δ: 1.22 (6H, d, J = 6.9Hz), 1.47 (3H, t, J = 7.3Hz), 1.60–1.74 (4H, m) 1.79–1.91 (1H, m), 1.92–2.02 (1H, m), 2.12–2.24 (1H, m), 2.48–2.60 (1H, m ), 2.85 (1H, sept, J = 6.9Hz), 3.66 (1H, dd, J = 1.5, 9.6Hz), 4.14 (2H, q, J = 7.3Hz) , 4.63 (1H, d, J = 13.9Hz), 4.83 (1H, d, J = 13.9Hz), 6.61–6.77 (2H, m), 6.93–7, 13 (6H, m), 7.32 (1H, s), 7.45 (1H, s).

Example 71

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5 By reaction and treatment in the same manner as in Example 12 using chroman-4-carboxylic acid (0.27 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (0.52 g) was obtained.

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 1.86-1.98 (1H, m) , 2.10-2.22 (1H, m), 2.94 (1H, Sept, J = 6.9Hz), 3.76 (1H, t, J = 6.2Hz) 3.92-4.03 (1H, m), 4.13 (2H, q, J = 7.3Hz), 4.39-4.49 (1H, m), 4.62 (1H, d, J

10 = 13.9Hz), 4.80 (1H, d, J = 13.9Hz), 6.74–6.89 (3H, m), 7.00–7.12 (3H, m), 7, 25 (2H, d, J = 8.4Hz), 7.32 (1H, s), 7.38 (1H, s).

Example 72

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Through reaction and treatment in the same manner as in Example 12 using 6-methoxychroman acid–

15 4-carboxylic (0.31 g) s and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazole) was obtained 4-yl) methyl] -N- (4-isopropylphenyl) -6-methoxychroman-4-carboxamide (0.39 g).

1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 1.85-1.97 (1H, m) , 2.12-2.24 (1H, m), 2.94 (1H, sept, J = 6.9Hz), 3.67 (3H, s), 3.74 (1H, t, J = 6, 2Hz), 3.87–3.99 (1H, m), 4.12 (2H, q, J = 7.3Hz), 4.33-4.45 (1H, m), 4.57 (1H, d, J = 13.9Hz), 4.85 (1H, d, J = 13.9Hz), 6.40 (1H, d, J = 2.4Hz), 6.62–6.76 (2H, m ), 7.06 (2H, d, J = 8.4Hz),

20 7.25 (2H, d, J = 8.4Hz), 7.32 (1H, s) 7.41 (1H, s).

Example 73 By reaction and treatment in the same manner as in Example 12 using 7-isopropyl-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.33 g) and [(1-ethylpyrazole -4-yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -7 was obtained -Isopropyl-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.46 g).

image 1

1H-NMR (CDCl3) δ: 1.17 (6H, dd, J = 2.6, 6.9Hz), 1.25 (6H, d, J = 6.9Hz), 1.41-1.57 ( 1H, m), 1.46 (3H, t, J = 7.3Hz), 1.82-2.07 (3H, m), 2.68-2.80 (2H, m), 2.92 ( 1H, sept, J = 6.9Hz), 3.71 (1H, t, J = 6.2Hz), 4.12 (2H, q, J = 7.3Hz), 4.43 (1H, d, J = 13.9Hz), 5.01 (1H, d, J = 13.9Hz), 6.74 (1H, s), 6.95 (1H, d, J = (0.8Hz) 7.07 (2H , d, J = 8.4Hz), 7.22 (2H, d, J = 8.4Hz), 7.36 (1H, s), 7.46 (1H, s).

Example 74

image4

By reaction and treatment in the same manner as in Example 4 using 7-methyl-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.29 g) and [(1-ethylpyrazole-4 -Yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -7-methyl was obtained –1,2,3,4 – tetrahydronaphthalen – 1– carboxamide (0.41 g). Melting point: 110-112 ° C.

15 Example 75

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By reaction and treatment in the same manner as in Example 37 using 7-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.48 g), N - ((1-ethylpyrazol-4-yl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3, 4 – tetrahydronaphthalen – 1 – carboximide (0.34 g).

20 fusion: 169-170 ° C.

Example 76

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By reaction and treatment in the same manner as in Example 37 using 4-benzyloxy-N - [(1-ethylpyrazol-4-yl) metih] -N- (4-isopropylphenyl) indan-1-carboxamide ( 0.70 g), N - [(1-ethylpyrazol-4-yl) methyl] -4-4 hydroxy-N- (4-isopropylphenyl) indan-1-carboxamide (0.51 g) was obtained. Melting point: 205–206 ° C.

Example 77

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By reaction and treatment in the same manner as in Example 37 using 6-benzyloxy-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.56 g), N - [(1- ethylpyrazol-4-yl) methyl] -6-hydroxy-N- (4-isopropylphenyl) -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.42 g). Melting point: 146-147 ° C.

Example 78

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Through reaction and treatment in the same manner as in Example 4 using 5-methoxyindan-1– acid

10 carboxylic (0.29 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.37 g) as starting materials, N - [(1-ethylpyrazole-4–) was obtained il) methyl] -N- (4-isopropylphenyl) -5-methoxyindan-1-carboxamide (0.47 g) Melting point: 115-116 ° C.

Example 79

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By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.26 g) and [(1-benzylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.46 g) as starting materials, N - [(1-benzylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.55 g).

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.39-1.55 (1H, m), 1.82-2.0.2 (3H, m) , 2.58–2.70 (1H, m), 2.78–2.98

20 (2H, m), 3.71 (1H, t, J = 6.2Hz), 4.61 (1H, d, J = 13.9Hz), 4.83 (1H, d, J = 13.9Hz ), 5.26 (2, H, s), 6.88 (1H, d, J = 8.4Hz), 6.98–7.13 (5H, m), 7.16–7.24 (4H , m), 7.28-7.43 (2H, m).

Example 80 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.56 g) and [(1-benzylpyrazole -4-yl) methyl] (4-isopropylphenyl) amine (0.61 g) as starting materials, benzyloxy-N - [(1-benzylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) was obtained –1,2,3,4–

image 1

5 tetrahydronaphthalen-1-carboxamide (0.67 g).

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.38-1.53 (1H, m), 1.77-2.07 (3H, m), 2 , 67-2.77 (2H, m), 2.91 (1H, sept, J = 6.9Hz), 3.70 (1H, t, J = 6.2Hz), 4.58 (1H, d, J = 13.9Hz), 4.84 (1H, d, J = 13.9Hz), 5.02 (2H, s), 5.26 (2H, s), 6.54 (1H, d, J = 7.7Hz), 6.69 (1H, d, J = 7.7Hz), 6.93-7.07 (3H, m) 7.13-7.4.7 (14H, m).

By reaction and treatment in the same manner as in Example 37 using 5-benzyloxy-N - [(1–

10 benzylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g), N - [(1-benzylpyrazole-4-] was obtained il) methyl) -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.47 g). Melting point: 130.1 ° C.

Example 81

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By means of the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.39 g) and (4-isopropylphenyl) [ (6-methoxypyridin-3-yl) methyl] amine (0.35 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(6-methoxypyridin-3-yl) methyl was obtained ] –1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.36 g).

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.57 (1H, m), 1.78-2.10 (3H, m), 2 , 70-2.80 (1H, m), 2.90 (1H, sept,

20 J = 6.9Hz), 3.74 (1H, t, J = 6.2Hz), 3.93 (3H, s), 4.79 (1H, d, J = 13.9Hz), 4.89 (1H, d, J = 13.9Hz), 5.03 (2H, s), 6.62 (1H, d, J = 7.5Hz), 6.67 (2H, m), 6.97–7 , 12 (3H, m), 7.17–7.47 (7H, m), 7.63 (1H, dd, J = 2.4, 8.4Hz), 7.89 (1H, d, J = 2.4Hz)

By reaction and treatment in the same manner as in Example 37 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(6-methoxypyridin-3-yl) methyl] -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.36 g), 5–

25 hydroxy-N- (4-isopropylphenyl) -N - [(6-methopyridin-3-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.25 g): Melting point: 157.9 ° C.

Example 82

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1- (tert-Butyloxycarbonyl) -4- (hydroxymethyl) pyrazole (3.98 g) was dissolved in methylene chloride (50 mL) and methanesulfonyl chloride (1.63 mL) was added under ice cooling. The mixture was stirred at room temperature for one day. The reaction mixture was concentrated and divided into water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue (4.20 g). A white amorphous solid (5.20 g) obtained by reaction and treatment in the same manner as in Example 6 using the residue and N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen- 1-carboxamide (5.96 g) was dissolved in 4 moles / L-HCl / dioxane (50 mL). The mixture was stirred at room temperature for 3 h and the reaction mixture was concentrated under reduced pressure. Ethyl acetate and hexane were added to the residue. The precipitated solid was collected

10 by filtration to give N- (4-isopropylphenyl) -7-methoxy-N - [(pyrazol-4-yl) methyl) -N-1,2,3,4-tetrahydronaphthalen-1-carboxamide (4, 17 g)

1H-NMR (CDCl3) δ: 1.19 (6H, d, J = 6.9Hz), 1.25-1.42 (1H, m), 1.78-1.98 (3H, m), 2 , 46–2.71 (2H, m), 2.91 (1H, sept, J = 6.9Hz), 3.60 (1H, t, J = 6.2Hz), 3.66 (3H, s) , 4.70 (1H, d, J = 13.9Hz), 4.81 (1H, d, J = 13.9Hz), 5.24 (2H, s), 6.42 (1H, d, J = 2.4Hz), 6.69 (1H, dd, J = 2.4, 8.4Hz), 6.95 (1H, d, J = 8.4Hz), 7.24 (2H, d, J = 8 , 4Hz), 7.34 (2H, d, J =

15 8.4Hz), 7.83 (2H, s).

Example 83

image 1

N- (4-Isopropylphenyl) -7-methoxy-N - ((pyrazol-4-yl) methyl) 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.44 g) and cyclopentyl bromide ( 0.12 mL) in DMF (5 mL) and sodium hydride (0.09 g) was added under cooling with

20 ice The mixture was stirred at the same temperature for 30 min and then at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N - [(1-cyclopentylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -7- methoxy-1,2, 3,4-tetrahydronaphthalen-1-carboxamide (0.38 g).

1 H NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m, 1.62-2.20 (11H, m), 2 , 52-2.65 (1H, m), 2.70-2.84 (1H, m), 2.89 (1H, sept J = 6.9Hz), 3.66 (3H, s), 3, 70 (1H, t, J = 6.2Hz), 4.50 (1H, d, J = 13.9Hz), 4.60 (1H, quint, J = 6.9Hz), 4.92 (1H, d , J = 13.9Hz), 6.43 (1H, d, J = 2.4Hz), 6.66 (1H, dd, J = 2.4, 8.4Hz) 6.94 (1H, d, J = 8.4Hz), 7.05 (2H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.4Hz), 7.34 (2H, s), 7.44 (2H , s).

Example 84 By reaction and treatment in the same manner as in Example 83 using N- (4-isopropylphenyl) -7- methoxy-N - [(pyrazol-4-yl) methyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.44 g) and isopropyl iodide (0.11 mL) as starting materials, N- (4-isopropylphenyl) -N - [(1-isopropylpyrazol-4-yl) was obtained ) methyl] –7 – methoxy, 1,2,3,4–

image 1

5 tetrahydronaphthalen-1-carboxamide (0.26 g).

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.36-1.53 (1H, m), 1.47 (6H, d, J = 6.9Hz) , 1.79-2.06 (3H, m), 2.52-2.65 (1H, m), 2.70-2.84 (1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.68 (3H, s), 3.70 (1H, t, J = 6.2Hz), 4.44 (1H, quint, J = 6.9Hz), 4.50 (1H, d, J = 13.9Hz), 4.94 (1H, d, J = 13.9Hz), 6.43 (1H, d, J = 2.4Hz), 6.66 (1H, dd, J = 2 , 4, 8.4Hz), 6.94 (1H, d, J = 8.4Hz), 7.05 (2H, d, J = 8.4Hz), 7.22 (2H, d, J = 8, 4Hz), 7.35 (2H, s), 7.44 (2H, s).

10 Example 85

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By reaction and treatment in the same manner as in Example 83 using N- (4-isopropylphenyl) -7- methoxy-N - [(pyrazole-4-yl) methyl] -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (0.44 g) and ethyl iodide (0.09 mL) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) was obtained ) –7 – methoxy – 1,2,3,4–

Tetrahydronaphthalen-1-carboxamide (0.31 g). This was dissolved in ethyl acetate and oxalic acid (0.07 g) was added. The precipitated solid was collected by filtration to give N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -7-methoxy-oxalate (0.06 g).

1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.36-1.53 (1H, m), 1.32 (3H, t, J = 6.9Hz) , 1.77-1.98 (3H, m), 2.47-2.70 (2H, m), 2.90 (1H, sept, J = 6.9Hz), 3.59 (1H, t, J = 6.2Hz), 3.64 (3H, s), 4.07 (2H, q, J = 6.9Hz), 4.56 (1H, d, J =

20 13.9Hz), 4.80 (1H, d, J = 13.9Hz), 6.41 (1H, d, J = 2.4Hz), 6.69 (1H, dd, J = 2.4, 8.4Hz), 6.94 (1H, d, J = 8.4Hz), 7.19 (2H, d, J = 8.4Hz), 7.27 (1H, s), 7.33 (2H, d, J = 8.4Hz), 7.53 (1H, s).

Example 86

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By reaction and treatment in the same manner as in Example 83 using N- (4-isopropylphenyl) -7–

25 methoxy-N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.44 g) and propyl iodide (0.01 mL) as starting materials, N- (4-isopropylphenyl) -N - [(1-propylpyrazol-4-yl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.31 g) was obtained.

1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 6.9Hz), 1.24 (6H, d, J = 6.9Hz), 1.38-1.54 (1H, m) , 1.77-2.04 (5H, m), 2.52-2.64 (1H, m), 2.70-2.84 (1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.65-3.75 (1H, m), 3.68 (3H, s), 4.02 (2H, t, J = 6.9Hz), 4.07 (2H, q, J = 6.9Hz), 4.55 (1H, d, J = 13.9Hz), 4.88 (1H, d, J = 13.9Hz), 6.44 (1H, d, J = 2.4Hz ), 6.66 (1H, dd, J = 2.4, 8.4Hz), 6.95 (1H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.4Hz) , 7.22 (2H, d, J = 8.4Hz), 7.35 (1H, s), 1.40 (1H, s).

Example 87

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By reaction and treatment in the same manner as in Example 82 using 1– (tert-butyloxycarbonyl) -4- (hydroxymethyl) pyrazole (578 mg) and 5-benzyloxy-N- (6-isopropylpyridin-3– il) –1,2,3,4– tetrahydronaphthalen – 1-carboxamide (1.17 g) as starting materials, 5-benzyloxy-N- hydrochloride (6–

10 isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (790 mg). Melting point: 184.7 ° C.

Example 88

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By reaction and treatment in the same manner as in Example 83 using 5– hydrochloride

15 benzyloxy-N- (6-isopropylpyridin-3-yl) -N [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.79 g) and ethyl iodide (0.12 mL) as starting materials, 5-benzyloxy-N - ((1-ethylpyrazol-4-yl) methyl) -N- (6- isopropylpyridin-3-yl) -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.43 g).

1H – NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 1.40–1.57 (1H, m) , 1.75-2.07 (3H, m), 2.65-2.77 (2H, m), 2.72 (1H, sept, J = 6.9Hz), 3.64 (1H, t, J = 6.2Hz), 4.14 (2H, q, J = 7.3Hz), 4.61 (1H, d, J = 13.9Hz), 4.85 (1H,

20 d, J = 13.9Hz), 5.03 (2H, s), 6.53 (1H, d, J = 7.7Hz), 6.72 (1H, d, J = 7.7Hz), 7 , 03 (1H, t, J = 7.7Hz), 7.24-7.43 (8H, m), 8.39 (1H, d, J = 1.5Hz).

Example 89

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By reaction and treatment in the same manner as in Example 37 using 5-benzyloxy-N - [(1-25 ethylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.43 g), N- [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3– was obtained il) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.33 g). Melting point: 172.8 ° C.

Example 90

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5 To a solution of N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (29.9 g) in ethanol ( 300 mL) 4 moles / L-HCl / dioxane (17.5 mL) was added at 0 ° C. The precipitated white solid was collected by filtration and recrystallized from ethanol: water (2: 3) to give N- [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2 hydrochloride , 3,4-tetrahydronaphthalen-1-carboxamide 1/2 hydrate (24.1 g). Melting point: 146.9 ° C.

10 Example 91

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(R) -7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.65 g) and [(4-dimethylaminophenyl) methyl) (4-isopropylphenyl) amine (1.0 g) se They were reacted and treated in the same manner as in Example 12. The solid obtained was dissolved in ethyl acetate. To this was added 4 moles / L-HCl / ethyl acetate (1 mL). The solvent is

15 evaporated under reduced pressure. The precipitated solid was recrystallized twice from ethanol to give (R) -N- [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen- hydrochloride 1-carboxamide 1/2 ethanol (0.20 g). Melting point: 151–159 ° C Optical purity 99.8% e.e.

20 Analysis conditions Column: Chiralcel OD (DAICEL) Development solvent: hexane / isopropanol = 85/15 Flow rate: 0.5 mL / min UV detection: 254 nm

25 Retention time: 26 min [α] D = + 113.5 ° (24 ° C, methanol, c = 1.0) Example 92

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By reaction and treatment in the same manner as in Example 91 using (S) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.95 g) and [(4 –Dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (1.48 g) as starting materials, (S) -N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) –7 hydrochloride was obtained –Methoxy–

5 1,2,3,4-tetrahydronaphthalen-1-carboxamide 1/2 ethanol (1.09 g). Melting point: 154–159 ° C 99.5% optical purity e.e, Analysis Conditions Column: CHIRALCEL OD (DAICEL) Development solvent: hexane / isopropanol = 85/15

10 Flow rate: 0.5 mL / min UV detection: 254 nm Retention time: 21.5 min [α] D = 113.1 ° (20 ° C, -methanol, c = 1.0) Example 93

image3

By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.63 g) and (4-acetylphenyl) [( 4-methoxyphenyl) methyl] amine (0.78 g) as starting materials, N- (4-acetiiphenyl) -7-methoxy-N - [(4-methoxyphenyl) methyl] -1,2,3,4 was obtained (0.33 g).

1H-NMR (CDCl3) δ: 1.39-1.57 (1H, m) 1.81-2.08 (3H, m), 2.59 (3H, s), 2.70-2.85 ( 1H, m), 3.60–3.70 (1H, m), 3.72

20 (3H, s), 3.79 (3H, s), 4.75 (1H, d, J = 13.9Hz), 5.07 (1H, d, J = 13.9Hz), 6.50 ( 1H, d, J = 2.4Hz), 6.69 (1H, dd, J = 2.4, 8.4Hz), 6.76-6.86 (2H, m), 6.97 (2H, d , J = 8.4Hz), 7.10–7.22 (4H, m), 7.90–7.98 (2H, m).

Example 94

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5

10

fifteen

twenty

25

30

Through reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.41 g), {[4– ( diethoxymethyl) phenyl] methyl} (4-isopropylphenyl) amine (0.65 g) as starting materials. The obtained residue was dissolved in a mixed solvent (15 mL) of methanol: 1 mol / L hydrochloric acid (1: 2) and reflux was heated for 3 h. The reaction mixture was concentrated under reduced pressure and divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N- [(4-formylphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.42 g).

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.58 (1H, m), 1.85-2.10 (3H, m), 2 , 50-2.63 (1H, m), 2.70-2.85 (1H, m), 2.89 (1H, sept, J = 6.9Hz), 3.71 (3H, s), 3 , 75–3.84 (1H, m), 4.89 (1H, d, J = 13.9Hz), 5.10 (1H, d, J = 13.9Hz), 6.53 (1H, d, J = 2.4Hz), 6.68 (1H, dd, J = 2.4, 8.4Hz), 6.96 (1H, d, J = 8.4Hz), 7.02 (2H, d, J = 8.4Hz), 7.20 (2H, d, J = 8.4Hz), 7.45 (2H, d, J = 8.4Hz), 7.81 (2H, d, J = 8.4Hz) , 9.98 (1H, s).

Example 95

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N - [(4-Formylphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.42 g) was dissolved in a mixed solvent (10 mL) of ethanol: tetrahydrofuran (2: 1) and sodium borhydride (0.15 g) was added under ice cooling. The mixture was stirred at room temperature for 3 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N- {[4 (hydroxymethyl) phenyl] methyl) -N- (4-isopropylphenyl) -7-methoxy-1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.25 g). Melting point: 143.2 ° C.

1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.58 (1H, m), 1.82-2.10 (3H, m), 2 , 51-2.65 (1H, m), 2.72-2.87 (1H, m), 2.89 (1H, sept, J = 6.9Hz), 3.71 (3H, s), 3 , 68–3.79 (1H, m), 4.68 (2H, s), 4.75 (1H, d, J = 13.9Hz), 5.08 (1H, d, J = 13.9Hz) , 6.52 (1H, d, J = 2.4Hz), 6.68 (1H, dd, J = 2.4, 8.4Hz), 6.92–7.06 (3H, m), 7, 18 (2H, d, J = 8.4Hz), 7.26-7.37 (4H, m).

Example 96

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By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.62 g) and [(4-bromophenyl) methyl ] (4-octylphenyl) amine (1.12 g) as starting materials, N - [(4bromophenyl) methyl] -7-methoxy-N- (4-octylphenyl) -1,2,3,4-tetrahydronaphthalen was obtained –1 – carboxamide (1.15 g).

1H-NMR (CDCl3) δ: 0.87 (3H, t, J = 4.5Hz), 1.20-1.38 (12H, m), 1.42-1.58 (1H, m), 1 , 82-2.08 (3H, m), 2.52-2.65 (3H, m), 2.71-2.85 (1H, m), 3.70 (3H, s), 3.67 –3.81 (1H, m), 4.72 (1H, d, J = 14.1Hz), 5.00 (1H, d, J = 14.0Hz), 6.48 (1H, d, J = 2.5Hz), 6.68 (1H, dd, J = 2.6, 8.4Hz), 6.91–7.01 (3H, m), 7.10–7.18 (4H, m), 7.37-7.45 (2H, m).

Example 97 By reaction and treatment in the same manner as in Example 12 using 8- (benzyloxy) chroman-4-carboxylic acid (0.47 g) and (4-isopropylphenyl) [(6-methoxypyridin-3 -Yl) methyl] amine (0.43 g) as starting materials, 8-benzyloxy-N- (4-isopropylphenyl) -N - [(6-methoxypyridin-3-yl) methyl) chroman-4- was obtained

image 1

5 carboxamide (0.61 g).

1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.88-2.02 (1H, m), 2.1-2.24 (1H, m), 2 , 91 (1H, sept, J = 6.9Hz), 3.79 (1H, t, J = 6.3Hz), 3.92 (3H, s), 4.05-4.16 (1H, m) , 4.51-4.61 (1H, m), 4.78 (1H, d, J = 13.9Hz), 4.87 (1H, d, J = 13.9Hz), 5.12 (2H, s), 6.48–6.57 (1H, m) 6.65–6.75 (3H, m), 6.98 (2H, d, J = 8.4Hz), 7.19–7.43 (7H, m), 7.60 (1H, dd, J = 2.4, 8.4Hz), 7.88 (1H, d, J = 2.4Hz).

10 Example 98

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By reaction and treatment in the same manner as in Example 17 using 8-benzyloxy-N- (4-isopropylphenyl) -N - [(6-methoxypyridin-3-yl) methyl] chroman-4-carboxamide ( 0.58 g) as a starting material, 8-hydroxy-N- (4-isopropylphenyl) -N - [(6-methoxypyridin-3-ylmethyl] chroman-4-carboxamide (0.35 g) was obtained. fusion:

15 141.2 ° C.
Example 99 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.42 g) and [(2,6-dimethoxypyridine –3 – yl) methyl] (4-isopropylphenyl) amine (0.43 g)
20 as starting materials, 5-benzyloxy-N - [(2,6-dimethoxypyridin-3-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4- tetrahydronaphthalen-1-carboxamide was obtained (0.71 g).
Through reaction and treatment in the same manner as in Example 17 using this compound (0.70 g), N - [(2,6-dimethoxypyridin-3-yl) methyl] -5-hydroxy- was obtained N– (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.41 g). Melting point: 190.5 ° C.
Example 100 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.42 g) and (4-isopropylphenyl) ) [(6-Phenoxypyridin-3-yl) methyl] amine (0.47 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(6-phenoxypyridin-3-yl] ) methyl] –1,2,3,4– image 1
5 tetrahydronaphthalen-1-carboxamide (0.42 g).
1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 6.9Hz), 1.38-1.55 (1H, m), 1.77-2.09 (3H, m), 2 , 67–2.87 (2H, m), 2.88 (1H, sept, J = 6.9Hz), 3.70–3.80 (1H, m), 4.82 (1H, d, J = 14.2Hz), 4.90 (1H, d, J = 14.2Hz), 5.01 (2H, s), 6.62 (1H, d, J = 7.7Hz), 6.74 (1H, d, J = 8.5Hz), 6.85 (1H, d, J = 8.5Hz), 6.97-7.42 (15H, m), 7.71-7.79 (1H, m), 7.94 (1H, d, J = 2.3Hz).
10 Example 101 image 1
To a solution of 5-benzyloxy-N- (4-isopropylphenyl) -N - [(6-phenoxypyridin-3-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.42 g) in methanol (3 mL) 10% palladium on carbon (0.05 g) and ammonium formate (0.23 g) were added and the mixture was stirred at room temperature for one day. The reaction mixture was filtered and the solvent
15 evaporated. The residue was purified by silica gel column chromatography to give 5-hydroxy-N- (4-isopropylphenyl) -N - [(6-phenoxypyridin-3-yl) methyl] –1,2,3,4-tetrahydronaphthalen –1 – carboxamide. This compound was dissolved in ethyl acetate and 4 moles / L-hydrochloric acid / dioxane (0.20 mL) were added. The precipitated solid was collected by filtration to give 5-hydroxy-N- (4-isopropylphenyl) -N - [(6-phenoxypyridin-3-yl) methyl] –1,2,3,4– tetrahydronaphthalen – 1– hydrochloride carboxamide (0.11 g).
20 1H – NMR (DMSO – d6) δ: 1.19 (6H, d, J = 6.9Hz), 1.27–1.43 (1H, m), 1.73–2.00 (3H, m ), 2.67-2.87 (2H, m), 2.89 (1H, sept, J = 6.9Hz), 3.51-3.71 (1H, m), 4.79 (1H, d , J = 14.7Hz), 4.92 (1H, d, J = 14.7Hz), 6.46 (1H, d, J = 7.5Hz), 6.62 (1H, d, J = 7, 8Hz), 6.84-6.92 (1H, m), 7.00 (1H, d, J = 8.4Hz), 7.07-7.47 (9H, m), 7.70 (1H, dd, J = 2.4, 8.4Hz), 7.91 (1H, d, J = 2.1Hz).
Example 102 image6
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.56 g) and [(6-dimethylaminopyridine-3 -Yl) methyl] (4-isopropylphenyl) amine (0.54 g) as starting materials, 5-benzyloxy-N - [(6-dimethylaminopyridin-3-yl) methyl) -N- (4-isopropylphenyl) was obtained - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g).
1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.38-1.53 (1H, m), 1.77-2.10 (3H, m), 2 , 61–2.78 (2H, m), 2.89 (1H, sept, J = 6.9Hz), 3.08 (6H, s) 3.67–3.77 (1H, m), 4, 71 (1H, d, J = 14.1Hz), 4.85 (1H, d, J = 14.1Hz), 5.03 (2H, s), 6.48 (1H, d, J = 8.7Hz ), 6.64 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 6.95–7.09 (3H, m) 7.19 (2H, d, J = 8.4Hz), 7.23–7.44 (5H, m), 7.54 (1H, dd, J = 2.4, 8.7Hz), 7.86 (1H, d, J = 2.1Hz)
Example 103 image 1
By reaction and treatment in the same manner as in Example 17 using 5-benzyloxy-N - [(6- dimethylaminopyridin-3-yl) methyl] -N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.83 g) as starting material, N - [(6-dimethylaminopyridin-3-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1, 2,3,4–
10 tetrahydronaphthalen-1-carboxamide (0.33 g). Melting point: 186.6 ° C
Example 104 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.85 g) and (4-isopropylphenyl) [( 1-phenylpyrazol-4-yl) methyl] amine (0.87 g) as
15 starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(1-phenylpyrazol-4-yl) methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1, 21 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.41-1.57 (1H, m), 1.80-2.10 (3H, m), 2 , 65–2.84 (2H, m), 2.93 (1H, sept, J = 6.9Hz), 3.71–3.82 (1H, m), 4.70 (1H, d, J = 14.4Hz), 4.92 (1H, d, J = 14.4Hz), 5.03 (2H, s), 6.60 (1H, d, J = 7.7Hz), 6.71 (1H, d, J = 8.1Hz), 7.00–7.16 (3H, m), 7.22–7.48 (10H, m), 7.58 (1H, s), 7.66 (2H, d, J = 7.6Hz), 7.95
20 (1H, s).
Example 105 image 1
To a solution of 5-benzyloxy-N- (4-isopropylphenyl) -N - [(1-phenylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.04 g) in methanol (10 mL) 10% palladium on carbon (0.10 g) and ammonium formate were added
25 (0.59 g) and the mixture was stirred at room temperature for one day. The reaction mixture was filtered and the solvent evaporated. The residue was purified by silica gel column chromatography to give 5-hydroxy-N- (4-isopropylphenyl) -N - [(1-phenylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen –1 – carboxamide (0.76 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.36-1.51 (1H, m), 1.78-2.08 (3H, m),, 2.50–2.71 (2H, m), 2.93 (1H, sept, J = 6.9Hz), 3.70–3.81 (1H, m), 4.72 (1H, d, J = 14.4Hz), 4.94 (1H, d, J = 14.4Hz), 6.36 (1H, d, J = 7.8Hz), 6.42 (1H, d, J = 7.5Hz) , 6.75 (1H, d, J = 7.8Hz), 7.12 (1H, d, J = 8.4Hz), 7.21–7.33 (3, H, m), 7.39– 7.49 (2H, m), 7.53 (1H, brs), 7.59 (1H, s), 7.69 (2H, d, J = 7.5Hz), 8.01 (1H, s) .
Example 106 image 1
To a solution of N - [(4-dimethylaminophenyl) methyl] -6-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g) in dimethylformamide (10 mL) 2-Chloro-N hydrochloride, N-dimethylethylamine (0.26 g) and potassium carbonate (0.62 g) were added and the mixture was stirred with heating at 50 ° C for 3 h. The mixture of
The reaction was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 6– [2– (dimethylamino) ethoxy] N - [(4-dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) –1, 2,3,4 – tetrahydronaphthalen – 1– carboxamide 1/5 hydrate (0.1 g). Melting point: 132.6 ° C.
MS (ESI) m / z: 514 [MH] +
15 Example 107 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl] -6-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen –1 – carboxamide (0.66 g) and 2– bromoethanol (0.16 mL) as starting materials, N - [(4-dimethylaminophenyl) methyl] –6– (2-hydroxyethoxy) –N–
20 (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.28 g). Melting point: 141.4 ° C.
Example 108 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl] -5-hydroxyN- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1 –Carboxamide (0.66 g) and 2–
Bromoethanol (0.32 mL) as starting materials, N - [(4-dimethylaminophenyl) methyl] -5- (2-hydroxyethoxy) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen was obtained –1 – carboxamide (0.49 g).
1 H-NMR (CDCl 3) δ: 1.20-1.30 (6H, m), 1.35-1.50 (1H, m), 1.70-2.10 (3H, m), 2.60 –2.70 (2H, m), 2.80–3.00 (1H, m), 2.94 (6H, s) 3.65–3.75 (1H, m), 3.85 4.00 (2H, m), 4.00-4.10 (2H, m), 4.72 (1H, d, J = 13.8Hz), 4.91 (1H, d, J = 13.8Hz), 6 , 60–6.70 (4H, m), 6.90–7.20 (7H, m).
Example 109 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen –1 – carbocamide (0.5 g) and iodide
10 ethyl (0.14 mL) as starting materials, 7-ethoxy-N - {[4– (ethylmethylamino) phenyl] methyl} -N- (4-isopropylphenyl) -1,2,3,4– was obtained tetrahydronaphthalen-1-carboxamide (0.1 g).
1H-NMR (CDCl3) δ: 1.12 (3H, t, J = 7.2Hz), 1.23 (6H, d, J = 6.9Hz), 1.37 (3H, t, J = 6, 9Hz), 1.30–1.55 (1H, m), 1.80–2.10 (3H, m), 2.50–2.65 (1H, m), 2.70–3.00 ( 2H, m), 2.90 (3H, s), 3.39 (2H, q, J = 7.2Hz), 3.60–3.70 (1H, m), 3.75-4.00 ( 2H, m), 4.53 (1H, d, J = 13.8Hz), 5.08 (1H, d, J = 13.8Hz), 6.45-6.70 (4H, m), 6, 85–7.20 (7H, m)
15 Example 110 image 1
N - [(4-Dimethylaminophenyl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.5 g) and ethyl iodide (0.14 mL) were dissolved in dimethylformamide (5 mL) and sodium hydride (0.07 g) was added under ice cooling. The mixture was stirred at room temperature for 24 h. The reaction mixture was divided into
20 water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N - [(4-dimethylaminophenyl) methyl] -7-ethoxy-N- (4-isopropylphenyl) -1,002.4- tetrahydronaphthalen-1-carboxamide (0.27 g).
1H – NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.37 (3H, t, J = 7.0Hz), 1.30–1.60 (1H, m) , 1.80-2.10 (3H, m), 2.50-2.65 (1H, m), 2.70-3.00 (2H, m), 2.94 (6H, s), 3 , 60–3.75 (1H, m), 3.75–3.95 (2H, m), 4.54 (1H, d, J = 3.9Hz), 5.09 (1H, d,
J = 13.9Hz), 6.45-6.55 (1H, m), 6.60-6.70 (3H, m), 6.85-7.00 (3H, m), 7.05 –7.20 (4H, m).
Example 111 By reaction and treatment in the same manner as in Example 110 using N - [(4-dimethylaminophenyl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (0.5 g) and butyl bromide (0.18 mL) as starting materials, 7-butoxy-N - [(4-dimethylaminophenyl) methyl] –N– (4– isopropylphenyl) was obtained ) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.15 g). image 1
1H – NMR (CDCl3) δ: 0.98 (3H, t, J = 7.3Hz), 1.23 (6H, d, J = 6.9Hz), 1.40–1.60 (3H, m) , 1.65–2.10 (5H, m), 2.50–2.65 (1H, m), 2.70–3.00 (2H, m), 2.94 (6H, s), 3 , 65–3.70 (1H, m), 3.75–3.90 (2H, m), 4.54 (1H, d, J = 13.9Hz), 5.10 (1H, d, J = 13.9Hz), 6.45–6.55 (1H, m), 6.60–6.70 (3H, m), 6.85–7.00 (3H, m), 7.10–7, 20 (4H, m).
Example 112 image4
By reaction and treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl) -7-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen –1 – carboxamide (0.5 g) and 2– iodopropane (0.17 mL) as starting materials, N - [(4-dimethylaminophenyl) methyl] –7 – isopropoxy-N– (4– isopropylphenyl) was obtained - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (35 mg).
1 H-NMR (CDCl3) δ: 1.10-1.35 (12H, m), 1.35-1.55 (1H, m), 1.80-2.10 (3H, m), 2, 50-2.65 (1H, m), 2.70-3.00 (2H, m), 2.94 (6H, s), 3.60-3.80 (1H, m), 4.30– 4.45 (1H, m), 4.53 (1H, d, J = 13.8Hz), 5.10 (1H, d, J = 13.8Hz), 6.45–6.55 (1H, m ), 6.60–6.75 (3H, m), 6.85–7.05 (3H, m), 7.10–7.25 (4H, m).
Example 113 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl] -5-hydroxyN- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen- 1-carboxamide (0.66 g) and 2-chloro-N, N-dimethylethylamine hydrochloride (0.32 g) as starting materials, 5– [2– (dimethylamino) ethoxy] –N - [(4 –Dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.54 g). This compound was dissolved in ethyl acetate and oxalic acid was added. The precipitated solid was recrystallized from ethyl acetate to give 5– [2– (dimethylamino) ethoxy] –N - [(4-dimethylaminophenyl) methyl] –N– (4– isopropylphenyl) –1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide oxalate 1/4 hydrate (93: 8 mg). Melting point: 155.7 ° C.
Example 114 image 1
5 By reaction and treatment in the same manner as in Example 110 using N - [(4-dimethylaminophenyl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.5 g), 2-chloro-N hydrochloride, N-dimethylethylamine (0.36 g) and sodium iodide (0.51 g) as starting materials, 7– [2 –– (dimethylamino) ethoxy] -N - ((4-dimethylaminophenyl) methyl) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (36 mg).
10 1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.55 (1H, m), 1.70-2.05 (5H, m), 2.33 (6H, s), 2.50–2.95 (3H, m), 2.94 (6H, s), 3.60–3.70 (1H, m), 3.85–4, 05 (2H, m), 4.64 (1H, d, J = 13.9Hz), 4.99 (1H, d, J = 13.9Hz), 6.50-6.75 (4H, m), 6.90–7.20 (7H, m).
Example 115 image 1
By means of the reaction and the treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.66 g) and (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) methyl chloride (0.38 g) as starting materials, 5– [ (5,6– dihydroimidazo [2,1-b] thiazol-3-yl) methoxy-N - [(4– dimethylaminophenyl) methyl] –N– (4-isopropylphenyl) –1,2,3,4– tetrahydronaphthalen– 1-carboxamide (0.16 g).
1 H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.50 (1H, m), 1.75-2.10 (3H, m), 2.64 (2H, t, J = 6.6Hz), 2.85-2.95 (1H, m), 2.94 (6H, s), 2.65-2.75 (1H, m), 3.84 (2H, t, J = 9.3Hz), 4.23 (2H, t, J = 9.3Hz), 4.61 (2H, s), 4.72 (1H, d, J = 14 , 1Hz), 4.91 (1H, d, J = 14.1Hz), 5.67 (1H, s), 6.60–6.75 (4H, m), 6.90–7.20 (7H , m).
Example 116 By reaction and treatment in the same manner as in Example 106 using N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4 -Tetrahydronaphthalen-1-carboxamide (0.66 g) and 3-chloro-N, N-dimethylpropylamine hydrochloride (0.32 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] –5– [3– (dimethylamino) propoxy] -N- (4-isopropylphenyl) 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.5 g). Oxalic acid was added to this compound. By recrystallization from isopropyl alcohol, N - [(4– dimethylaminophenyl) methyl] –5– [3– (dimethylamino) propoxy] –N– (4-isopropylphenyl) –1,2,3,4 – tetrahydronaphthalen – 1– was obtained carboxamide oxalate 4/5 hydrate (0.18 g). Melting point: 100.8 ° C. image 1
Example 117 image4
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy– 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (2.3 g) and 4 - {[(4– Isopropylphenyl) amino] methyl} methyl benzoate (2.3 g) as starting materials, 4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (4-Isopropylphenyl) amino] methyl} methyl benzoate (2.56 g).
1 H-NMR (CDCl3) δ: 1.22 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.80-2.10 (3H, m), 2.70-2.76 (2H, m), 2.80-2.95 (1H, m), 3.72-3.82 (1H, m), 3.92 (3H, s), 4, 90 (1H, d, J = 14.2Hz), 5.04 (1H, d, J = 14.2Hz), 5.03 (2H, s) 6.64 (1H, d, J = 7.7Hz) , 6.73 (1H, d, J = 8.1Hz), 6.95–7.45 (12H, m), 7.97 (2H, d, J = 8.3Hz).
Example 118 image 1
20 Methanol (14 mL) and 1 mol / L of aqueous sodium hydroxide solution (7 mL) were added to 4 - {[N– (5-benzyloxy– 1,2,3,4-tetrahydronaphthalen – 1-ylcarbonyl) - N - (4-Isopropylphenyl) amino] methyl) methyl benzoate (2.56 g) and the mixture was stirred with heating at 50-60 ° C. After completing the reaction, the reaction mixture was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography of
25 silica gel to give 4 - {(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (4-isopropylphenyl) amino] methyl}} benzoic acid (2, g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.80-2.15 (3H, m), 2 , 70-2.80 (2H, m), 2.82-2.95 (1H, m), 3.72-3.85 (1H, m), 4.94 (1H, d, J = 14, 1Hz), 5.06 (1H, d, J = 14.1Hz), 5.03 (2H, s), 6.66 (1H, d, J = 7.8Hz), 6.73 (1H, d, J = 8.1Hz), 6.90–7.50 (12H, m), 8.04 (2H, d, J = 8.4Hz).
Example 119 image5
By reaction and treatment in the same manner as in Example 17 using 4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (4– isopropylphenyl) amine] methyl} benzoic acid (2 g) as a starting material, 4 - {[N– (5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (4– isopropylphenyl) amino] methyl} benzoic dihydrate (0.13 g). Melting point: 231.4 ° C.
10 Example 120 image 1
By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.7 g) and [(5-ethylthiophene-2-yl) methyl ] (4-Isopropylphenyl) amine (1.04 g) as starting materials, N - [(5-ethylthiophene-2-yl) methyl) -N- (4-isopropylphenyl) -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (0.18
15 g)
MS (ESI) m / z: 418 [MH] +
1H – NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.30 (3H, t, J = 7.5Hz), 1.40–1.60 (1H, m) , 1.80–2.10 (3H, m), 2.55–2.70 (1H, m), 2.82 (2H, q, J = 7.5Hz), 2.72–3.00 ( 2H, m), 3.65–3.80 (1H, m), 4.90 (1H, d, J = 14.6Hz), 5.03 (1H, d, J = 14.6Hz), 6, 56 (1H, d, J = 3.4Hz), 6.62 (1H, d, J = 3.4Hz), 6.90–7.30 (8H, m).
20 Example 121 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.13 g) and [(5-ethylthiophene-2 -Yl) methyl] (4-isopropylphenyl) amine (1.04 g) as starting materials, 5-benzyloxy-N - [(5-ethylthiophene-2-yl) methyl] -N- (4-isopropylphenyl) was obtained –1,2,3,4–
Tetrahydronaphthalen-1-carboxamide (1.01 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.29 (3H, t, J = 7.5Hz), 1.35-1.55 (1H, m) , 1.80–2.10 (3H, m), 2.81 (2H, q, J = 7.5Hz), 2.60–3.00 (3H, m), 3.70–3.80 ( 1H, m), 4.90 (1H, d, J = 14.4Hz), 5.03 (1H, d, J = 14.4Hz), 5.03 (2H, s), 6.50–6, 75 (4H, m), 7.00–7.12 (3H, m), 7.15–7.50 (7H, m).
Example 122 image5
By reaction and treatment in the same manner as in Example 12 using 8-benzyloxychroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0, 51 g) as starting materials, 8-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-carboamide (1 g) was obtained.
MS (ESI) m / z: 535 [MH] +
By reaction and treatment in the same manner as in Example 17 using this compound, N - [(4-dimethylaminophenyl) methyl] -8-hydroxy-N- (4-isopropylphenyl) chroman-4- was obtained carboxamide (0.7 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.90-2.30 (2H, m), 2.85-3.10 (1H, m), 2 , 94 (6H, s), 3.70–3.85 (1H, m), 4.00–4.20 (1H, m), 5.00–5.15 (1H, m), 4.70 (1H, d, J = 13.8Hz), 4.90 (1H, d, J = 13.8Hz), 5.47 (1H, s), 6.45-6.85 (5H, m), 6 , 90–7.30 (6H, m).
15 Example 123 image 1
By reaction and treatment in the same manner as in Example 12 using 7-benzyloxychroman-4-carboxylic acid (0.6.g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0 , 57 g) as starting materials, 7-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (1.2 g) was obtained.
1 H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.80-2.00 (1H, m), 2.05-2.25 (1H, m), 2.85-3.05 (1H, m), 2.94 (6H, s), 3.65-3.75 (1H, m), 3.90-4.05 (1H, m), 4, 40 4.55 (1H, m), 4.69 (1H, d, J = 13.9Hz), 4.91 (1H, d, J = 13.9Hz), 4.99 (2H, s), 6 , 40–7.45 (16H, m).
Example 124 By reaction and treatment in the same manner as in Example 17 using 7-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (1, 0 g) as a starting material, N- [(4-dimethylaminophenyl) methyl] -7-hydroxy-N- (4-isopropylphenyl) chroman-4-carboxamide (0.54 g) was obtained. Melting point: 173.1 ° C. image 1
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.80-2.00 (1H, m), 2.10-2.25 (1H, m), 2 , 94 (6H, s), 2.80–3.05 (1H, m) 3.65–3.75 (1H, m), 3.85–4.00 (1H, m), 4.35– 4.50 (1H, m), 4.77 (1H, d, J = 13.9Hz), 4.86 (1H, d, J = 13.9Hz), 5.87 (1H, s), 6, 18 (1H, d, J = 2.5Hz), 6.26 (1H, dd, J = 2.5Hz, 8.3Hz), 6.60-7.30 (9H, m).
Example 125 image 1
By reaction and treatment in the same manner as in Example 12 using 8-cyanochroman-4-carboxylic acid (0.7 g) and [(4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0 , 92 g) as starting materials, 8-cyano-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (1.0 g) was obtained. Melting point: 178.8 ° C.
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.80-2.30 (2H, m), 2.80-3.10 (1H, m), 2 , 94 (6H, s), 3.65–3.80 (1H, m), 4.10-4.25 (1H, m), 4.55-4.70 (1H, m), 4, 72 (1H, d, J = 13.8Hz), 4.85 (1H, d, J = 13.8Hz), 6.60-7.50 (11H, m).
Example 126 image 1
8-Cyano-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (0.9 g) was dissolved in acetone (12.8 mL) and 1 mol / L was added of aqueous solution of sodium hydroxide (6.4 mL) and aqueous hydrogen peroxide
20 to 30% (3.8 mL)). The mixture was heated at reflux for 2 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 8-carbamoyl-N - [(4-dimethylaminophenyl) methyl) -N- (4-isopropylphenyl) chroman-4-carboxamide (21 mg) .
MS (ESI) m / z: 472 [MH] +
1 H NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.90-2.25 (2H, m), 2.80-3.10 (1H, m), 2.94 (6H, s), 3.75-3.90 (1H, m), 4.10-4.30 (1H, m) 4.60-4.80 (1H, m), 4.72 (1H, d, J = 13.9Hz), 4.88 (1H, d, J = 13.9Hz), 5.87 (1H, brs), 6.55-6.70 (2H, m), 6 , 85–7.30 (8H, m), 7.73 (1H, brs), 8.04 (1H, dd, J = 1.6, 7.7Hz).
Example 127 By reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl] ) methyl] (4-isopropylphenyl) amine (0.57 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -7-fluoro-N- (4-isopropylphenyl) -1,2,3 was obtained ,4- image 1
5 tetrahydronaphthalen-1-carboxamide (0.85 g). This compound was dissolved in ethyl acetate and 4 moles / L of HCl / dioxane were added. This precipitated solid was collected by filtration to give N- [(4-dimethylaminophenyl) methyl] -7-fluoro-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide hydrochloride (0, 85 g).
Melting point: 165.6 ° C
1H – NMR (DMSO – d6) δ: 1.19 (6H, d, J = 6.9Hz), 1.30–1.50 (1H, m), 1.70–2.00 (3H, m) , 2.40-2.75 (2H, m), 2.75-3.05
10 (1H, m), 2.99 (6H, s), 3.40–3.90 (1H, m), 4.75 (1H, d, J = 14.7Hz), 4.92 (1H, d, J = 14.7Hz), 6.70–6.85 (1H, m), 6.90–7.35 (10H, m).
Example 128 image 1
Through the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4– acid
Tetrahydronaphthalen-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl) methyl] (4-methoxyphenyl) amine (0.54 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] was obtained] –7 – fluoro – N– (4 – methoxyphenyl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide. This compound was dissolved in ethyl acetate and 4 moles / L of HCl / dioxane was added. The precipitated solid was collected by filtration to give N - [(4-dimethylaminophenyl) methyl] -7-fluoro-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide 1/2 hydrochloride hydrate (0.52 g). Melting point: 125.4 ° C.
20 Example 129 image 1
By reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.41 g) and (4-bromophenyl) [( 4-dimethylaminophenyl) methyl] amine (0.64 g) as starting materials, N- (4-bromophenyl) -N - [(4-dimethylaminophenyl) methyl)] - 7-fluoro-1,2,3, 4 – tetrahydronaphthalen – 1–
Carboxamide (0.26 g).
1H-NMR (CDCl3) δ: 1.40-1.70 (1H, m), 1.75-2.10 (3H, m), 2.55-2.90 (2H, m 2.95 (6H , s), 3.55-3.70 (1H, m), 4.71 (1H, d, J = 14.1Hz), 4.92 (1H, d, J = 14.1Hz), 6.60 –7.20 (9H, m), 7.40–7.60 (2H, m).
Example 130 image 1
5 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.5 g) and [( 4-dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0.45 g) as starting materials, 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -8-fluoro-N- (4-isopropylphenyl) was obtained ) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.73 g).
1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-2.10 (4H, m), 2.55-2.95 (3H, m), 2 , 94 (6H, s), 3.70–3.85 (1H, m), 10 4.71 (1H, d, J = 14.6Hz), 4.86 (1H, d, J = 14.6Hz ), 5.01 (2H, s), 6.60–6.85 (4H, m), 7.00–7.45 (11H, m).
Example 131 image 1
By reaction and treatment in the same manner as in Example 17 using 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -8-fluoro-N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.73 g) as
Starting material, N - [(4-dimethylaminophenyl) methyl] -8-fluoro-5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4- tetrahydronaphthalen-1-carboxamide (0, 19 g) Melting point: 209.0 ° C.
1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.65-2.05 (3H, m), 2 , 40–2.55 (1H, m), 2.60–2.80 (1H, m), 2.85–3.00 (1H, m), 2.94 (6H, s), 3.70 –3.80 (1H, m), 4.67 (1H, d, J = 14.1Hz), 4.98 (1H, d, J = 14.1Hz), 6.20–6.30 (1H, m), 6.40–6.55 (1H, m), 6.60–6.70 (2H, m), 6.90–7.20 (6H, m), 7.61 (1H, s) .
20 Example 132 image 1
The 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.03 g) was dissolved in dimethylformamide (27 mL) and sodium hydride was added (0.20 g) under ice cooling. The mixture was stirred at the same temperature for 30 min. A solution of 3-chloromethyl-2,6-dimethoxypyridine (0.95 g) in dimethylformamide 25 (6 mL) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 3 h. The
reaction mixture was partitioned in water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N - [(2,6-dimethoxypyridin-3-yl) methyl] -N- (6-isopropylpyridin-3-yl ) –1,2,3,4– tetrahydronaphthalen – 1-carboxamide (1.43 g).
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.40-1.65 (1H, m), 1.75-2.15 (3H, m), 2 , 60–2.80 (2H, m), 2.95–3.15 (1H, m), 3.55–3.75 (1H, m), 3.69 (3H, s), 3.89 (3H, s), 4.78 (1H, d, J = 14.1Hz), 4.97 (1H, d, J = 14.1Hz), 5.03 (2H, s), 6.25 (1H , d, J = 8.0Hz), 6.63 (1H, d, J = 7.7Hz), 6.12 (1H, d, J = 8.0Hz), 7.06 (1H, t, J = 7.9Hz), 7.14 (1H, d, J = 8.3Hz), 7.25–7.45 (6H, m), 7.55 (1H, d, J = 8.0Hz), 8, 30 (1H, d, J = 2.3Hz).
Example 133 image4
To a solution of 5-benzyloxy-N - [(2,6-dimethoxypyridinyl) methyl] -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g) in trifluoroacetic acid (2.4 mL) thioanisole (0.49 mL) was added and the mixture was stirred at room temperature for one day. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and partitioned with ethyl acetate. The organic layer was washed with saturated brine and dried over sulfate
15 anhydrous magnesium. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N - [(2,6-dimethoxypyridin-3-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl ) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.36 g).
Melting point: 164.0 ° C.
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.35-1.60 (1H, m), 1.75-2.10 (3H, m), 2 , 45–2.70 (2H, m), 2.95–3.15 (1H,
20 m), 3.60–3.75 (1H, m), 3.70 (3H, s), 3.89 (3H, s), 4.82 (1H, d, J = 141, Hz), 4.95 (1H, d, J = 14.1Hz), 6.08 (1H, 5), 6.26 (1H, d, J = 8.1Hz), 6.44 (1H, d, J = 7 , 8Hz), 6.51 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz), 7.16 (1H, d, J = 8.1Hz), 7 , 34 (1H, dd, J = 2.4Hz, 8.1Hz), 7.54 (1H, d, J = 8.1Hz), 8.31 (1H, d, J = 2.4Hz).
Example 134 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl) methyl] (6-isopropylpyridin-3-yl) amine (0.48 g) as starting materials, 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (6-isopropylpyridin-3-yl) was obtained ) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.39 g).
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.40-2.10 (4H, m), 2.60-3.10 (3H, m), 2 , 94 (6H, s), 3.55–3.70 (1H, m), 30 4.72 (1H, d, J = 14.6Hz), 4.96 (1H, d, J = 14.6Hz ), 5.04 (2H, s), 6.50–7.50 (14H, m), 8.30 (1H, d, J = 2.4Hz).
Example 135 By reaction and treatment in the same manner as in Example 17 using 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (6-isopropylpyridin-3-yl) -1.2 , 3,4-tetrahydronaphthalen-1-carboxamide (0.39 g) as starting material, N - [(4-dimethylaminophenyl) methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) was obtained - 1,2,3,4– image 1
5 tetrahydronaphthalen-1-carboxamide (60 mg).
MS (ESI) m / z: 444 [MH] +
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.40-1.70 (1H, m), 1.75-2.15 (3H, m), 2 , 50–2.70 (2H, m), 2.95 (6H, s), 3.00–3.10 (1H, m), 3.55–3.70 (1H, m 4.79 (1H , d, J = 14.1Hz), 4.89 (1H, d, J = 14.1Hz), 5.72 (1H, s), 6.40-8.30 (1H, d, J = 2, 1Hz)
10 Example 136 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.5 g) and [(4 –Dimethylaminophenyl) methyl] (4-isopropylphenyl) amine (0.45 g) as starting materials, 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) –8-methyl -
1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.6 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.50-1.75 (2H, m), 1.90-2.05 (2H, m, 2, 11 (3H, s), 2.45-2.60 (1H, m), 2.85-3.05 (2H, m), 2.93 (6H, s), 3.60-3.65 ( 1H, m), 4.64 (1H, d, J = 13.9Hz), 4.87 (1H, d, J = 13.9Hz), 5.02 (2H, s), 6.55-6, 70 (3H, m), 6.85-7.45 (12H, m).
Example 137 image2
By reaction and treatment in the same manner as in Example 133 using 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -8-methyl-1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.5 g) as starting material, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -8-methyl-1, 2,3,4– tetrahydronaphthalen-1-carboxamide (0.34 g). Melting point: 189.5 ° C.
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz) 1.50-1.75 (2H, m), 1.90-2.10 (2H, m), 2, 09 (3H, s), 2.30–2.50 (1H, m), 2.70–3.00 (2H, m), 2.93 (6H, s), 3.60–3.70 ( 1H, m), 4.72 (1H, d, J = 13.8Hz), 4.83 (1H, d, J = 13.8Hz), 5.72 (1H, s), 6.35-6, 75 (4H, m), 7.00–7.30 (6H, m).
Example 138 image5
By reaction and treatment in the same manner as in Example 132 using 5-chloromethyl-2-methoxypyridine (0.63 g) and 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -1, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.87 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(6-methoxypyridin-3– il) methyl] - 1, 2,3,4-tetrahydronaphthalen-1-carboxamide (1.23 g).
10 1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 7.0Hz), 1.40-1.60 (1H, m), 1.80-2.15 (3H, m), 2.65-2.80 (2H, m), 3.00-3.20 (1H, m), 3.60-3.75 (1H, m), 3.92 (3H, s), 4, 81 (1H, d, J = 14.3Hz), 4.90 (1H, d, J = 14.3Hz), 5.04 (2H, s), 6.50-6.80 (3H, m), 7.00–7.50 (7H, m), 7.60–7.70 (1H, m) 7.87 (1H, d, J = 2.2Hz), 8.02 (1H, s), 8 , 32 (1H, d, J = 2.3Hz).
Example 139 image 1
15 To a solution of 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- [6-methoxypyridin-3-yl] methyl] –1,2,3,4-tetrahydronaphthalen– 1-carboxamide (1 , 23 g) in trifluoroacetic acid (7 mL) thioanisole (1.40 mL) was added and the mixture was stirred at room temperature for one day. The reaction mixture was divided into saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in ethyl acetate. To this was added 4 moles / L of
20 HCl / dioxane (0.63 mL) and the precipitated solid was collected by filtration to give 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - [(6-methoxypyridin-3-yl) dihydrochloride methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.43 g).
MS (ESI) m / z: 432 [MH] +
1H-NMR (DMSO-d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.35-1.60 (1H, m), 1.70-2.00 (3H, m) , 2.30-2.60 (2H, m), 3.20-3.45 (1H, m), 3.45-3.70 (1H, m), 3.83 (3H, s), 4 , 60–5.10 (2H, m), 6.45–6.70 (2H, m) 6.80–7.00 (2H, m), 7.30–8.25 (4H, m), 25 8.80 (1H, s).
Example 140 By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.39 g) and (4-isopropylphenyl) [(4-Pyrrolidinophenyl) methyl] amine (0.56 g) as starting materials, N- (4-isopropylphenyl) -7-methoxy-N - [(4-pyrrolidinophenyl) methyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.3 g). image 1
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.3Hz), 1.35-1.60 (1H, m), 1.80-2.10 (7H, m), 2 , 50-2.65 (1H, m), 2.70-2.95 (2H, m), 3.20-3.35 (4H, m), 3.69 (3H, s), 3.60 –3.80 (1H, m), 4.56 (1H, d, J = 13.8Hz), 5.07 (1H, d, J = 13.8Hz), 6.40–7.20 (11H, m).
Example 141 image 1
By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.39 g) and {[4– (imidazole –1-yl) phenyl] methyl} (4-isopropylphenyl) amine (0.55 g) as starting materials, N - {[4– (imidazol-1-yl) phenyl] methyl) -N- (4 -Isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide 1/2 hydrate (0.28 g). Melting point: 110.7 ° C.
1H-NMR (CDCI3) δ: 1.24 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.80-2.10 (3H, m), 2 , 50-2.68 (1H, m), 2.70-3.00 (2H,
15 m), 3.72 (3H, s), 3.65-3.80 (1H, m), 4.84 (1H, d, J = 14.2Hz), 5.06 (1H, d, J = 14.2Hz), 6.52 (1H, d, J = 2.5Hz), 6.60–6.70 (1H, m), 6.90–7.10 (3H, m), 7.15 –7.50 (8H, m), 7.86 (1H, s).
Example 142 image 1
The 2,4-dimethyl-5– (hydroxymethyl) thiazole (0.65 g) was dissolved in methylene chloride (5 mL) and
20 methanesulfonyl (0.37 mL) under ice cooling. The mixture was stirred at room temperature for one day. The reaction mixture was concentrated and the residue was divided into water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated. By means of the reaction and treatment of the residue obtained and 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.8 g) thereof so that in Example 132, 5-benzyloxy-N - [(2,4-dimethylthiazol-5-yl) methyl] -N- (6–
Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.64g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.40-1.70 (1H, m), 1.80-2.10 (3H, m), 2 , 00 (3H, s), 2.60–2.80 (2H, m), 2.64 (3H, s), 3.00–3.20 (1H, m), 3.60–4.93 (1H, d, J = 15.0Hz), 5.01 (1H, d, J = 15.0Hz), 5.04 (2H, s), 6.61 (1H, d, J = 7.5Hz) , 6.73 (1H, d, J = 8.1Hz), 7.00–7.50 (8H, m), 8.37 (1H, d, J = 2.4Hz).
Example 143 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - [(2,4-dimethylthiazol-5-yl) methyl] -N- (6-isopropylpyridin-3– il) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.64 g) as a starting material, N - [(2,4-dimethylthiazol-5-yl) methyl] dihydrochloride was obtained –5– hydroxy-N– (6-isopropylpyridine) –1,2,3,4– image 1
5 tetrahydronaphthalen-1-carboxamide 5/2 hydrate (0.72 g).
MS (ESI) m / z: 436 [MH] +
1H – NMR (DMSO – d6) δ: 1.27 (6H, d, J = 6.9Hz), 1.10–1.50 (1H, m), 1.65–2.05 (3H, m) , 1.94 (3H, s), 2.35-2.55 (2H, m), 2.65 (3H, s), 3.10-3.30 (1H, m), 3.45-3 , 60 (1H, m), 4.92 (1H, d, J = 15.4Hz), 5.02 (1H, d, J = 15.4Hz), 6.46 (1H, d, J = 7, 6Hz), 6.63 (1H, d, J = 7.9Hz), 6.90 (1H, t, J = 7.8Hz), 7.59 (1H, d, J = 8.2Hz), 7, 89 (1H, d, J = 8.3Hz), 8.56
10 (1H, s).
Example 144 image 1
By reaction and treatment in the same manner as in Example 142 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1, 2 g) and 3-hydroxymethyl-6– (2-methoxyethoxy) pyridine 15 (0.55 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - {[ 6– (2-methoxyethoxy) pyridin-3-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.0.7 g).
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.80-2.10 (3H, m), 2 , 65–2.80 (2H, m), 2.95–3.15 (1H, m), 3.45 (3H, s), 3.60–3.70 (1H, m), 3.70 –3.80 (2H, m), 4.40–4.50 (2H, m), 4.80 (1H, d, J = 15Hz), 4.90 (1H, d, J = 15Hz), 5 , 03 (2H, s), 6.57 (1H, d, J = 7.8Hz), 6.73 (1H, d, J = 7.8Hz), 6.78 (1H, d, J = 8, 4Hz), 7.06 (1H, t, J = 7.8Hz),
20 7.17 (1H, d, J = 8.4Hz), 7.20–7.45 (6H, m), 7.60 (1H, dd, J = 2.4Hz, 8.7Hz), 7, 85 (1H, d, J = 2.1Hz), 8.33 (1H, d, J = 2.4Hz).
Example 145 image 1
Through reaction and treatment in the same manner as in Example 133 using 5-benzyloxy-N– (6–
25 isopropylpyridin-3-yl) -N - {[6- (2-methoxyethoxy) pyridin-3-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.07 g) as the material of Starting, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[6– (2-methoxyethoxy) pyridin-3-yl] methyl}} - 1,2,3,4-tetrahydronaphthalen1 was obtained -Carboxamide (0.72 g).
1H-NMR (CDCl3) δ: 1.16 (6H, d, J = 6.9Hz), 1.40-1.55 (1H, m), 1.75-2.10 (4H, m), 2 , 50-2.65 (2H, m), 3.00-3.20 (1H, m), 3.45 (3H, s), 3.60-3.70 (1H, m), 3.70 –3.80 (2H, m), 4.40–4.50 (2H, m), 4.83 (1H, d, J = 14.4Hz), 4.90 (1H, d, J = 14, 4Hz), 6.30–6.45 (2H, m), 6.70–6.90 (2H, m), 7.10–7.35 (2H, m), 7.61 (1H, dd, J = 2.4Hz, 8.5Hz), 7.86 (1H, d, J = 2.2Hz), 8.34 (1H, d, J = 2.3Hz).
Example 146 image 1
5 By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.82 g) and [(5-ethylthiophene] 2-yl) methyl] (4-isopropylphenyl) amine (1.04 g) as starting materials, N - [(5-ethylthiophene-2-yl) methyl) -N- (4-isopropylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.26 g).
MS (ESI) m / z: 448 [MH] +
10 1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 7.0Hz), 1.29 (3H, t, J = 7.6Hz), 1.35-1.55 (1H, m ), 1.80–2.10 (3H, m), 2.50–2.65 (1H, m), 2.70–3.00 (2H, m), 2.80 (2H, q, J = 7.6Hz), 3.70 (3H, s), 3.60–3.80 (1H, m), 4.73 (1H, d, J = 14.6Hz), 5.19 (1H, d , J = 14.6Hz), 6.50-6.70 (4H, m), 6.90-7.30 (5H, m).
Example 147 image 1
By means of the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.54 g) and {[4– (imidazole –1-yl) phenyl} methyl} (4-isopropylphenyl) amine (0.55 g) as starting materials, 5-benzyloxy-N - ([4– (imidazol-1-yl) phenyl] methyl) - N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.62 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 7.2Hz), 1.40-1.60 (1H, m), 1.80-2.15 (3H, m), 2 , 70–2.80 (2H, m), 2.80–3.00 (1H,
20 m), 3.70–3.85 (1H, m), 4.93 (1H, d, J = 14.1Hz), 5.01 (1H, d, J = 14.1Hz), 5.04 (2H, s), 6.65 (1H, d, J = 7.8Hz), 6.73 (1H, d, J = 7.8Hz), 6.95–7.50 (16H, m), 7 , 87 (1H, s).
Example 148 By reaction and treatment in the same manner as in Example 133 using 5-benzyloxy-N - {[4– (imidazol-1-yl) phenyl] methyl} -N- (4-isopropylphenyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.62 g) as the starting material, 5-hydroxy-N - {[4– (imidazol-1-yl) phenyl] methyl} -N- (4-Isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.36 g). image 1
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.80-2.15 (3H, m), 2 , 50-2.75 (2H, m), 2.85-3.00 (1H, m), 3.70-3.85 (1H, m), 4.97 (2H, s), 6.45 6.60 (2H, m), 6.80–7.10 (4H, m), 7.15–7.45 (7H, m) 7.89 (1H, s).
Example 149 image 1
Through reaction and treatment in the same manner as in Example 12 using 1,2,3,4– acid
Tetrahydronaphthalen-1-carboxylic acid (0.70 g) and (4-butylphenyl) [(4-dimethylaminophenyl) methyl] amine (0.54 g) as starting materials, N- (4-butylphenyl) -N- [(4-dimethylaminophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.81 g).
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.4Hz), 1.26-1.37 (2H, m), 1.50-1.52 (1H, m), 1 , 55–1.64 (2H, m), 1.89–1.91 (1H, m), 1.95–2.04 (2H, m), 2.58 (2H, t, J = 7, 4Hz), 2.65-2.67 (1H, m), 2.82-2.85 (1H, m), 2.94 (6H, s), 3.10-3.75 (1H, m) , 4.72 (1H, d, J = 13.9Hz), 4.93 (1H, d, J = 13.9Hz), 6.63 (2H, m), 6.94–7.13 (10H, m).
15 Example 150 image 1
By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.34 g) and (4-ethylphenyl) [(4-morpholinophenyl) methyl] amine (0.59 g) as starting materials, N- (4-ethylphenyl) -N - [(4-morpholinophenyl) methyl] -1,2,3,4-tetrahydronaphthalenecarboxamide (0.60 g) was obtained .
1H-NMR (CDCl3) δ: 1.22 (3H, t, J = 7.8Hz), 1.47-1.51 (1H, m), 1.87-1.91 (1H, m, 1 , 94-2.05 (2H, m), 2.63 (2H, q, J = 7.8Hz), 2.59-2.67 (1H, m), 2.80-2.85 (1H, m), 3.16 (4H, t, J = 4.8Hz), 3.71-3.76 (1H, m), 3.87 (4H, t, J = 4.8Hz), 4.75 ( 1H, d, J = 13.8Hz), 4.94 (1H, d, J = 13.8Hz), 6.81–6.84 (2H, m), 6.95–7.17 (10H, m ).
Example 151 image 1
By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.34 g) and (4-ethylphenyl) (2-piperidinoethyl) Amine (0.47 g) as starting materials, N- (4-ethylphenyl) -N- (2-piperidinoethyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.65 g) was obtained.
1H-NMR (CDCl3) δ: 1.22-1.28 (4H, m), 1.43-1.60 (7H, m), 1.94-2.01 (2H, m) 2.39– 2.56 (6H, m), 2.63-2.70 (3H, m), 2.78-2.90 (1H, m), 3.61-3.75 (2H, m), 4, 10–4.17 (1H, m) 7.00–7.13 (3H, m), 7.18–7.28 (5H, m).
Example 152 image 1
5 By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.70 g) and [(4-dimethylaminophenyl) methyl] - ( 6-methoxypyridin-3-yl) amine (0.49 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (6-methoxypyridin-3-yl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.54 g).
1H-NMR (CDCl3) δ: 1.45-1.54 (1H, m), 1.86-2.02 (3H, m), 2.63-2.71 (1H, m), 2.80 –2.91 (1H, m), 2.94 (6H, s), 3.66–
10 3.71 (1H, m), 3.91 (3H, s), 4.71 (1H, d, J = 13.9Hz), 4.92 (1H, d, J = 13.9Hz), 6 , 62–6.66 (3H, m), 6.95–6.98 (1H, m), 7.03–7.12 (5H, m), 7.19 (1H, dd, J = 2, 7, 8.7Hz), 7.89 (1H, d, J = 2.5Hz).
Example 153 image 1
Through reaction and treatment in the same manner as in Example 12 using 1,2,3,4– acid
Tetrahydronaphthalen-1-carboxylic acid (0.34 g) and [(4-benzyloxyphenyl) methyl] (4-isopropylphenyl) amine (0.66 g) as starting materials, N - [(4-benzyloxyphenyl) methyl] was obtained. –N– (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.52 g). Melting point: 120-121 ° C.
Example 154 image 1
By reaction and treatment in the same manner as in Example 17 using N - [(4-benzyloxyphenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1- carboxamide (0.39 g) as starting material, N - [(4-hydroxyphenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.23) g). Melting point: 156 ° C.
Example 155 By reaction and treatment and in the same manner as in Example 83 using 5-benzyloxy-N- (4-isopropylphenyl) -N- [(pyrazol-4-yl) methyl] -1,2, 3,4-tetrahydronaphthalen-1-carboxamide (0.52 g) and 3-chloro-N, N-dimethylpropylamine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) was obtained ) –N - ({1– image 1
5 [3 (dimethylamino) propyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.1 g). Through reaction and treatment in the same manner as in Example 105 using this compound, N - ({1– [3– (dimethylamino) propyl] pyrazol-4-yl} methyl) –5-hydroxy– was obtained N– (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.73 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.43-1.46 (1H, m), 1.81-2.05 (5H, m), 2 , 21-2.27 (8H, m), 2.57-2.62 (2H,
10 m), 2.92 (1H, sept, J = 6.9Hz), 3.68-3.73 (1H, m), 4.13 (2H, t, J = 6.9Hz), 4.61 (1H, d, J = 14.3Hz), 4.83 (1H, d, J = 14.3Hz), 6.36 (1H, d, J = 7.8Hz), 6.43 (1H, d, J = 7.8Hz), 6.81 (1H, t, J = 7.8Hz), 7.06 (2H, d, J = 8.3Hz), 7.22 (2H, d, J = 8.3Hz ), 7.36 (1H, s), 7.42 (1H, s).
Example 156 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.63 g) and (4-ethylphenyl) [ (4-morpholinophenyl) methyl] amine (0.56 g) as starting materials, 5-benzyloxy-N- (4-ethylphenyl) -N - [(4-morpholinophenyl) methyl] -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.75 g). Through reaction and treatment in the same manner as in Example 17 using this compound, N- (4-ethylphenyl) -5-hydroxy-N [(4-morpholinophenyl) methyl] -1,2,3 was obtained , 4 – tetrahydronaphthalen – 1–
20 carboxamide (0.51 g). Melting point: 200 ° C.
Example 157 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.66 g) and (4-butylphenyl) [( 4-dimethylaminophenyl) methyl] amine (0.55 g) as
25 starting materials, 5-benzyloxy-N- (4-butylphenyl) -N - [(4-dimethylaminophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.98 g) was obtained. By reaction and treatment in the same manner as in Example 17 using this compound, N- (4-butylphenyl) -N - [(4-dimethylaminophenyl) methyl] -5,5-hydroxy-1 was obtained, 2,3,4– tetrahydronaphthalen-1-carboxamide (0.44 g). Melting Point: 138 ° C
Example 158 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.72 g) and (4-ethylphenyl) (2-Piperidinoethyl) amine (0.50 g)) as starting materials, 5-benzyloxy-N- (4-ethylphenyl) -N- (2-piperidinoethyl) -1,2,3,4-tetrahydronaphthalen was obtained 1-carboxamide (1.19 g). Through reaction and treatment in the same manner as in Example 105 using this compound, N- (4-ethylphenyl) -5-hydroxy-N- (2-piperidinoethyl) -1,2,3,4 was obtained –Tetrahydronaphthalen – 1 – carboxamide (0.77 g). image 1
1H-NMR (CDCl3) δ: 1.35-2.00 (9H, m), 2.42-2.57 (7H, m), 2.67 (2H, q, J = 7.6Hz), 3 , 48 (1H, s), 3.65-3.75 (3H, m), 4.06-4.13 (1H, m), 6.34 (1H, d, J = 7.8Hz), 6 , 66 (1H, d, J = 78Hz), 6.81 (1H, d, J = 7.8Hz), 7.21-7.26 (4H, m).
Example 159 image4
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.94 g) and [(3,4-dibenzyloxyphenyl) ) methyl] (4-isopropylphenyl) amine (2.5 g) as starting materials, 5-benzyloxy-N - [(3,4-dibenzyloxyphenyl) methyl] -N- (4-isopropylphenyl) -1,2 , 3,4- tetrahydronaphthalen-1-carboxamide (2.64 g). Through the reaction and treatment in the same way as in the
Example 17 using this compound, N - [(3,4-dihydroxyphenyl) methyl] -5-hydroxy-N- [4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1, 35 g)
1H-NMR (CDCl3) δ: 1.23 (6H, m), 1.37-1.42 (1H, m), 1.82-1.97 (6H, m), 2.35 2.43 ( 1H, m), 2.48-2.55 (1H, m), 2.89 (1H, sept, J = 6.9Hz), 3.71-3.76 (1H, m), 4.70 ( 1H, d, J = 13.8Hz), 4.82 (1H, d, J = 13.8Hz), 6.30 (1H, dd, J = 2.0, 8.0Hz), 6.47 (1H , d, J = 8.0Hz), 6.61 (2H, t, J = 7.7Hz), 6.90-6.98 (4H, m), 7.17 (2H, d, J = 8, 4Hz)
20 Example 160 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.59 g) and [(4-benzyloxyphenyl) methyl ] (4-Isopropylphenyl) amine (0.58 g) as starting materials, 5-benzyloxy-N - [(4-benzyloxyphenyl) methyl] -N- (4-isopropylphenyl) -1,2,3,4 -
Tetrahydronaphthalen-1-carboxamide (0.74 g). Through reaction and treatment in the same manner as in Example 17 using this compound, 5-hydroxy-N - [(4-hydroxyphenyl) methylj-N- (4-isopropylphenyl) -1,2,3 was obtained , 4– tetrahydronaphthalen-1-carboxamide (0.33 g). Melting point: 241–243 ° C.
Example 161 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenylmethyl) ] (6-methoxypyridin-3-yl) amine (0.91 g) as starting materials, 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (6-methoxypyridin-3-yl) was obtained –1,2,3,4– image 1
5 tetrahydronaphthalen-1-carboxamide (1.35 g). By reaction and treatment in the same manner as in Example 105 using this compound, N - [(4-dimethylaminophenyl) methyl) -5-hydroxy-N- (6-methoxypyridin-3-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.34 g).
1H-NMR (CDCl3) δ: 1.45-1.5 (1H, m), 1.81-2.05 (3H, m), 2.59-2.62 (2H, m), 2.94 (6H, s), 3.65–3.70 (1H, m), 3.92 (3H, m), 4.83 (2H, s), 6.38 (1H, d, J = 7.8Hz ), 6.46 (1H, d, J = 7.8Hz), 6.64-6.71 (3H, m), 6.82 (1H, d, J = 7.8Hz),
10 7.05–7.09 (2H, m), 7.19–7.22 (2H, m), 7.91 (1H, brs).
Example 162 image 1
The aniline (93.1 mg) was dissolved in dichloroethane (5 mL) and 4-dimethylaminobenzaldehyde (149 mg), acetic acid (0.06 mL) and sodium triacetoxyborohydride (0.42 g) were added. The mixture was stirred at room temperature for one day. 15 Saturated aqueous sodium hydrogen carbonate (2 mL) was added to the reaction solution and the mixture was stirred for a while, after which the aqueous layer was absorbed using a diatomaceous earth column. The organic layer obtained was concentrated under reduced pressure and dichloromethane (5 mL) was added to the residue. To this solution was added a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid chloride (0.23 g) in dichloromethane (5 mL) and the mixture was stirred at room temperature for a day. Hydrogen carbonate was added
20 saturated aqueous sodium (2 mL) to the reaction solution. The mixture was stirred for a while, after which the aqueous layer was absorbed using a diatomaceous earth column. The organic layer obtained was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give N - [(4-dimethylaminophenyl) methyl] -7-methoxy-N-phenyl-1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (260 mg).
1H-NMR (CDCl3) δ: 1.42-1.54 (1H, m), 1.83-2.04 (3H, m), 2.53-2.86 (2H, m), 2.93 (6H, s), 3.65-3.72 (1H, m), 3.70
25 (3H, s), 4.62 (1H, d, J = 13.9Hz), 5.08 (1H, d, J = 13.9Hz), 6.53 (1H, d, J = 2.5Hz ), 6.62–6.69 (3H, m), 6.95 (1H, d, J = 8.4Hz), 7.05–7.13 (3H, m), 7.30–7.34 (4H, m).
Example 163 By reaction and treatment in the same manner as in Example 162 using 4-methoxyaniline (0.12 g) as the starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] was obtained] –7 – methoxy – N– (4– methoxyphenyl) –1,2,3,4-tetrahydronaphthalenecarboxamide (0.12 g). image 1
1H-NMR (CDCl3) δ: 1.43-1.55 (1H, m), 1.80-2.05 (3H, m), 2.56-2.62 (1H, m), 2.70 –2.85 (1H, m), 2.93 (6H, s), 3.66– 3.70 (1H, m), 3.70 (3H, s), 3.79 (3H, s), 4.57 (1H, d, J = 13.8Hz), 5.05 (1H, d, J = 13.8Hz), 6.51 (1H, d, J = 2.5Hz), 6.62–6 , 69 (3H, m), 6.81-6.85 (2H, m), 6.93-6.97 (3H, m), 7.09-7.13 (2H, m).
Example 164 image 1
By reaction and treatment in the same manner as in Example 162 using 4-cyclohexylaniline (0.18 g) as a starting material instead of aniline, N- (4-cyclohexylphenyl) -N- [ (4-dimethylaminophenyl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.088 g).
1H-NMR (CDCl3) δ: 1.34-2.03 (14H, m), 2.44-2.61 (2H, m), 2.71-2.85 (1H, m), 2.93 (6H, s), 3.68-3.72 (1H, m), 3.68 (3H, s), 4.58 (1H, d, J = 13.9Hz), 5.06 (1H, d , J = 13.9Hz), 6.51 (1H, d, J = 2.5Hz), 6.63-6.68 (3H, m), 6.93-6.98 (3H,
15 m), 7.12–7.16 (4H, m).
Example 165 image 1
Through the reaction and treatment in the same manner as in Example 162 using 3,4-dimethylaniline (0.12 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl) was obtained. –N– (3,4 – dimethylphenyl) –7–
20 methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.29 g).
1H-NMR (CDCl3) δ: 1.35-1.51 (1H, m), 1.86-2.02 (3H, m), 2.21 (3H, s), 2.23 (3H, s ), 2.51-2.63 (1H, m), 2.69-2.83 (1H, m), 2.93 (6H, s), 3.69 (3H, s), 3.69– 3.74 (1H, m), 4.50-4.65 (1H, m), 4.96-5.08 (1H, m), 6.52 (1H, d, J = 2.4Hz), 6.62–6.68 (3H, m), 6.73–6.76 (1H, m), 6.86 (1H, d, J = 1.7Hz), 6.94 (1H, d, J = 8.5Hz), 7.05 (1H, d, J = 8.5Hz), 7.06- 7.12 (2H, m).
Example 166 image 1
Through reaction and treatment in the same manner as in Example 162 using 3,4-dichloroaniline (0.16 g) as a starting material instead of aniline, N- (3,4-dichlorophenyl) - was obtained N - [(4-dimethylaminophenyl) methyl] -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.14 g).
1H-NMR (CDCl3) δ: 1.42-1.56 (1H, m), 1.80-2.03 (3H, m), 2.55-2.82 (2H, m) 2.94 ( 6H, s), 3.60–3.69 (1H, m), 3.71 (3H, s), 3.58–3.70 (1H, m), 4.97–5.05 (1H, m), 6.45-6.46 (1H, m), 6.62-6.71 (3H, m), 6.85-6.88 (1H, m), 6.96-6.98 ( 1H, m), 7.05–7.09 (2H, m), 7.20 (1H, brs), 7.39 (1H, d, J = 8.4Hz).
Example 167 image4
N– (4-Isopropylphenyl) –7-methoxy-N - [(4-nitrophenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.2 g) was dissolved in ethanol (8.1 mL) and tin chloride (1.5 g) and conc. hydrochloric acid were added. (2.7. ML). The mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was divided into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over
15 mg sulfate. The solvent was evaporated under reduced pressure and the solid obtained was recrystallized from a mixed solvent of chloroform and diisopropyl ether to give N - [(4-aminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2 , 3,4- tetrahydronaphthalen-1-carboxamide (1.0 g). Melting point: 115-117 ° C.
Example 168 image 1
By reaction and treatment in the same manner as in Example 162 using 4-morpholinoaniline (0.18 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] - 7-methoxy-N- (4– morpholinophenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.33 g).
1H-NMR (CDCl3) δ: 1.40-1.47 (1H, m), 1.82-2.05 (3H, m), 2.56-2.84 (2H, m), 2.93 (6H, s), 3.13-3.16 (4H, m), 3.66-3.73 (1H, m), 3.69 (3H, s) 3.83-3.86 (4H, m), 4.57 (1H, d, J = 13.8Hz), 5.05 (1H, d, J = 13.8Hz), 6.52 (1H, s), 6.62–6.68 ( 3H, m), 6.80-6.83 (2H, m), 6.93-7.02 (3H, m), 7.13 (2H, d, J = 8.4Hz).
Example 169 image5
By reaction and treatment in the same manner as in Example 162 using 2,6-dimethylaniline (0.12 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] was obtained] -N- (2,6-dimethylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.16 g).
1H-NMR (CDCl3) δ: 1.24-1.28 (1H, m), 1.89-2.10 (3H, m), 2.10 (6H, s), 2.40-2.45 (1H, m) 2.76-2.83 (1H, m), 2.90
10 (6H, s), 3.72-3.78 (3H, m), 3.77 (3H, s), 6.49 (1H, s), 6.66 (2H, d, J = 8, 6Hz), 6.80–6.88 (4H, m), 7.00–7.05 (2H, m), 7.08–7.11 (1H, m).
Example 170 image 1
By reaction and treatment and in the same manner as in Example 162 using 3,4-dimethoxyaniline
15 (0.15 g) as the starting material instead of aniline, N- (3,4-dimethoxyphenyl) -N - [(4-dimethylaminophenyl) methyl] -7-methoxy-1,2,3,4 was obtained –Tetrahydronaphthalen – 1 – carboxamide (0.18 g).
1H-NMR (CDCl3) δ: 1.40-1.51 (1H, m), 1.82-2.05 (3H, m), 2.56-2.62 (1H, m), 2.72 –2.81 (1H, m), 2.93 (6H, s), 3.66– 3.74 (1H, m), 3.69 (6H, s), 3.87 (3H, s), 4.53–4.63 (1H, m), 5.00–5.10 (1H, m), 6.45 (1H, d, J = 2.1Hz), 6.52 (1H, d, J = 2.1Hz), 6.63–6.69 (4H, m), 6.78 (1H, d, J = 8.7Hz), 6.95 (1H, d, J = 8.4Hz), 7 , 12 (2H, d, J = 8.7Hz).
Example 171 By reaction and treatment in the same manner as in Example 162 using 3,4,5-trimethoxyaniline (0.18 g) as a starting material instead of aniline, N - [(4 -Dimethylaminophenyl) methyl] -7-methoxy-N- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.22 g). image 1
1H-NMR (CDCl3) δ: 1.42-1.59 (1H, m), 1.80-2.05 (3H, m), 2.52-2.64 (1H, m), 2.71 –2.85 (1H, m), 2.92 (6H, s), 3.67– 3.85 (13H, m), 4.58 (1H, d, J = 13.8Hz), 5.04 (1H, d, J = 13.8Hz), 6.22 (2H, s), 6.51 (1H, d, J = 2.4Hz), 6.63–6.73 (3H, m), 6 , 96 (1H, d, J = 8.4Hz), 7.14-7.16 (2H, m).
Example 172 image 1
Through reaction and treatment ii in the same manner as in Example 162 using 4-cyanoaniline (0.12 g)
10 As a starting material instead of aniline, N- (4-cyanophenyl) -N - [(4-dimethylaminophenyl) methyl] -7-methoxy- 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.097 g).
1H-NMR (CDCl3) δ: 1.20-1.27 (1H, m), 1.79-2.05 (3H, m), 2.55-2.65 (1H, m), 2.70 –2.84 (1H, m), 2.94 (6H, s), 3.55– 3.66 (1H, m), 3.72 (3H, s), 4.72 (1H, d, J = 14.1Hz), 5.03 (1H, d, J = 14.1Hz), 6.47 (1H, d, J = 2.4Hz), 6.62 (2H, d, J = 8.1Hz) , 6.70 (1H, dd, J = 2.4, 8.1Hz), 6.97 (1H, d, J = 8.1Hz), 7.05 (2H, d, J = 8.1Hz), 7.18–7.20 (2H, m), 7.63–7.66
15 (2H, m).
Example 173 image 1
Through the reaction and treatment in the same manner as in Example 162 using 2-fluoroaniline (0.11 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] -N was obtained - (2 – fluorophenyl) –7 – methoxy–
20 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.41 g).
1H-NMR (CDCl3) δ: 1.42-1.54 (1H, m), 1.79-2.08 (3H, m), 2.55-2.61 (1H, m, 2.71– 2.85 (1H, m), 2.92 (6H, s), 3.58– 3.68 (1H, m), 3.69 (1.5H, s), 3.76 (1.5H, s), 4.16 (0.5H, d, J = 14.1Hz), 4.39 (0.5H, d, J = 14.1Hz), 5.28 (0.5H, d, J = 14 , 1Hz), 5.52 (0.5H, d, J = 14.1Hz), 6.48-6.49 (0.5H, m), 6.59-6.70 (3.5H, m) , 6.93–7.25 (7H, m).
Example 174 By reaction and treatment in the same manner as in Example 162 using 3-fluoroaniline (0.11 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] was obtained] –N– (3-fluorophenyl) –7 – methoxy– 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.26 g). image 1
1H-NMR (CDCl3) δ: 1.42-1.50 (1H, m), 1.86-2.02 (3H, m), 2.56-2.83 (2H, m), 2.93 (6H, s), 3.65-3.69 (1H, m), 3.70 (3H, s), 4.62 (1H, d, J = 13.9Hz), 5.04 (1H, d , J = 13.9Hz), 6.48 (1H, d, J = 2.4Hz), 6.62–6.70 (3H, m), 6.80–7.11 (6H, m), 7 , 26–7.31 (1 H, m).
Example 175 image 1
By reaction and treatment in the same manner as in Example 162 using 4-fluoroaniline (0.11 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] - N– (4-fluorophenyl) –7-methoxy– 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.36 g).
1H-NMR (CDCl3) δ: 1.38-1.56 (1H, m), 1.79-2.05 (3H, m), 2.52-2.65 (1H, m 2.71-2 , 82 (1H, m), 2.93 (6H, s), 3.61– 3.67 (1H, m), 3.71 (3H, s), 4.60 (1H, d, J = 13 , 8Hz), 5.04 (1H, d, J = 13.8Hz), 6.49 (1H, d, J = 2.4Hz), 6.61-6.70 (3H,
15 m), 6.94-7.10 (7H, m).
Example 176 image 1
Through the reaction and treatment in the same manner as in Example 162 using 3-cyanoaniline (0.12 g) as a starting material instead of aniline, N- (3-cyanophenyl) -N- [( 4 – dimethylaminophenyl) methyl] –7 – methoxy–
20 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.14 g).
1H-NMR (CDCl3) δ: 1.42-1.51 (1H, m), 1.79-2.05 (3H, m), 2.54-2.83 (2H, m), 2.94 (6H, s), 3.48-3.62 (1H, m), 3.73 (3H, s), 4.67 (1H, d, J = 14.1Hz), 5.01 (1H, d , J = 14.1Hz), 6.47 (1H, d, J = 2.4Hz), 6.62 (2H, d, J = 8.7Hz), 6.70 (1H, dd, J = 2, 4, 8.1Hz), 6.97 (1H, d, J = 8.1Hz), 7.05 (2H, d, J = 8.7Hz), 7.26-7.35 (2H, m), 7.46 (1H, t, J = 7.8Hz), 7.60 (1H, d, J = 7.8Hz).
Example 177 image 1
By reaction and treatment in the same manner as in Example 162 using 2-chloroaniline (0.12 g) as a starting material instead of aniline, N- (2-chlorophenyl) -N - [( 4-dimethylaminophenyl) methyl] –7-methoxy– 5 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.24 g).
1 H-NMR (CDCl 3) δ: 1.40-1.55 (1H, m), 1.73-2.12 (3H, m), 2.50-2.65 (1H, m), 2.70 –2.84 (1H, m), 2.93 (6H, s), 3.40– 3.52 (1H, m), 3.64 (1.5H, s), 3.76 (1.5H , s), 3.85 (0.5H, d, J = 14.0Hz), 3.97 (0.5H, d, J = 14.1Hz), 5.64 (0.5H, d, J = 14.1Hz), 5.80 (0.5H, d, J = 14.0Hz), 6.46-6.47 (0.5H, m), 6.60-6.71 (3H, m), 6.81–6.82 (1H, m), 6.88–6.98 (1.5H, m), 7.04–7.16 (3H, m), 7.24–7.32 (1H , m), 7.50–7.55 (1H, m).
10 Example 178 image 1
Through the reaction and treatment in the same manner as in Example 162 using 3-chloroaniline (0.12 g) as a starting material instead of aniline, N- (3-chlorophenyl) -N - [( 4-dimethylaminophenyl) methyl] –7-methoxy– 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.23 g).
1 H-NMR (CDCl3) δ: 1.42-1.51 (1H, m), 1.79-2.05 (3H, m), 2.54-2.83 (2H, m), 2, 93 (6H, s), 3.63-3.68 (1H, m), 3.69 (3H, s) 4.62 (1H, d, J = 14.0Hz), 5.03 (1H, d , J = 14.0Hz), 6.48 (1H, d, J = 2.5Hz), 6.62-6.70 (3H, m) 6.91-7.11 (6H, m), 7, 23–7.29 (1H, m).
Example 179 image 1
By reaction and treatment in the same manner as in Example 162 using 4-chloroaniline (0.12 g) as a starting material instead of aniline, N- (4-chlorophenyl) -N- [ (4-dimethylaminophenyl) methyl] –7-methoxy– 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.30 g).
1H-NMR (CDCl3) δ: 1.45-1.53 (1H, m), 1.78-2.03 (3H, m), 2.55-2.82 (2H, m), 2.93 (6H, s), 3.61-3.68 (1H, m), 3.71 (3H, s), 4.61 (1H, d, J = 13.9Hz), 5.03 (1H, d , J = 13.9Hz), 6.48 (1H, d, J = 2.4Hz), 6.61-6.70 (3H, m), 6.94-7.07 (3H, m), 7 , 07–7.10 (2H, m), 7.21–7.32 (2H, m).
Example 180 image5
Through the reaction and treatment in the same manner as in Example 162 using o-toluidine (0.11 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] -7 was obtained -Methoxy-N- (2-methylphenyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.22 g).
1H-NMR (CDCl3) δ: 1.37-1.50 (1H, m), 1.81-2.10 (3H, m), 2.26 (3H, s), 2.53 2.61 ( 1H, m), 2.70–2.82 (1H, m), 2.93
10 (6H, s), 2.42-2.53 (1H, m), 3.61 (18H, s), 3.74 (12H, s), 3.97 (0.6H, d, J = 13.5Hz), 4.33 (0.4H, d, J = 13.5Hz), 5.19 (0.4H, d, J = 13.5Hz), 5.58 (0.6H, d, J = 13.5Hz), 6.48-7.26 (11H, m).
Example 181 image 1
By reaction and treatment in the same manner as in Example 162 using m-toluidine (0.11 g)
15 As the starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] -7-methoxy-N- (3-methylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0 , 23 g).
1H-NMR (DMSO-d6) δ: 1.30-1.40 (1H, m), 1.80-1.95 (3H, m), 2.29 (3H, s), 2.50-2 , 72 (2H, m), 2.86 (6H, s), 3.61– 3.67 (1H, m), 3.67 (3H, s), 4.64 (1H, d, J = 13 , 9Hz), 4.83 (1H, d, J = 13.9Hz), 6.45 (1H, d, J = 2.4Hz), 6.63 (2H, d, J = 8.4Hz), 6 , 70 (1H, dd, J = 2.4, 8.4Hz), 6.92–7.02 (4H, m), 7.08 (1H, s), 7.15 (1H, d, J = 7.5Hz), 7.26-7.31 (1H, m).
Example 182 By reaction and treatment in the same manner as in Example 162 using p-toluidine (0.11 g) as a starting material instead of aniline, N - [(4-dimethylamino-phenyl) methyl was obtained ] –7-Methyloxy-N– (4-methylphenyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.27 g). image 1
1H-NMR (DMSO-d6) δ: 1.30-1.40 (1H, m), 1.79-1.97 (3H, m), 2.29 (3H, s), 2.48-2 , 68 (2H, m), 2.86 (6H, s), 3.57-3.62 (1H, m), 3.67 (3H, s), 4.63 (1H, d, J = 13 , 9Hz), 4.83 (1H, d, J = 13.9Hz), 6.45-6.46 (1H, m), 6.60-6.70 (3H, m), 6.95–7 , 25 (7H, m).
Example 183 image 1
By reaction and treatment in the same manner as in Example 162 using 2-isopropylaniline (0.14
10 g) as the starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] -N- (2-isopropylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide was obtained (0.12 g).
1H – NMR (DMSO – d6) δ: 1.01–1.05 (3H, m), 1.13–1.23 (3H, m), 1.23–1.40 (1H, m), 1 , 71–1.98 (3H, m), 2.51–2.70 (3H, m), 2.85 (6H, m) 2.92–3.05 (0.5H, m), 3, 13–3.23 (0.5H, m), 3.61 (1.5H, s), 3.70 (1.5H, s), 4.09 (0.5H, d, J = 14.1Hz ), 4.26 (0.5H, d, J = 14.1Hz), 5.09 (0.5H, d, J = 14.1Hz), 5.32 (0.5H, d, J = 14, 1Hz), 6.45 (1H, d, J = 2.4Hz), 6.63 (2H, d,
15 J = 8.6Hz), 6.64–6.73 (1H, m), 6.85–7.04 (4H, m), 7.14–7.18 (1H, m) 7.31– 7.39 (1H, m), 7.45-7.49 (1H, m).
Example 184 image 1
Through the reaction and treatment in the same manner as in Example 162 using 3-isopropylaniline (0.14 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] -N was obtained - (3 – isopropylphenyl) –7–
20 methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.28 g).
1H-NMR (DMSO-d6) δ: 1.07-1.12 (6H, m), 1.27-1.42 (1H, m), 1.82-1.90 (3H, m), 2 , 49-2.68 (3H, m), 2.86 (6H, s), 3.56-3.60 (1H, m), 3.66 (3H, s), 4.60 (1H, d , J = 14.1Hz), 4.92 (1H, d, J = 14.1Hz), 6.44 (1H, d, J = 2.4Hz), 6.62–6.71 (3H, m) , 6.93–7.02 (5H, m), 7.20 (1H, d, J = 7.8Hz), 7.32 (1H, d, J = 7.8Hz).
Example 185 By reaction and treatment in the same manner as in Example 162 using 2-methoxyaniline (0.12 g) as the starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] was obtained] –7 – methoxy-N– (2– methoxyphenyl) –1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.29 g). image 1
1H-NMR (DMSO-d6) δ: 1.32-1.42 (1H, m), 1.74-1.92 (3H, m), 2.49-2.68 (2H, m, 2, 85 (6H, s), 3.47-3.51 (1H, m), 3.63 (1.5H, s), 3.71 (1.5H, s), 3.82 (1.5H, s), 3.84 (1.5H, s), 3.99 (0.5H, d, J = 14.1Hz), 4.11 (0.5H, d, J = 14.1Hz), 5, 17 (0.5H, d, J = 14.1Hz), 5.33 (0.5H, d, J = 14.1Hz), 6.46 (0.5H, d, J = 2.4Hz), 6 , 60–6.70 (3.5H, m), 6.89–7.03 (5H, m), 7.16 (1H, d, J = 8.4Hz), 7.30–7.35 ( 1H, m).
Example 186 image4
Through the reaction and treatment in the same manner as in Example 162 using 3-methoxyaniline (0.12 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl) -7 was obtained –Methoxy-N– (3– methoxyphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.20 g).
1H-NMR (DMSO-d6) δ: 1.33-1.42 (1H, m), 1.81-1.96 (3H, m), 2.55-2.70 (2H, m), 2 , 86 (6H, s), 3.65 (3H, s), 3.70
15 (3H, s), 3.61-3.73 (1H, m), 4.62 (1H, d, J = 14.2Hz), 4.91 (1H, d, J = 14.2Hz), 6.46 (1H, d, J = 2.4Hz), 6.46–6.76 (5H, m), 6.91–7.02 (4H, m), 7.32 (1H, t, J = 8.0Hz).
Example 187 image 1
By reaction and treatment in the same manner as in Example 162 using 4-ethoxyaniline (0.14 g) 20 as a starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] - was obtained N– (4-ethoxyphenyl) –7-methoxy– 1,2,3,4-ttrahydronaphthalen-1-carboxamide (0.28 g).
1H-NMR (DMSO-d6) δ: 1.25-1.40 (1H, m), 1.27 (3H, t, J = 6.9Hz), 1.78-1.94 (3H, m) , 2.54-2.64 (2H, m), 2.86 (6H, s) 3.57-3.63 (1H, m), 3.67 (3H, s), 3.99 (2H, q, J = 6.9Hz), 4.58 (1H, d, J = 14.1Hz), 4.87 (1H, d, J = 14.1Hz) 6.44 (1H, d, J = 2, 4Hz), 6.63 (2H, d, J = 8.4Hz), 6.70 (1H, dd, J = 2.4, 8.4Hz), 6.91–7.09 (7H, m).
Example 188 image5
By reaction and treatment in the same manner as in Example 162 using 4-bromoaniline (0.17 g) as a starting material instead of aniline, N- (4-bromophenyl) -N - [( 4-dimethylaminophenyl) methyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.25 g).
1H-NMR (DMSO-d6) δ: 1.36-1.47 (1H, m) 1.79-1.94 (3H, m), 2.51-2.64 (2H, m), 2, 86 (6H, s), 3.55-3.60 (1H, m)
10 3.67 (3H, s), 4.65 (1H, d, J = 14.1Hz), 4.88 (1H, d, J = 14.1Hz), 6.44 (1H, d, J = 2.4Hz), 6.63 (2H, d, J = 8.7Hz), 6.67–6.73 (1H, m) 6.95–7.03 (3H, m), 7.16 (2H , d, J = 8.4Hz), 7.62 (2H, d, J = 8.4Hz).
Through reaction and treatment in the same manner as in Example 162 using 2,4-dichloroaniline (0.16
15 g) as the starting material instead of aniline, N- (2,4-dichlorophenyl) -N - [(4-dimethylaminophenyl) methyl] -7- methoxy-1,2,3,4-tetrahydronaphthalen-1 was obtained -Carboxamide (0.12 g).
1H-NMR (CDCl3) δ: 1.42-1.56 (1H, m), 1.75-1.86 (1H, m), 1.9.7-2.05 (2H, m), 2 , 56–2.63 (1H, m), 2.72–2.82 (1H, m), 2.94 (6H, s), 3.40–3.48 (1H, m), 3.65 (1.5H, s), 3.75 (1.5H, s), 3.82 (0.5H, d, J = 14.0Hz), 3.92 (0.5H, d, J = 14, 1Hz), 5.63 (0.5H, d, J = 14.1Hz), 5.78 (0.5H, d, J = 14.0Hz), 6.41-6.42 (0.5H, m ), 6.60–6.82 (4.5H, m), 6.94–7.15 (4H, m),
20 7.54–7.55 (1H, m).
Example 190 By reaction and treatment in the same manner as in Example 162 using 2,4-dimethylaniline (0.12 g) as a starting material instead of aniline, N - [(4-dimethylaminophenyl) was obtained methyl] -N- (2,4-dimethylphenyl) -7- methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.29 g). image7 image 1
1H-NMR (CDCl3) δ: 1.40-1.50 (1H, m), 1.80-2.07 (3H, m), 2.20 (1.8H, s), 2.22 (1 , 2H, s), 2.23 (1.8H, s), 2.30 (1.2H, s) 1.52-1.60 (1H, m), 1.72-1.81 (1H, m), 2.92 (6H, m), 3.45-3.57 (1H, m), 3.60 (1.8H, s), 3.73 (1.2H, s), 3.95 (0.6H, d, J = 13.6Hz), 4.30 (0.4H, d, J = 13.7Hz), 5.24 (0.4H, d, J = 13.7Hz), 5, 56 (0.6H, d, J = 13.6Hz), 6.48-7.17 (10H, m).
Example 191 image 1
By reaction and treatment in the same manner as in Example 162 using 2,4,6-trimethylaniline
10 (0.14 g) as the starting material instead of aniline, N - [(4-dimethylaminophenyl) methyl] -7-methoxy-N- (2,4,6-trimethylphenyl) -1,2,3 was obtained , 4-tetrahydronaphthalen-1-carboxamide (0.095 g).
1H-NMR (CDCl3) δ: 1.37-1.49 (1H, m), 1.69-1.93 (3H, m), 1.90 (3H, s), 2.12 (3H, s ), 2.28 (3H, s), 2.52-2.62 (1H, m), 2.73-2.80 (1H, m), 2.91 (6H, s), 3.41– 3.45 (1H, m), 3.69 (3H, s), 4.17 (1H, d, J = 13.5Hz), 5.5 (1H, d, J = 13.5Hz), 6, 53–6.69 (4H, m), 6.80–6.84 (1H, m), 6.94 (2H, d, J = 8.1Hz), 7.11–7.25 (2H, m ).
15 Example 192 image 1
By reaction and treatment in the same manner as in Example 162 using 2,4-dimethoxyaniline (0.15 g) as a starting material instead of aniline, N- (2,4-dimethoxyphenyl) - was obtained N - [(4-dimethylaminophenyl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.39 g).
1H-NMR (DMSO-d6) δ: 1.37-1.45 (1H, m), 1.74-1.93 (3H, m), 2.55-2.63 (2H, m), 2.85 (3H, s), 2.86 (3H, s), 3.50– 3.54 (1H, m), 3.63–3.83 (9H, m), 3.89 (0, 5H, d, J = 14.1Hz), 3.99-4.05 (0.5H, m), 5.16 (0.5H, d, J = 14.2Hz), 5.32 (0.5H , d, J = 14.1Hz), 6.44-6.70 (6H, m), 6.77-6.81 (1H, m), 6.92-7.03 (3H, m).
Example 193 By reaction and treatment in the same manner as in Example 162 using 5-amino-1,3-dioxaindane (0.14 g) as a starting material, instead of aniline, N- ( 1,3-dioxaindan-5-yl) -N - [(4-dimethylaminophenyl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.12 g). image 1
1H-NMR (DMSO-d6) δ: 1.37-1.43 (1H, m), 1.79-1.94 (3H, m), 2.55-2.64 (2H, m), 2 , 87 (6H, s), 3.64–3.66 (1H, m), 3.67 (3H, s), 4.55–4.62 (1H, m), 4.82–4.89 (1H, m), 6.04–6.06 (2H, m), 6.45 (1H, d, J = 2.4Hz), 6.57–6.72 (4H, m), 6.82 –6.83 (1H, m), 6.89–7.03 (4H, m).
Example 194 image 1
By reaction and treatment in the same manner as in Example 162 using 4-dimethylaminoaniline (0.14 g) as a starting material instead of aniline, N- (4-dimethylaminophenyl) -N- [ (4-dimethylaminophenyl) methyl] –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.16 g).
1H-NMR (DMSO-d6) δ: 1.30-1.40 (1H, m), 1.78-1.94 (3H, m), 2.56-2.64 (2H, m), 2 , 87 (12H, s), 3.64–3.68 (1H, m), 3.66 (3H, s), 4.56 (1H, d, J = 14.1Hz), 4.85 (1H , d, J = 14.1Hz), 6.45 (1H, d, J = 2.4Hz), 6.62–6.71 (5H, m), 6.93–7.02
15 (5H, m).
Example 195 image 1
N - [(4-Aminophenyl) methyl] -N- (4-isopropylfenii) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (6.47 g) was stirred using di-tert dicarbonate –Butyl (in an amount as a solvent) at 80 ° C for 2 h. The reaction mixture 20 was divided into saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give a solid (6.55 g). Of the solid, 2.0 g was dissolved in dimethylformamide (3 mL) and sodium hydride (0.34 g) was added under cooling. The mixture was stirred at the same temperature for 30 min and methyl iodide (0.28 mL) was added to the reaction mixture, followed by stirring for 1 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer is
washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was dissolved in 4 moles / L of HCl / dioxane (5 mL). The mixture was stirred at room temperature for one day. The reaction mixture was divided into saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent evaporated
5 under reduced pressure and the residue obtained was purified by silica gel column chromatography to give N- (4-isopropylphenyl) -7-methoxy-N - [(4-methylaminophenyl) methyl] -1,2,3,4 –Tetrahydronaphthalene – 1 – carboxamide (1.45 g).
1H – NMR (DMSO – d6) δ: 1.17 (3H, d, J = 6.9Hz), 1.19 (3H, d, J = 6.9Hz), 1.30 1.39 (1H, m ), 1.80–1.94 (3H, m), 2.50– 2.64 (2H, m), 2.61 (3H, s), 2.88 (1H, sept, J = 6.9Hz ), 3.55-3.60 (1H, m), 3.67 (3H, s), 4.56 (1H, d, J = 14.1Hz), 4.87 (1H, d, J = 14 , 1Hz), 6.43-6.46 (3H, m), 6.68-6.72 (1H, m), 6.91-6.97 (3H, m), 7.10 (2H, d , J = 8.4Hz), 7.28 (2H, d, J
10 = 8.4Hz).
Example 196 image 1
By reaction and treatment in the same manner as in Example 162 using N - [(4-aminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen –1 – carboxamide (0.33 g) and ethyl iodide
15 (0.07 mL) as starting materials, N - [(4-ethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4- tetrahydronaphthalen-1-carboxamide was obtained (0.29 g).
1 H-NMR (DMSO-d 6) δ: 1.13-1.18 (9H, m), 1.31-1.35 (1H, m), 1.83-1.93 (3H, m), 2 , 49–2.70 (2H, m), 2.86 (1H, sept, J = 6.9Hz), 2.99 (2H, q, J = 7.1Hz), 3.39 3.58 (1H , m), 3.68 (3H, s), 4.57 (1H, d, J = 14.2Hz), 4.90 (1H, d, J = 14.2Hz), 6.47-6.50 (3H, m), 6.69 (1H, dd, J = 2.5, 8.4Hz), 6.92-6.96 (3H, m), 7.11 (2H, d, J = 8, 3Hz), 7.26 (2H, d, J = 8.3Hz).
20 Example 197 image 1
By reaction and treatment in the same manner as in Example 162 using N - [(4-aminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen –1 – carboxamide (0.33 g) and benzyl bromide (0.1 mL) as starting materials, N - [(4-benzylaminophenyl) methyl] –N– (4-isopropylphenyl) –7–
Methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.13 g). Melting point: 135–138 ° C.
Example 198 By reaction and treatment in the same manner as in Example 162 using N - [(4-aminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4 -Tetrahydronaphthalen-1-carboxamide (0.41 g) and pentyl bromide (0.14 mL) as starting materials, N- (4-isopropylphenyl) -7-methoxy-N - [(4– image 1
5 pentylaminophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.19 g).
1H-NMR (CDCl3) δ: 0.90-0.95 (3H, m), 1.23 (6H, d, J = 6.9Hz), 1.36-1.64 (7H, m), 1 , 85-2.04 (3H, m), 2.54-2.61 (1H, m), 2.71-2.92 (2H, m), 3.08 (2H, t, J = 7, 1Hz), 3.59 (1H, brs), 3.66-3.71 (1H, m), 3.69 (3H, s), 4.55 (1H, d, J = 13.9Hz), 5 , 05 (1H, d, J = 13.9Hz), 6.49–6.53 (3H, m), 6.67 (1H, dd, J = 2.6, 8.3Hz), 6.93– 6.98 (3H, m), 7.05–7.08 (2H, m), 7.16 (2H, d, J = 8.3Hz).
10 Example 199 image 1
N– (4-Isopropylphenyl) –7-methoxy-N - ((4-methylaminophenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.77 g) was dissolved in ethanol (8 mL) and butylaldehyde (250 mg) and sodium cyanoborhydride (0.22 g) were added Acetic acid was added to this solution to pH 5-6 and the mixture was stirred at room temperature for 2 h.
The reaction was divided into saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography to give N - {[4– (butylmethylamino) phenyl] methyl} -N- (4-isopropylphenyl) -7-methoxy-1 , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.51 g).
1H – NMR (CDCl3) δ: 0.94 (3H, t, J = 7.3Hz), 1.22 (6H, d, J = 6.9Hz), 1.22–1.57 (5H, m) , 1.87-2.02 (3H, m), 2.52-2.60
20 (1H, m), 2.73-2.86 (2H, m), 2.89 (3H, s), 3.25 (2H, t, J = 6.9Hz), 3.67 (3H, s), 3.67-3.73 (1H, m), 4.54 (1H, d, J = 13.8Hz), 5.08 (1H, d, J = 13.8Hz), 6.53 ( 1H, d, J = 2.4Hz), 6.58 (2H, d, J = 8.7Hz), 6.65 (1H, dd, J = 2.4, 8.4Hz), 6.92 (1H , d, J = 8.4Hz), 6.99 (2H, d, J = 8.4Hz), 7.11–7.22 (4H, m).
Example 200 7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.47 g) and (4-bromophenyl) [(4-dimethylaminophenyl) methyl] amine (0.70 g) were reacted as starting materials, and were treated in the same manner as in Example 12. The solid obtained was dissolved in ethyl acetate (4 mL). To this was added 4 moles / L of HCl / ethyl acetate (0.35 mL) and the precipitated solid was collected by filtration to give N- (4-bromophenyl) -N- [(4-dimethylaminophenyl) methyl] hydrochloride] –7 – methoxy – 1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide (0.65 g). image 1
Melting point: 104-113 ° C
Example 201 image 1
Through reaction and treatment in the same manner as in Example 200 using 7-methoxy acid -
10 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.50 g) and [(4-dimethylaminophenyl) methyl] (4-methoxyphenyl) amine (0.62 g) as starting materials, hydrochloride of N - [(4-dimethylaminophenyl) methyl] -7-methoxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.79 g). Melting point: 152 ° C.
Example 202 image 1
By means of the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.57 g) and [(4-dimethylaminophenyl) methyl] -4-methoxyphenyl) amine (0.51 g) as starting materials, 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N- (4-methoxyphenyl) -1,2,3, 4– tetrahydronaphthalen-1-carboxamide (0.83 g). Through reaction and treatment in the same manner as in Example 17 using this compound, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-methoxyphenyl) -1,2, 3.4–
Tetrahydronaphthalen-1-carboxamide (0.33 g). Melting point: 195–197 ° C.
Example 203 image 1
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.57 g) and [(4-dimethylaminophenyl) methyl ] phenylamine (0.61 g) as materials of
After starting, 5-benzyloxy-N - [(4-dimethylaminophenyl) methyl] -N-phenyl-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.80 g) was obtained. By reaction and treatment in the same manner as in Example 17 using this compound, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N-phenyl-1,2,3,4- was obtained tetrahydronaphthalen-1-carboxamide (0.083 g). Melting point: 138-143 ° C.
Example 204 image 1
Through reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N– (4–
isopropylphenyl) –1,2,3,4-tetratidronaphtaIen-1-carboxamide (0.65 g) and 4– (chloromethyl) -2-methylthiazole (0.30 g) as
5 starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(2-methylthiazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 58 g). By reaction and treatment in the same manner as in Example 133 using this compound (0.51 g), 5-hydroxy-N- (4-isopropylphenyl) -N - [(2-methylthiazole-4) was obtained - il) methyl] -1,2,3,4-tetratidronaphthalen-1-carboxamide (0.22 g).
1H-NMR (CDCl3) δ: 1.22 (6H, d, J = 6.9Hz), 1.38-1.48 (1H, m), 1.82-1.90 (1H, m), 1 , 92-2.00 (2H, m), 2.58-2.60 (2H,
10 m), 2.68 (3H, s), 2.89 (1H, sept, J = 6.9Hz), 3.80-3.84 (1H, m), 5.01 (2H, s), 6.23 (1H, d, J = 7.8Hz), 6.48 (1H, d, J = 7.8Hz), 6.72 (1H, d, J = 7.8Hz), 7.11 (1H , s), 7.17-7.25 (4H, m), 7.69 (1H, s).
Example 205 image 1
Through reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N– (4–
15 methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.63 g) and 4- (chloromethyl) -2-methylthiazole (0.30 g) as starting materials, 5-benzyloxy was obtained N– (4-methoxyphenyl) -N - [(2-methylthiazol-4-yl) methyl] –1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.64 g). Through reaction and treatment in the same manner as in Example 133 using this compound (0.50 g), 5-hydroxy-N- (4-methoxyphenyl) -N - [(2-methylthiazole-4) was obtained -Yl) methyl] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.31 g).
1 H-NMR (CDCl3) δ: 1.39-1.45 (1H, m), 1.79-1.84 (1H, m), 1.90-2.00 (2H, m), 2, 55–2.59 (2H, m), 2.69 (3H, s), 3.78– 3.83 (1H, m), 3.79 (3H, s), 4.97 (1H, d, J = 14.9Hz), 5.02 (1H, d, J – 14.9Hz), 6.25 (1H, d, J = 7.8Hz), 6.48 (1H, d, J = 7.8Hz ), 6.74 (1H, t, J = 7.8Hz), 6.86-6.88 (2H, m), 7.08 (1H, s), 7.13-7.23 (2H, m ), 7.34 (1H, s).
Example 206 image 1
25 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.57 g) and (4-bromophenyl) [ (4-dimethylaminophenyl) methyl] amine (0.61 g) as starting materials, 5-benzyloxy-N- (4-bromophenyl) -N - [(4-dimethylaminophenyl) methyl] -1,2,3, 4– tetrahydronaphthalen-1-carboxamide (1.14 g). By reaction and treatment in the same manner as in Example 133 using this compound, N- (4-bromophenyl) -N - [(dimethylaminophenyl) methyl] -5-hydroxy-1,2,3, 4-
Tetrahydronaphthalen-1-carboxamide (0.23 g). Melting point: 218-220 ° C.
Example 207 image 1
To a solution of 2-tolualdehyde (120 mg) in 1,2-dichloroethane (5 mL) was added 4-isopropylaniline (171 mL), acetic acid (57.2 μL) and sodium triacetoxyborohydride (445 mg), and the mixture was stirred for a day. Hydrogen - saturated aqueous sodium carbonate (2 mL) was added to the reaction solution and the mixture was applied to an ExtruteNT-3 column (Merck) and eluted with ethyl acetate (10 mL) 10 min later. The solution obtained was treated with Sep-Pak Plus Silica (Waters) and the solution obtained was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride (5 mL) and 4-dimethylaminopyridine (30 mg), 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (250 mg) and N-cyclohexylcarbodiimide were added –N'-methylpolystyrene HL (1.5 g). The mixture was stirred for one day and the reaction mixture was filtered under reduced pressure. The solvent was evaporated under reduced pressure
10 and THF (5 mL) and Ambersep 900 OH (800 mg) were added. The mixture was stirred for 3 h. The reaction mixture was filtered under reduced pressure. Aberlyst (1 g) was added and the mixture was stirred for one day. The reaction mixture was filtered under reduced pressure and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give N- (4-isopropylphenyl) -7-methoxy-N- (2-tolylethyl) -1,2,3,4-tetrahydronaphthalene-1-carboxamide (106 mg ).
15 MS (ESI) m / z: 428 [MH] +
Example 208 image 1
By means of the reaction and treatment in the same manner as in Example 207 using 1-naphthaldehyde (156 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy- was obtained. N - [(1-20 naphthyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (258.9 mg).
MS (ESI) m / z: 464 [MH] +
Example 209 image 1
By reaction and treatment in the same manner as in Example 207 using 2,4-25 dichlorobenzaldehyde (175 mg) as a starting material instead of 2-tolualdehyde, N - [(2,4-dichlorophenyl) was obtained ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (258.8 mg).
MS (ESI) m / z: 482 [MH] + Example 210 image 1
By reaction and treatment in the same manner as in Example 207 using 4-nitrobenzaldehyde (151 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy- was obtained. N - [(4– nitrophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (218.9 mg).
MS (ESI) m / z: 459 [MH] +
Example 211 image 1
By reaction and treatment in the same manner as in Example 207 using 3-tolualdehyde (120 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy was obtained. –N– (3-tolylmethyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (145.4 mg).
MS (ESI) m / z: 428 [MH] +
Example 212 image3
By reaction and treatment in the same manner as in Example 207 using 4-tolualdehyde (120 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy- was obtained. N– (4-tolylmethyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (116.4 mg).
MS (ESI) m / z: 428 [MH] +
Example 213 By reaction and treatment in the same manner as in Example 207 using 2-fluorobenzaldehyde (1.24 mg) as a starting material instead of 2-tolualdehyde, N - [(2-fluorophenyl) was obtained. ) methyl] –N– (4– isopropylphenyl) –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (148 mg). image 1
MS (ESI) m / z: 432 [MH] +
Example 214 image 1
By reaction and treatment in the same manner as in Example 207 using 3-fluorobenzaldehyde (124 mg) as a starting material instead of 2-tolualdehyde, N - ((3-fluorophenyl) methyl] -N was obtained - (4-10 isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (190.9 mg).
MS (ESI) m / z: 432 [MH] +
Example 215 image 1
By reaction and treatment in the same manner as in Example 207 using 4-fluorobenzaldehyde 15 (124 mg) as a starting material instead of 2-tolualdehyde, N - [(4-fluorophenyl) methyl] - was obtained N– (4– isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (184.2 mg).
MS (ESI) m / z: 432 [MH] +
Example 216 By reaction and treatment in the same manner as in Example 207 using 3-cyanobenzaldehyde (131 mg) as a starting material instead of 2-tolualdehyde, N - [(3-cyanophenyl) methyl] was obtained. –N– (4– isopropylphenyl) –7-methoxy – 1,2,3,4-tetrahydronaphthalen-1-carboxamide (191 mg). image 1
MS (ESI) m / z: 439 [MH] +
Example 217 image 1
Through reaction and treatment in the same manner as in Example 207 using 2,4-dimethylbenzaldehyde (134 mg) as a starting material instead of 2-tolualdehyde, N - [(2,4-10 dimethylphenyl) was obtained ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (119.4 mg).
MS (ESI) m / z: 442 [MH] +
Example 218 image 1
Through reaction and treatment in the same manner as in Example 207 using 2.5–
15 dimethylbenzaldehyde (134 mg) as the starting material instead of 2-tolualdehyde, N - [(2,5-dimethylphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3, 4-tetrahydronaphthalen-1-carboxamide (123.3 mg). MS (ESI) m / z: 442 [MH] +
Example 219 By reaction and treatment in the same manner as in Example 207 using 2-methoxybenzaldehyde (136 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7- methoxy-N - [(2-methoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (190.9 mg). image 1
MS (ESI) m / z: 444 [MH] +
Example 220 image 1
By reaction and treatment in the same manner as in Example 207 using 3-methoxybenzaldehyde (136 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -N - [( 3– 10 methoxyphenyl) methyl] –7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carbbxamide (173.1 mg).
MS (ESI) m / z: 444 [MH] +
Example 221 image 1
By reaction and treatment in the same manner as in Example 207 using 2-chlorobenzaldehyde 15 (141 mg) as a starting material instead of 2-tolualdehyde, N - [(2-chlorophenyl) methyl] - was obtained N– (4– isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (117.5 mg).
MS (ESI) m / z: 448 [MH] +
Example 222 By reaction and treatment in the same manner as in Example 207 using 3-chlorobenzaldehyde (141 mg) as a starting material instead of 2-tolualdehyde, N - [(3-chlorophenyl) methyl] was obtained. –N– (4– isopropylphenyl) –7-methoxy – 1,2,3,4-tetrahydronaphthalen-1-carboxamide (197.6 mg). image 1
MS (ESI) m / z: 448 [MH] +
Example 223 image 1
Through the reaction and treatment in the same manner as in Example 207 using 2,3-difluorobenzaldehyde (142 mg) as a starting material instead of 2-tolualdehyde, N - [(2,3-10 difluorophenyl) was obtained ) methyl} –N– (4-isopropylphenyl) –7-methoxy] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (130.2 mg).
MS (ESI) m / z: 450 [MH] +
Example 224 image 1
By reaction and treatment in the same manner as in Example 207 using 2,4-15 difluorobenzaldehyde (142 mg) as a starting material instead of 2-tolualdehyde, N - [(2,4- difluorophenyl) was obtained ) methyl] -5-N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (179.1 mg).
MS (ESI) m / z: 450 [MH] +
Example 225 By reaction and treatment in the same manner as in Example 207 using 2,5-difluorobenzaldehyde (142 mg) as a starting material instead of 2-tolualdehyde, N - [(2,5- difluorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (212.6 mg). image 1
MS (ESI) m / z: 450 [MH] +
Example 226 image 1
Through the reaction and treatment in the same manner as in Example 207 using 2,6-difluorobenzaldehyde (142 mg) as a starting material instead of 2-tolualdehyde, N - [(2,6-10 difluorophenyl) was obtained ) methyl) -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (87.8 mg).
MS (ESI) m / z: 450 [MH] +.
Example 227 image 1
By reaction and treatment in the same manner as in Example 207 using 3,4-15 difluorobenzaldehyde (142 mg) as a starting material instead of 2-tolualdehyde, N - [(3,4- difluorophenyl) was obtained ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (126.6 mg).
MS (ESI) m / z: 450 [MH] +
Example 228 By reaction and treatment in the same manner as in Example 207 using 3,5-difluorobenzaldehyde (142 mg) as a starting material instead of 2-tolualdehyde, N - [(3,5- difluorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (151 mg). image 1
MS (ESI) m / z: 450 [MH] +
Example 229 image 1
Through the reaction and treatment in the same manner as in Example 207 using 2,3-methylenedioxybenzaldehyde (150 mg) as the starting material instead of 2-tolualdehyde, N - [(1,3-10 dioxaindan) was obtained –4-yl) methy] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (184.4 mg).
MS (ESI) m / z: 458 [MH] +
Example 230 image 1
By reaction and treatment in the same manner as in Example 207 using 4-ethoxybenzaldehyde 15 (150 mg) as a starting material instead of 2-tolualdehyde, N - [(4-ethoxyphenyl) methyl] - was obtained N– (4– isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboamide (177.4 mg).
MS (ESI) m / z: 458 [MH] +
Example 231 By reaction and treatment in the same manner as in Example 207 using 3,4-ethylenedioxybenzaldehyde (164 mg) as starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) - was obtained 7-methoxy-N - [(4-oxacroman-6-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (167.6 mg). image 1
MS (ESi) m / z: 472 [MH] +
Example 232 image 1
By reaction and treatment in the same manner as in Example 207 using 4-propoxybenzaldehyde (164 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -10-7-methoxy was obtained. –N - [(4-propoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (172.6 mg).
MS (ESI) m / z: 472 [MH] +
Example 233 image 1
By reaction and treatment in the same manner as in Example 207 using 3.5-15 dimethoxybenzaldehyde (166 mg) as a starting material instead of 2-tolualdehyde, N - [(3,5-dimethoxyphenyl) ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (199.9 mg).
MS (ESI) m / z: 474 [MH] +
Example 234 By reaction and treatment in the same manner as in Example 207 using 2,3-dimethoxybenzaldehyde (166 mg) as a starting material instead of 2-tolualdehyde, N - [(2,3- dimethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (332 mg). image 1
MS (ESI) m / z: 474 [MH] +.
Example 235 image 1
By reaction and treatment in the same manner as in Example 207 using 2,4-dimethoxybenzaldehyde (166 mg) as a starting material instead of 2-tolualdehyde, N - [(2,4-10 dimethoxyphenyl) ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (69.3 mg).
MS (ESI) m / z: 474 [MH] +
Example 236 image 1
By reaction and treatment in the same manner as in Example 207 using 2.5-15 dimethoxybenzaldehyde (166 mg) as a starting material instead of 2-tolualdehyde, N - [(2,5-dimethoxyphenyl) ) methyl) -N- (4-isopropylphenyl) -7-methoxy-1,3,4-tetrahydronaphthalen-1-carboxamide (122.5 mg).
MS (ESI) m / z: 474 [MH] +
Example 237 By reaction and treatment in the same manner as in Example 207 using 2,6-dimethoxybenzaldehyde (166 mg) as a starting material instead of 2-tolualdehyde, N - [(2,6- dimethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-oxamide (248.9 mg). image 1
MS (ESI) m / z: 474 [MH] +
Example 238 image 1
Through the reaction and treatment in the same manner as in Example 207 using 3,4-dimethoxybenzaldehyde (166 mg) as a starting material instead of 2-tolualdehyde, N - [(3,4-10 dimethoxyphenyl) ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (96.1 mg).
MS (ESI) m / z: 474 [MH] +
Example 239 image 1
By reaction and treatment in the same manner as in Example 207 using 2–15 trifluoromethylbenzaldehyde (174 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy was obtained –N - [(2-Trifluoromethylphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (179.1 mg).
MS (ESI) m / z: 482 [MH] +
Example 240 By reaction and treatment in the same manner as in Example 207 using 3-trifluoromethylbenzaldehyde (174 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7- was obtained methoxy-N- (fluoromethylphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (186.2 mg). image 1
MS (ESI) m / z: 482 [MH] +
Example 241 image 1
By reaction and treatment in the same manner as in Example 207 using 4-trifluoromethylbenzaldehyde (174 mg) as starting material instead of 2-tolualdehyde, N- (4-10 isopropylphenyl) -7-methoxy was obtained –N - [(4-trifluoromethylphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (207.9 mg).
MS (ESI) m / z: 482 [MH] +
Example 242 image 1
By reaction and treatment in the same manner as in Example 207 using 2,3-15 dichlorobenzaldehyde (175 mg) as a starting material instead of 2-tolualdehyde, N - [(2,3-dichlorophenyl) was obtained ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (302.3 mg).
MS (ESI) m / z: 482 [MH] +
Example 243 By reaction and treatment in the same manner as in the Example. 207 using 2,6-dichlorobenzaldehyde (175 mg) as a starting material instead of 2-tolualdehyde, N - [(2,6-dichlorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1 was obtained , 2,3,4-tetrahydronaphthalen-1-carboxamide (93.1 mg). image 1
MS (ESI) m / z: 482 [MH] +
Example 244 image 1
Through the reaction and treatment in the same manner as in Example 207 using 3,4-dichlorobenzaldehyde (175 mg) as a starting material instead of 2-tolualdehyde, N - [(3,4-10 dichlorophenyl) was obtained ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (288.2 mg).
MS (ESI) mn / z: 482 [MH] +
Example 245 image 1
By reaction and treatment in the same manner as in Example 207 using 3.5-15 dichlorobenzaldehyde (175 mg) as a starting material instead of 2-tolualdehyde, N - [(3,5- dichlorophenyl) was obtained ) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (3,044 mg).
MS (ESI) m / z: 462 [MH] +
Example 246 By reaction and treatment in the same manner as in Example 207 using 2-bromobenzaldehyde (185 mg) as a starting material instead of 2-tolualdehyde, N - [(2-bromophenyl) methyl) was obtained. –N– (4– isopropylphenyl) –7-methoxy – 1,2,3,4-tetrahydronaphthalen-1-carboxamide (157.6 mg). image 1
MS (ESI) m / z: 492 [MH] +
Example 247 image 1
By reaction and treatment in the same manner as in Example 207 using 3-bromobenzaldehyde (185 mg) as a starting material instead of 2-tolualdehyde, N - [(3-bromophenyl) methyl] -N was obtained - (4-10 isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide (214.4 mg).
MS (ESI) m / z: 492 [MH] +
Example 248 image 1
By reaction and treatment in the same manner as in Example 207 using 2,3,4-15 trimethoxybenzaldehyde (196 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) was obtained. - 7-methoxy-N - [(2,3,4-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (365.1 mg).
MS (ESI) m / z: 504 [MH] +
Example 249 By reaction and treatment in the same manner as in Example 207 using 3,4,5-trimethoxybenzaldehyde (196 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) was obtained. ) - 7-methoxy-N - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (139.3 mg). image 1
MS (ESI) m / z: 504 [MH] +
Example 250 image 1
By reaction and treatment in the same manner as in Example 207 using 3-phenoxybenzaldehyde (198 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy- was obtained. N - [(3– 10 phenoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (153.8 mg).
MS (ESI) m / z: 506 [MH] +
Example 251 image 1
By reaction and treatment in the same manner as in Example 207 using 4-phenoxybenzaldehyde 15 (198 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) -7-methoxy was obtained –N - [(4– phenoxyphenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (188.1 mg).
MS (ESI) m / z: 506 [MH] +
Example 252 By reaction and treatment in the same manner as in Example 207 using 2,3,5-trichlorobenzaldehyde (209 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) was obtained. ) - 7-methoxy-N - [(2,3,5-trichlorophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (400.7 mg). image 1
MS (ESI) m / z: 516 [MH] +
Example 253 image 1
By reaction and treatment in the same manner as in Example 207 using 2,3,6-trichlorobenzaldehyde (2099 mg) as a starting material instead of 2-tolualdehyde, N- (4-isopropylphenyl) - was obtained 10 7-Methoxy-N - [(2,3,6-trichlorophenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (112.7 mg).
MS (ESI) m / z: 516 [MH] +
Example 254 image 1
Through reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N– (4–
15 isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (5.94 g) and 1- (tert-butoxycarbonyl) -4- (hydroxymethyl) pyrazole (2.95 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (3.00 g) was obtained.
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 7.0Hz), 1.44-1.50 (1H, m), 1.82-2.05 (3H, m 2.69 –2.74 (2H, m), 2.87–2.94 (1H, m) 3.70–3.75 (1H, m), 4.69 (1H, d, J = 14.4Hz), 4.86 (1H, d, J = 14.4Hz), 6.58 (1H, d, J = 7.8Hz), 6.70 (1H, d, J =
20 7.8Hz), 7.01-7.07 (3H, m), 7.21-7.42 (7H, m), 7.51 (2H, s).
Example 255 By reaction and treatment in the same manner as in Example 83 using N- (4-isopropylphenyl) -7- methoxy-N - [(pyrazol-4-yl) methyl] -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (1.32 g) and methyl bromoacetate (0.31 mL) as starting materials, 2– (4 - {[N– (4-isopropylphenyl) –N– (7 –Methoxy – 1,2,3,4 – tetrahydronaphthalen – 1– image 1
Ylcarbonyl) amino] methyl} pyrazol-lyl) methyl acetate (0.35 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.37-1.53 (1H, m), 1.78-2.07 (3H, m), 2 , 52–2.62 (1H, m), 2.68–2.85 (1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.64–3.73 (1H, m), 3.69 (3H, s), 3.77 (3H, s), 4.60 (1H, d, J = 13.9Hz), 4.87 (1H, d, J = 13.9Hz) , 4.88 (2H, s), 6.45 (1H, d, J = 2.4Hz), 6.66 (1H, dd, J = 2.4, 8.4Hz), 6.95 (1H, d, J = 8.4Hz), 7.06 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4Hz), 7.42 (1H, s), 7, 49 (1H, s)
10 Example 256 image 1
2– (4 - {[N– (4-isopropylphenyl) -N- (7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) amino] methyl} pyrazol-1-yl) methyl acetate ( 0.34 g) was dissolved in a mixed solvent (10 mL) of ethanol: THF (2: 1) and sodium borhydride (0.11 g) and lithium chloride (0.12 g) were added. The mixture was stirred. at 50 ° C for 3 h. The reaction mixture was concentrated to
The pressure was reduced and it was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N - ((1– (2-hydroxyethyl) pyrazol-4-yl) methyl) -N- (4-isopropylphenyl) -7-methoxy-1 , 2,3,4– tetrahydronaphthalen-1-carboxamide (0.23 g).
1H-NMR (CDCl3) δ: 1.20 (6H, d, J = 6.9Hz), 1.28-1.45 (1H, m), 1.77-1.99 (3H, m), 2 , 47-2.71 (2H, m), 2.91 (1H, sept,
20 J = 6.9Hz), 3.52–3.62 (1H, m), 3.64 (3H, s), 3.68 (2H, t, J = 5.6Hz), 4.08 (2H , t, J = 5.6Hz), 4.57 (1H, d, J = 13.9Hz), 4.76 (1H, d, J = 13.9Hz), 6.40 (1H, d, J = 2.4Hz), 6.69 (1H, dd, J = 2.4, 8.4Hz), 6.94 (1H, d, J = 8.4Hz), 7.19 (2H, d, J = 8 , 4Hz), 7.25 (1H, s), 7.33 (2H, d, J = 8.4Hz), 7.52 (1H, s).
Example 257 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2, 3,4-tetrahydronaphthalen-1-carboxamide (1.00 g) and ethyl bromoacetate (0.40 mL) as starting materials, 2– (5– {N - [(1-ethylpyrazole-4-yl)) was obtained methyl] –N– (4-isopropylphenyl) carbamoyl} -5,6,7,8-tetrahydronaphthalen-1-yloxy) ethyl acetate (1.09 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.28 (3H, t, J = 7.1Hz), 1.45 (3H, t, J = 7, 1Hz), 1.39-1.56 (1H, m), 1.78-2.06 (3H, m), 2.61-2.85 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.64-3.74 (1H, m), 4.12 (2H, q, J = 7.1Hz), 4.18 (2H, q, J = 7.1Hz), 4.56 (2H, s), 4.59 (1H, d, J = 13.9Hz), 4.83 (1H, d, J = 13.9Hz), 6.53 (1H, d, J = 8 , 1Hz), 6.59 (1H, d, J = 8.1Hz), 7.01 (1H, t, J = 8.1Hz), 7.05 (2H, d, J = 8.4Hz), 7 , 22 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.41 (1H, s).
Example 258 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -6-hydroxy-N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (1.00 g) as starting material, 2– (5– {N - [(1-ethylpyrazol-4-yl) methyl) -N- (4-isopropylphenyl) carbamoyl was obtained ) –5,6,7,8 – tetrahydronaphthalen – 2–
10-yloxy) ethyl acetate (1.11 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.30 (3H, t, J = 7.1Hz), 1.45 (3H, t, J = 7, 1Hz), 1, З9–1.57 (1H, m), 1.79–2.02 (3H, m), 2.52–2.67 (1H, m), 2.74–2.89 ( 1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.59-3.69 (1H, m), 4.12 (2H, q, J = 7.1Hz), 4, 25 (2H, q, J = 7.1Hz), 4.54 (2H, s), 4.59 (1H, d, J = 13.9Hz), 4.81 (1H, d, J = 13.9Hz ), 6.58 (1H, d, J = 2.4Hz), 6.65 (1H, dd, J = 2.4, 8.4Hz), 6.82 (1H, d, J = 8.4Hz) , 7.04 (2H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.4Hz), 7.33
15 (1H, s), 7.40 (1H, s).
Example 259 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (1.00 g) as starting material, 20 obtained 2– (8– {N - [(1-ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) carbamoyl} -5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl acetate (0.94 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.31 (3H, t, J = 7.1Hz), 1.45 (3H, t, J = 7, 1Hz), 1.37–1.55 (1H, m), 1.78–2.05 (3H, m), 2.51–2.65 (1H, m), 2.70–2.84 ( 1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.61-3.72 (1H, m), 4.14 (2H, q, J = 7.1Hz), 4, 27 (2H, q, J = 7.1Hz), 4.51 (2H, s), 4.65 (1H, d, J = 13.9Hz), 4.76 (1H, d, J = 13.9Hz ), 6.50 (1H, d, J =
25 2.4Hz), 6.65 (1H, dd, J = 2.4, 8.4Hz), 6.95 (1H, d, J = 8.4Hz), 7.05 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4Hz), 7.31 (1H, s), 7.42 (1H, s).
Example 260 By reaction and treatment in the same manner as in Example 12 using 4-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl) methyl] (4– Isopropylphenyl) amine (0.37, g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -4-methoxyindan-1-carboxamide (0, 39 g). image 1
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.31 (3H, t, J = 7.1Hz), 2.01-2.17 (1H, m) , 2.24–2.39 (1H, m), 2.60–2.75 (1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.00–3.12 ( 1H, m), 3.79 (3H, s), 3.96 (1H, t, J = 6.2Hz), 4.12 (2H, q, J = 7.1Hz) 4.65 (1H, d , J = 13.9Hz), 4.79 (1H, d, J = 13.9Hz), 6.66 (2H, d, J = 8.4Hz), 6.99 7.16 (3H, m), 7.23 (2H, d, J = 8.4Hz), 7.31 (1H, s), 7.39 (1H, s).
Example 261 image 1
10 By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2, 3,4-tetrahydronaphthalen-1-carboxamide (0.42 g) and 2-chloro-N, N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 5– [2– (dimethylamino) ethyloxy] was obtained. –N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.15 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.1Hz), 1.39-1.53 (1H, m) , 1.71-2.07 (3H, m), 2.35 (6H,
15 s), 2.56-2.69 (2H, m), 2.75 (2H, t, J = 5.8Hz), 2.92 (1H, sept, J = 6.9Hz), 3.66 –3.75 (1H, m), 4.04 (2H, t, J = 5.8Hz), 4.12 (2H, q, J = 7.1Hz), 4.58 (1H, d, J = 13.9Hz), 4.83 (1H, d, J = 13.9Hz), 6.54 (1H, d, J = 8.1Hz), 6.64 (1H, d, J = 8.1Hz), 6.98–7.22 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.41 (1H, s).
Example 262 image 1
20 By reaction and treatment in the same manner as in Example 256 using 2– (5– {N - [(1– ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) carbamoyl) - 5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl acetate (0.56 g) as a starting material, N - [(1-ethylpyrazol-4-yl) methyl] -6- (2– hydroxyethoxy) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.46 g). Melting point: 137.3 ° C.
1H – NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 1.40–1.55 (1H, m) , 1.80-2.12 (3H, m), 2.53-2.68
25 (1H, m), 2.77-3.00 (2H, m) 3.59-3.69 (1H, m), 3.87-3.95 (2H, m), 3.97-4 , 05 (2H, m), 4.13 (2H, q, J = 7.3Hz), 4.60 (1H, d, J = 13.9Hz), 4.81 (1H, d, J = 13, 9Hz), 6.60 (1H, d, J = 2.4Hz), 6.65 (1H, dd, J = 2.4, 8.4Hz), 6.82 (1H, d, J = 8.4Hz ) ‚7.04 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.40 (1H, s).
Example 263 By reaction and treatment in the same manner as in Example 256 using 2– (5– {N - [(1– ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) carbamoyl} -5,6,7,8-tetrahydronaphthalen-1-yloxy) ethyl acetate (0.60 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -5- (2 -Hydroxyethoxy) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.46 g). image 1
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.1Hz), 1.39-1.55 (1H, m) , 1.77-2.19 (3H, m), 2.60-2.72 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.66-3.73 ( 1H, m), 3.87-3.96 (2H, m), 4.03 (2H, t, J = 4.3Hz) 4.13 (2H, q, J = 7.1Hz), 4.59 (1H, d, J = 13.9Hz), 4.83 (1H, d, J = 13.9Hz), 6.57 (1H, d, J = 8.1Hz), 6.65 (1H, d, J = 8.1Hz), 6.97–7.10 (3H, m) 7.22 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.40 (1H, s ).
Example 264 image4
By reaction and treatment in the same manner as in Example 256 using 2– (8– {N - [(1– ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) -carbamoyl} - 5,6,7,8-tetrahydronaphthalen-2-yloxy) ethyl acetate (0.47 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -7- (2– hydroxyethoxy) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.40 g).
15 1H – NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.1Hz), 1.39-1.55 (1H, m ), 1.69-2.05 (3H, m), 2.51-2.84 (3H, m), 2.93 (1H, Sept, J = 6.9Hz), 3.63-3.72 (1H, m), 3.82-3.98 (4H, m), 4.13 (2H, q, J = 7.1Hz), 4.43 (1H, d, J = 13.9Hz), 4 , 99 (1H, d, J = 13.9Hz), 6.41 (1H, d, J = 2.4Hz), 6.66 (1H, dd, J = 2.4, 8.4Hz), 6, 94 (1H, d, J = 8.4Hz), 7.08 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.4Hz), 7.44 (2H, s ).
Example 265 image2
By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -6-hydroxy-N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.42 g) and 2-chloro-N, N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 6– [2– (dimethylamino) ethoxy] was obtained - N - [(1-ethylpyrazol-4-yl) methyl) -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.19 g).
25 1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.43 (3H, t, J = 7.1Hz), 1.40-1.53 (1H, m ), 1.69-2.04 (3H, m), 2.31 (6H, s), 2.52-2.67 (1H, m), 2.69 (2H, t, J = 5.8Hz ), 2.73-2.90 (1H, m), 2.92 (1H, sept, J = 6.9Hz), 3.60–3.70 (1H, m), 4.00 (2H, t , J = 5.8Hz), 4.12 (2H, q, J = 7.1Hz), 4.58 (1H, d, J = 13.9Hz), 4.82 (1H, d, J = 13, 9Hz), 6.59 (1H, d, J = 2.4Hz), 6.66 (1H, dd, J = 2.4, 8.4Hz) 6.80 (1H, d, J = 8.4Hz) , 7.04 (2H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.4Hz), 7.32 (1H, s), 7.40 (1H, s).
Example 266 By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -7-hydroxy-N- (4-isopropylphenyl) -1, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.42 g) and 2-chloro-N, N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 7– [2– (dimethylamino) was obtained ethoxy] –N - [(1 – ethylpyrazole – 4– image 1
5-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.15 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.43 (3H, t, J = 7.1Hz), 1.39-1.56 (1H, m) , 1.77-2.07 (3H, m), 2.33 (6H, s), 2.50-2.83 (4H, m), 2.92 (1H, sept, J = 6.9Hz) , 3.63-3.73 (1H, m), 3.94 (2H, t, J = 5.8Hz), 4.13 (2H, q, J = 7.1Hz), 4.63 (1H, d, J = 13.9Hz), 4.78 (1H, d, J = 13.9Hz), 6.48 (1H, d, J = 2.4Hz), 6.68 (1H, dd, J = 2 , 4, 8.4Hz), 6.94 (1H, d, J = 8.4Hz), 7.06 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8, 4Hz), 7.32 (1H, s), 7.41 (1H, s).
10 Example 267 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.42 g) and 3-chloro-N, N-dimethylpropylamine hydrochloride (0.24 g) as starting materials, 5– [3– (dimethylamino) propoxy] was obtained - N - [(1–
Ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide. This was dissolved in ethyl acetate and oxalic acid (0.12 g) was added. The precipitated solid was collected by filtration to give 5– [3– (dimethylamino) propoxy] -N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide 3/2 oxalate (0.36 g). Melting point: 142.6 ° C.
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.44 (3H, t, J = 7.1Hz), 1.36-1.57 (1H, m) 1.72-2.07 (3H, m), 2.14-2.31
20 (2H, m), 2.52-2.67 (2H, m), 2.88 (6H, s) 2.92 (1H, sept, J = 6.9Hz), 3.20-3.47 (2H, m), 3.67–3.78 (1H, m), 3.92–4.08 (2H, m), 4.14 (2H, q, J = 7.1Hz), 4.58 (1H, d, J = 13.9Hz), 4.80 (1H, d, J = 13.9Hz), 6.53 (1H, d, J = 8.1Hz), 6.59 (1H, d, J = 8.1Hz), 6.96–7.10 (3H, m), 7.24 (2H, d, J = 8.4Hz), 7.36 (1H, s), 7.40 (1H, s).
Example 268 image 1
By reaction and treatment in the same manner as in Example 106 using N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) -1,2, 3,4-tetrahydronaphthalen-1-carboxamide (0.46 g) and 1,4-dibromobutane (1.33 mL) as starting materials, 5– (4-bromobutoxy) -N - [(1-ethylpyrazole) was obtained 4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.52 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.38-1.51 (1H, m), 1.45 (3H, t, J = 7.1Hz) , 1.66-2.10 (7H, m), 2.57-2.69 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.48 (2H, t, J = 5.8Hz), 3.65-3.75 (1H, m), 3.94 (2H, t, J = 5.8Hz), 4.13 (2H, q, J = 7.1Hz), 4.58 (1H, d, J = 13.9Hz), 4.84 (1H, d, J = 13.9Hz), 6.54 (1H, d, J = 8.4Hz), 6.62 (1H , d, J = 8.4Hz), 6.96–7.09 (3H, m), 7.22 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.41 (1H, s).
Example 269 image 1
To a solution 5– (4-bromobutoxy) -N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalene-1-carboxamide (0, 52 g) in acetonitrile (10 mL) dimethylamine hydrochloride (0.69 g) and potassium carbonate (1.30 g) were added and the mixture was heated at reflux for 1.5 h. The reaction mixture was concentrated under pressure.
10 reduced and the residue was divided into water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 5– [4– (dimethylamino) butoxy] –N - [(1-ethylpyrazol-4-yl) methyl] –N– (4– isopropylphenyl) -1,2,3,4- tetrahydronaphthalen 1-carboxamide (0.27 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.45 (3H, t, J = 7.1Hz) , 1.64-2.07 (7H, m), 2.31 (6H,
15 s), 2.39-2.71 (4H, m), 2.92 (1H, sept, J = 6.9Hz), 3.65-3.76 (1H, m), 3.92 (2H , t, J = 5.8Hz), 4.12 (2H, q, J = 7.1Hz), 4.58 (1H, d, J = 13.9Hz), 4.83 (1H, d, J = 13.9Hz), 6.53 (1H, d, J = 8.0Hz), 6.62 (1H, d, J = 8.0Hz), 6.96–7.10 (3H, m), 7, 22 (2H, d, J = 8.4Hz), 7.33 (1H, s), 7.41 (1H, s).
Example 270 image 1
By reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.35 g) and (4-isopropylphenyl) [(1-phenylpyrazole –4-yl) methyl] amine (0.58 g) as starting materials, N- (4-isopropylphenyl) -N - [(1-phenylpyrazol-4-yl) methyl] -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.42 g).
1H-NMR (CDCl3) δ: 1.25 (6H, d, J = 6.9Hz), 1.41-1.60 (1H, m), 1.83-2.09 (3H, m. 2, 59-2.72 (1H, m), 2.79-3.00 (2H,
25 m), 3.70–3.81 (1H, m), 4.72 (1H, d, J = 14.4Hz), 4.89 (1H, d, J = 14.4Hz), 6.90 –6.99 (1H, m), 7.17 (5H, m), 7.21–7.31 (3H, m), 7.37–7.47 (2H, m), 7.58 (1H , s), 7.66 (2H, d, J = 9.0Hz), 7.94 (1H, s).
Example 271 image 1
5
10
fifteen
twenty
25
30
To a solution of 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.27 g) in chloride of methylene (2 mL) tetra-n-butylammonium hydrogen sulfate (0.66 g), 2– (chloromethyl) pyridine hydrochloride (0.19 g) and 1 mol / L of aqueous sodium hydroxide solution were added (2.26 mL) and the mixture was stirred at room temperature for one day. The reaction mixture was divided into water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N- (4-isopropylphenyl) -N- {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.19 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.38-1.56 (1H, m), 1.78-2.07 (3H, m), 2 , 61–2.82 (2H, m), 2.91 (1H, sept, J = 6.9Hz), 3.67–3.77 (1H, m), 4.64 (1H, d, J = 14.4Hz), 4.86 (1H, d, J = 14.4Hz), 5.01 (2H, s), 5.40 (2H, s), 6.59 (1H, d, J = 7, 7Hz), 6.69 (1H, d, J = 8.2Hz), 6.87–7.08 (4H, m), 7.15–7.49 (10H, m), 7.57–7, 66 (1H, m), 8.56 (1H, d, J = 5.7Hz).
Example 272 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (4-isopropylphenyl) -N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.19 g) as a starting material, 5-hydroxy-N- (4-isopropylphenyl) -N - {[1– ( 2-pyridylmethyl) pyrazol-4-yl] methyl) -1,2,3,4-terahydronaphthalen-1-carboxamide (0.08 g).
MS (ESI) m / z: 481 [MH] +
1H – NMR (DMSO – d6) δ: 1.19 (6H, d, J = 6.9Hz), 1.27–1.42 (1H, m), 1.70–2.00 (3H, m) , 2.37-2.57 (2H, m), 2.91 (1H, sept, J = 6.9Hz), 3.50-2.60 (1H, m), 4.66 (1H, d, J = 14.7Hz), 4.73 (1H, d, J = 14.7Hz), 5.56 (2H, s), 6.41 (1H, d, J = 7.5Hz), 6.60 ( 1H, d, J = 7.8Hz), 6.85 (1H, t, J = 7.8Hz), 7.10–7.22 (3H, m), 7.27–7.37 (3H, m ) 7.59–7.68 (1H, m) 7.74 (1H, s), 8.14 (1H, m), 8.73 (1H, d, J = 4.5Hz).
Example 273 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.36 g) and benzyl bromide (0.18 mL) as starting materials, 5-benzyloxy-N - [(1-benzylpyrazol-4-yl) was obtained ) methyl] –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.34 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.54 (1H, m), 1.76-2.06 (3H, m), 2 , 61–2.78 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.58–3.68 (1H, m), 4.60 (1H, d, J = 14.7Hz), 4.84 (1H, d, J = 14.7Hz), 5.01 (2H, s), 5.24 (2H, s), 6.52 (1H, d, J = 7, 8Hz), 6.70 (1H, d, J = 8.1Hz), 6.98 (1H, t, J = 8.0Hz), 7.11–7.18 (3H, m), 7.22– 7.43 (11H, m), 8.38 (1H, d, J = 2.4Hz).
Example 274 By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - [(1-benzylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.34 g) as starting materials, N - [(1-benzylpyrazol-4-yl) methyl hydrochloride] -5-hydroxy-N- was obtained (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.27 g). image 1
1H – NMR (DMSO – d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.37–1.55 (1H, m) 1.72–1.95 (3H, m) 2 , 37-2.58 (3H, m), 3.23-3.39 (1H, m), 4.63-4.90 (2H, m 5.27 (2H, s), 6.46 (1H , d, J = 7.5Hz), 6.64 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz), 7.05–7.15 (2H, m) 7.23–7.38 (4H, m), 7.60–7.88 (2H, m), 8.03–8.18 (1H, m), 8.69–8.82 (1H , m).
Example 275 image4
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 2- (chloromethyl) pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridine) was obtained –3 – yl) –N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.74 g).
1 H NMR (CDCl 3) δ: 1.31 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.78-2.07 (3H, m), 2.61-2.82 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.58-3.67 (1H, m), 4.66 (1H, d, J = 14.4Hz), 4.86 (1H, d, J = 14.7Hz), 5.03 (2H, s), 5.41 (2H, s), 6.54 (1H, d, J = 7 , 8Hz), 6.71 (1H, d, J = 8.1Hz), 6.90–7.03 (2H, m), 7.15–7.50 (10H, m), 7.58–7 , 67 (1H, m), 8.39 (1H, d, J = 2.4Hz), 8.57 (1H, dd, J = 0.6, 4.8Hz).
Example 276 image2
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6– isopropylpyridin-3-yl) -N - [(1– (2-pyridylmethyl) pyrazol-4-yl ) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) as starting material, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N- dihydrochloride was obtained {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.56 g).
MS (ESI) m / z: 482 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.37–1.55 (1H, m), 1.70–1.95 (3H, m) , 2.34-2.58 (2H, m), 3.24-3.65 (2H, m), 4.50-5.05 (2H, m), 5.62 (2H, s), 6 , 49 (1H, d, J = 7.7Hz), 6.54 (1H, d, J = 7.9Hz), 6.87 (1H, t, J = 7.8Hz), 7.23 (1H, d, J = 7.9Hz), 7.31–7.43 (1H, m), 7.63–7.90 (3H, m), 8.05–8.29 (2H, m), 8, 63–8.79 (2H, m).
Example 277 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 3– (chloromethyl) pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N– (6–
10 isopropylpyridin-3-yl) -N - {[1– (3-pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.68 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.38-1.55 (1H, m), 1.75-2.07 (3H, m), 2 , 60–2.82 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4.61 (1H, d, J = 14.5Hz), 4.84 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.28 (2H, s), 6.49 (1H, d, J = 7, 7Hz), 6.71 (1H, d, J = 8.1Hz), 7.00 (1H, t, J = 7.9Hz), 7.18 (1H, d, J = 8.3Hz), 7, 23–7.51 (10H, m), 8.38 (1H, d, J = 2.4Hz), 8.50 (1H, d, J = 2.0Hz), 8.57 (1H, dd, J = 1.6, 4.8Hz).
15 Example 278 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - {[1- (3-pyridylmethyl) pyrazol-4-yl ] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g) as a starting material, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N- dihydrochloride was obtained {[1– (3–
Pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.51 g).
MS (ESI) m / z: 482 [MH] +
1H-NMR (DMSO-d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.33-1.53 (1H, m), 1.69-1.93 (3H, m) , 2.36-2.61 (2H, m), 3.20-3.64 (2H, m), 4.60-4.96 (2H, m), 5.55 (2H, s), 6 , 47 (1H, d, J = 7.6Hz), 6.65 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz), 7.30–7, 44 (1H, m), 7.68–7.92 (2H, m), 7.98–8.16 (2H, m), 8.27 (1H, d, J = 8.1Hz), 8, 61–8.82 (2H, m), 8.88 (1H, d, J
25 = 5.1Hz).
Example 279 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 4-fluorobenzyl chloride (0.36 mL) as starting materials, 5-benzyloxy-N - ({1– [ (4– fluorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g). image 1
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.37-1.53 (1H, m), 1.77-2.07 (3H, m), 2 , 60–2.81 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57–3.66 (1H, m), 4.60 (1H, d, J = 14.5Hz), 4.84 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.22 (2H, 6.49 (1H, d, J = 7.7Hz), 6.71 (1H, d, J = 8.1Hz), 6.92–7.05 (3H, m), 7.11–7.20 (3H, m), 7.24–7.44 (8H , m), 8.36 (1H, d, J = 2.4Hz).
Example 280 image4
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(4-fluorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6– isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) as starting material, N- ({1 - [(4-fluorophenyl) methyl] pyrazole hydrochloride was obtained –4 – yl} methyl) –5 – hydroxy-N– (6– isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.59 g).
15 MS (ESI) m / z: 499 [MH] +
1H-NMR (DMSO-d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.33-1.50 (1H, m), 1.68-1.94 (3H, m) , 2.34–2.60 (2H, m), 3.20–3.63 (2H, m), 4.60–4.87 (2H, m), 5.26 (2H, s), 6 , 45 (1H, d, J = 7.6Hz), 6.63 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7.8Hz), 7.07–7, 22 (4H, m), 7.25–7.37 (1H, m), 7.57–7.78 (2H, m), 7.92–8.10 (1H, m), 8.59– 8.75 (1 H, m).
Example 281 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 4-chlorobenzyl chloride (0.48 g) as starting materials, 5-benzyloxy-N - ({1– [ (4– chlorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g). image2
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.37-1.57 (1H, m), 1.77-2.07 (3H, m), 2 , 60–2.82 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4.59 (1H, d, J = 14.5Hz), 4.84 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.22 (2H, s), 6.49 (1H, d, J = 7, 7Hz), 6.72 (1H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.9Hz), 7.11 (2H, d, J = 8.4Hz), 7, 17 (1H, d, J = 8.3Hz), 7.24-7.43 (10H, m), 8.37 (1H, d, J = 2.4Hz).
Example 282 image4
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(4-chlorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6– isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) as starting material, N - ({1 - [(4-chlorophenyl) methyl] pyrazole hydrochloride was obtained –4 – yl} methyl) –5 – hydroxy-N– (6– isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.65 g).
15 MS (ESI) m / z: 515 [MH] +
1H-NMR (DMSO-d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.36-1.53 (1H, m), 1.67-1.95 (3H, m) , 2.33-2.57 (2H, m), 3.17-3.67 (2H, m), 4.59-4.89 (2H, m), 5.27 (2H, s), 6 , 45 (1H, d, J = 7.8Hz), 6.63 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7.8Hz), 7.15 (2H, d, J = 8.4Hz), 7.22–7.36 (1H, m), 7.41 (2H, d, J = 8.4Hz), 7.57–, 7.78 (2H, m) , 7.90–8.08 (1H, m), 8.58–8.72 (1H, m).
20 Example 283 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 4- (trifluoromethyl) benzyl chloride (0.48g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridine) -
25 3-yl) -N - ({1 - [(4-trifluoromethylphenyl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.84 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.37-1.57 (1H, m), 1.78-2.07 (3H, m), 2 , 60–2.82 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.58–3.68 (1H, m), 4.61 (1H, d, J = 14.5Hz), 4.85 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.31 (2H, s), 6.49 (1H, d, J = 7, 7Hz), 6.71 (1H, d, J = 8.1Hz), 6.96 (1H, t, J = 7.9Hz), 7.18 (1H, d, J = 8.3Hz), 7, 23–7.46 (10H, m), 7.60 (2H, d, J = 8.2Hz), 8.38 (1H, d, J = 2.4Hz)
Example 284 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylphenyl) methyl ] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g) as a starting material, 5-hydroxy-N- hydrochloride (6-isopropylpyridin-3) was obtained –Il) –N - ({1 - [(4– image 1
Trifluoromethylphenyl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.67 g).
MS (ESI) m / z: 549 [MH] +
1H – NMR (DMSO – d6) δ: 1.27 (6H, d, J = 6.9Hz), 1.33-1.50 (1H, m), 1.70–1.96 (3H, m) , 2.34–2.59 (2H, m), 3.12–3.67 (2H, m), 4.64–4.87 (2H, m), 5.40 (2H, s), 6 , 45 (1H, d, J = 7.5Hz), 6.62 (1H, d, J = 7.8Hz), 6.84 (1H, t, J = 7.7Hz), 7.22–7, 40 (3H, m), 7.57-7.77 (4H, m), 7.89-8.05 (1H, m), 8.56-8.71 (1H, m).
10 Example 285 image 1
By reaction and treatment in the same manner as in the Example using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1 hydrochloride, -1, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 3-chloromethyl-6-isopropylpyridine (0.51g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3) –Il) -
15 N - ({1 - [(6-isopropylpyridin-3-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.77 g).
1H-NMR (CDCl3) δ: 1.28 (6H, d, J = 6.9Hz), 1.31 (6H, d, J = 6.9Hz), 1.37-1.54 (1H, m) , 1.77-2.07 (3H, m), 2.60-2.82 (2H, m), 2.99-3.17 (2H, m), 3.57-3.67 (1H, m), 4.61 (1H, d, J = 14.7Hz), 4.83 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.24 (2H, s) , 6.50 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 6.99 (1H, t, J = 8.0Hz 7.10–7, 19 (2H, m), 7.25–7.45 (9H, m), 8.38 (1H, d, J = 2.4Hz), 8.42 (1H, d, J = 2.1Hz).
Example 286 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(6-isopropylpyridin-3 -Yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) as starting material, 5-hydroxy-N dihydrochloride was obtained (6 –Isopropylpyridin – 3 – il) –N– image 1
5 ({1 - [(6-isopropylpyridin-3-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.57 g).
MS (ESI) m / z: 524 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.35 (6H, d, J = 6.9Hz), 1.37 1.50 (1H, m ), 1.70–1.97 (3H, m), 2.34– 2.60 (2H, m), 3.23–3.62 (3H, m), 4.63–4.88 (2H , m), 5.52 (2H, s), 6.47 (1H, d, J = 7.5Hz), 6.64 (1H, d, J = 8.1Hz), 6.87 (1H, t , J = 7.8Hz), 7.30–7.45 (1H, m), 7.72–7.89 (2H, m), 7.96–8.16 (2H, m), 8.25 (1H, dd, J = 1.8, 8.1Hz), 8.58–
10 8.78 (2H, m).
Example 287 image 1

By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 5–
15 (chloromethyl) -2.4] -dimethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N- ({1 - [(2,4-dimethylthiazole-5-yl) methyl] pyrazole) was obtained. 4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.92 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.37-1.57 (1H, m), 1.77-2.09 (3H, m), 2 , 34 (3H, s), 2.39 (3H, s), 2.67– 2.83 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.57–3 , 67 (1H, m), 4.59 (1H, d, J = 14.4Hz), 4.82 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.31 (2H, s), 6.50 (1H, d, J = 7.5Hz), 6.72 (1H, d, J = 8.1Hz), 7.01 (1H, t, J = 8.0Hz) , 7.18 (1H, d, J = 8.4Hz),
20 7.24–7.42 (8H, m), 8.36 (1H, d, J = 2.4Hz).
Example 288 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1– [(2,4-dimethylthiazol-5-yl) methyl] pyrazol-4-yl} methyl) –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.91 g) as starting material, N - ({1– [] hydrochloride was obtained (2,4-dimethylthiazol-yl) methyl] pyrazol-4-yl} methyl) -5- hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.35 g). image 1
MS (ESI) m / z: 516 [MH] +
1H-NMR (DMSO-d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.34-1.50 (1H, m), 1.70-1.95 (3H, m) , 2.34 (3H, s), 2.37-2.57 (2H, m), 2.62 (3H, s), 3.17-3.67 (2H, m), 4.60-4 , 85 (2H, m), 5.43 (2H, s), 6.44 (1H, d, J = 7.7Hz), 6.63 (1H, d, J = 7.9Hz), 6.87 (1H, t, J = 7.8Hz), 7.25-7.39 (1H, m), 7.60-7.80 (2H, m) 7.92-8.07 (1H, m), 8.57–8.72 (1H, m).
Example 289 image4
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methylcarboxamide (0, 78 g) and 4-methoxybenzyl chloride (0.41 mL) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methoxyphenyl)) methyl) pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g).
1 H NMR (CDCl 3) δ: 1.30 (6H, d, J = 6.9Hz), 1.37-1.53 (1H, m), 1.75-2.07 (3H, m), 2.60-2.82 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57-3.67 (1H, m), 3.79 (3H, s), 4.59 (1H, d, J = 14.4Hz), 4.83 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.19 (2H, s), 6, 50 (1H, d, J = 7.5Hz), 6.71 (1H, d, J = 8.1Hz), 6.86 (2H, d, J = 6.3Hz), 6.99 (1H, t , J = 8.1Hz), 7.10–7.18 (3H, m) 7.23–7.45 (8H, m), 8.37 (1H, d, J = 2.4Hz).
Example 290 image2
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(4-methoxyphenyl) methyl] pyrazole– 4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g) as a starting material, 5-hydroxy-N- (6-isopropylpyridin-3-yl) hydrochloride was obtained –N - ({1 - [(4– methoxyphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.54 g).
25 MS (ESI) m / z: 511 [MH] +
1H – NMR (DMSO – d6) δ: 1.27 (6H, d, J = 6.9Hz), 1.31-1.50 (1H, m), 1.70–1.96 (3H, m) , 2.35-2.60 (2H, m), 3.10-3.70 (2H, m), 3.73 (3H, s), 4.61-4.85 (2H, m), 5 , 18 (2H, s), 6.43 (1H, d, J = 7.7Hz), 6.62 (1H, d, J = 7.9Hz), 6.80–6.92 (3H, m) , 7.11 (2H, d, J = 8.4Hz), 7.22–7.34 (1H, m), 7.51–7.68 (2H, m), 7.83–7.97 ( 1H, m), 8.52-8.67 (1H, m).
Example 291 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 4-chloromethyl-1-ethylpyrazole (0.43 g) as starting materials, 5-benzyloxy-N - ({1 - [(1 – ethylpyrazole – 4– image 1
5-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.58 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.46 (3H, t, J = 7.2Hz), 1.38-1.55 (1H, m) 1.73-2.07 (3H, m), 2.60-2.80 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57-3.66 (1H , m), 4.14 (2H, q, J = 7.2Hz), 4.58 (2H, s), 4.65 (1H, d, J = 14.7Hz), 4.78 (1H, d , J = 14.4Hz), 5.02 (2H, s), 6.16 (1H, s), 6.52 (1H, d, J = 7.7Hz), 6.72 (1H, d, J = 5.1 Hz), 7.03 (1H, t, J = 7.9Hz), 7.17 (1H, d, J = 8.3Hz), 7.23–7.56 (9H, m), 8.35 (1H, d, J = 2.4Hz).
10 Example 292 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(1- ethylpyrazol-4-yl) methyl] pyrazol-4-yl} methyl) -N - (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.44 g) as starting material, N - ({1 - [(1-ethylpyrazole) hydrochloride was obtained –4 – il) methyl] pyrazol – 4-yl} methyl) –5 – hydroxy–
15 N– (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.34 g).
MS (ESI) m / z: 499 [MH] +
1H – NMR (DMSO – d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.32 (3H, t, J = 7.2Hz), 1.38-1.50 (1H, m), 1.70-1.96 (3H, m), 2.36-2.58 (2H, m), 3.08-3.50 (2H, m), 4.08 (2H, q, J = 7.2Hz), 4.58-4.81 (2H, m), 5.10 (2H, s), 6.43 (1H, d, J = 7.5Hz), 6.62 (1H, d, J = 8.1Hz), 6.87 (1H, t, J = 7.7Hz), 7.18-7.36 (2H, m), 7.48-7.68 (3H, m), 7.82–7.97 (1H, m), 8.50–8.63
20 (1H, m).
Example 293 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide (0.66 g) and 4– (methyl bromomethyl) benzoate (0.31 g) as starting materials, 4 - [(4 - {[ N– (5 – benzyloxy – 1,2,3,4– image 1
5-tetrahydronaphthalen-1-ylcarbonyl) -N- (6-isopropylpyridin-3-yl) amino] methyl} pyrazol-1-yl) methyl] methyl benzoate (0.61 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.37-1.54 (1H, m), 1.77-2.08 (3H, m), 2 , 60–2.82 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.58–3.68 (1H, m), 3.91 (3H, s), 4 , 62 (1H, d, J = 14.5Hz), 4.85 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.31 (2H, s), 6.50 (1H, d, J = 7.7Hz), 6.71 (1H, d, J = 8.1Hz), 6.98 (1H, t, J = 7.9Hz), 7.14–7.46 ( 12H, m), 8.01 (1H, dd, J = 1.7, 8.3Hz), 8.38 (1H, d, J = 2.4Hz).
10 Example 294 image 1
By reaction and treatment in the same manner as in Example 101 using 4 - [(4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (6-Isopropylpyridin-3-yl) amino] methyl} pyrazol-1-yl) methyl] methyl benzoate (0.61 g) as a starting material, 4 - [(4 - {[hydrochloride was obtained N– (5 – hydroxy – 1,2,3,4–
Tetrahydronaphthalen-1-ylcarbonyl) -N- (6-isopropylpyridin-3-yl) amino] methyl} pyrazol-1-yl) methyl] methyl benzoate (0.51).
MS (ESI) m / z: 539 [MH] +
1H-NMR (DMSO-d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.35-1.50 (1H, m), 1.72-1.97 (3H, m) , 2.36–2.60 (2H, m), 3.15–3.70 (2H, m), 3.85 (3H, s), 4.65–4.90 (2H, m), 5 , 38 (2H, s), 6.45 (1H, d, J = 7.6Hz), 6.62 (1H, d, J = 7.8Hz), 6.85 (1H, t, J = 7, 8Hz), 7.21 (2H, d, J = 8.3Hz), 7.29–7.42 (1H, m), 7.58–7.75 (1H, m), 7.90–8, 02 (4H, m), 8.58-8.71 (1H, m).
Example 295 4 - [(4 - {[N– (5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (6-isopropylpyridin-3-yl) amino] methyl} pyrazole– 1-yl) methyl] methyl benzoate (0.36 g) was dissolved in a mixed solvent (4 mL) of ethanol: 1 mol / L of aqueous sodium hydroxide solution (1: 1) and the mixture was stirred at room temperature for one day. The reaction mixture is image 1
5 concentrated under reduced pressure and the residue was divided into water and toluene. Citric acid was added to the aqueous layer until the mixture was acidified. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in ethyl acetate. To this was added 4 mol / L of HCl / dioxane. The precipitated solid was collected by filtration to give 4 - [(4 - {[N– (5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N- (6-isopropylpyridin-3–) hydrochloride il) amino] methyl} pyrazole-1–
10 il) methyl] benzoic (0.27 g).
MS (ESI) m / z: 525 [MH] +
1H – NMR (DMSO – d6) δ: 1.26 (6H, d, J = 6.9Hz), 1.33–1.51 (1H, m), 1.70–1.98 (3H, m) , 2.34–2.60 (2H, m), 3.07–3.60 (2H, m), 4.65–4.89 (2H, m), 5.37 (2H, s) 6, 44 (1H, d, J = 7.5Hz), 6.61 (1H, d, J = 7.8Hz), 6.85 (1H, t, J = 7.7Hz), 7.18 (2H, d , J = 7.9Hz), 7.27–7.40 (1H, m), 7.52–7.73 (2H, m), 7.80–7.97 (3H, m), 8.50 –8.68 (1H, m).
15 Example 296 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 4-bromobenzyl chloride (0.75 g) as starting materials, 5-benzyloxy-N - ({1 - [(4 -
Bromophenyl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.38-1.54 (1H, m), 1.75-2.07 (3H, m), 2 , 61–2.82 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4.59 (1H, d, J = 14.4Hz), 4.84 (1H, d, J = 14.7Hz), 5.03 (2H, s), 5.20 (2H, s), 6.48 (1H, d, J = 7, 5Hz), 6.72 (1H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.8Hz), 7.05 (2H, d, J = 8.1Hz), 7, 17 (1H, d, J = 8.1Hz), 7.25-7.49 (10H, m), 8.37 (1H, d, J = 2.4Hz).
Example 297 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(4-bromophenyl) methyl] pyrazol-4-yl} methyl) -N– (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g) as starting material, N - ({1 - [(4-bromophenyl) hydrochloride) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N– (6– image 1
5 isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.68 g).
MS (ESI) m / z: 559, 561 [MH] +
1H-NMR (DMSO-d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.34-1.52 (1H, m), 1.69-1.95 (3H, m) , 2.34-2.58 (2H, m), 3.18-3.66 (2H, m), 4.62-4.90 (2H, m), 5.26 (2H, s), 6 , 44 (1H, d, J = 7.6Hz), 6.63 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7.8Hz), 7.08 (2H, d, J = 8.4Hz), 7.23-7.42 (1H, m), 7.54 (2H, d, J = 8.3Hz), 7.59-7.79 (2H, m), 7.92–8.10 (1H, m), 8.60–8.79 (1H,
10 m)
Example 298 image 1
By reaction and treatment in the same manner as in Example 271, using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- [(pyrazole-4-yl) methyl] - hydrochloride] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and
As 3-chlorobenzyl chloride (0.38 mL) as starting materials, 5-benzyloxy-N - ({1 - [(3-chlorophenyl) methyl] pyrazol-4-yl} methyl) -N– (6 -Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.77 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.56 (1H, m), 1.87-2.07 (3H, m), 2 , 62–2.83 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.58–3.68 (1H, m), 4.62 (1H, d, J = 14.4Hz), 4.84 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.23 (2H, s), 6.51 (1H, d, J = 7, 5Hz), 6.71 (1H, d, J = 8.1Hz), 6.93-7.19 (3H, m), 7.24-7.47 (11H, m), 8.40 (1H, d, J = 2.4Hz).
20 Example 299 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(3-chlorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6– isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.77 g)
As a starting material, N - ({1 - [(3-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6- isopropylpyridin-3-yl) -1 hydrochloride was obtained, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.62 g).
MS (ESI) m / z: 515 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.34-1.54 (1H, m), 1.70–1.96 (3H, m) , 2.37-2.62 (2H, m) 3.21-3.70 (2H, m), 4.60-4.92 (2H, m), 5.30 (2H, s), 6, 46 (1H, d, J = 7.6Hz), 6.6.3 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7.8Hz), 7.02–7 , 12 (1H, m), 7.20 (1H, s), 7.27–7.44 (3H, m), 7.62–7.82 (2H, m), 7.93–8.12 (1H, m), 8.63-8.85 (1H, m).
Example 300 image 1
By reaction and treatment in the same manner as in Example 271 using 5– hydrochloride
10 benzyloxy-N– (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78.8) and chloride of 2-chlorobenzyl (0.38 mL) as starting materials, 5-benzyloxy-N - ({1 - [(2-chlorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridine) was obtained –3 – yl) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide (0.77 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.55 (1H, m), 1.76-2.08 (3H, m), 2 , 61–2.82 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4.66 (1H, d, J = 14.4Hz), 4.84 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.38 (2H, s), 6.53 (1H,
15 d, J = 7.5Hz), 6.71 (1H, d, J = 8.1Hz), 6.96–7.06 (2H, m), 7.13–7.45 (12H, m) , 8.38 (1H, d, J = 2.4Hz).
Example 301 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(2-chlorophenyl) methyl] pyrazol-4-yl} methyl) -N- (6– isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) 20 as a starting material, N- ({1 - [(2-chlorophenyl) methyl hydrochloride was obtained ] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.61 g).
MS (ESI) m / z: 515 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.32–1.53 (1H, m), 1.70–1.98 (3H, m) , 2.36-2.61 (2H, m), 3.21-3.67 (2H, m) 4.64-4.90 (2H, m), 5.37 (2H, s), 6, 47 (1H, d, J = 7.6Hz), 6.64 (1H, d, J = 7.9Hz), 6.79–6.91 (2H, m), 7.23–25 7.50 ( 4H, m), 7.57-7.85 (2H, m), 7.93-8.17 (1H, m), 8.62-8.94 (1H, m).
Example 302 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 4-methylbenzyl chloride (0.42g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridine) was obtained 3 – il) –N– image 1
5 ({1 - [(4-methylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.53 (1H, m), 1.77-2.07 (3H, m), 2 , 33 (3H, s), 2.62-2.80 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57-3.64 (1H, m), 4 , 60 (1H, d, J = 14.4Hz), 4.84 (1H, d, J = 14.7Hz), 5.03 (2H, s), 5.21 (2H, s), 6.50 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 6.99 (1H, t, J = 8.0Hz), 7.03–7.18 ( 5H, m), 7.24-7.42 (8H, m), 8.37 (1H, d, J = 2.4Hz).
10 Example 303 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6– isopropylpyridin-3-yl) -N - ({1 - [(4-methylphenyl) methyl] pyrazole– 4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g) as starting materials, 5-hydroxy-N- hydrochloride (6-isopropylpyridin-3-yl) was obtained –N - ({1 - [(4–
15 methylphenyl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.55 g).
MS (ESI) m / z: 495 [MH] +
1H-NMR (DMSO-d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.35-1.52 (1H, m), 1.68-1.95 (3H, m) , 2.27 (3H, s), 2.34-2.58 (2H, m), 3.25-3.63 (2H, m), 4.65-4.91 (2H, m), 5 , 21 (2H, s), 6.45 (1H, d, J = 7.6Hz), 6.64 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7, 8Hz), 7.03 (2H, d, J = 8.0Hz), 7.14 (2H, d, J = 7.9Hz), 7.25–7.40 (1H, m), 7.64– 7.86 (2H, m), 7.99–8.17 (1H, m),
20 8.66-8.82 (1H, m).
Example 304 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide (0.78 g) and 2– (chloromethyl) –5-methylpyridine (0.43 g) as starting materials, 5-benzyloxy-N– ( 6 – isopropylpyridin – 3 – il) - image 1
5 N - ({1 - [(5-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.71 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.40-1.57 (1H, m), 1.74-2.09 (3H, m), 2 , 32 (3H, s), 2.61–2.80 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.58–3.67 (1H, m), 4 , 65 (1H, d, J = 14.5Hz), 4.85 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.36 (2H, s), 6.54 (1H, d, J = 7.7Hz), 6.71 (1H, d, J = 8.1Hz), 6.89 (1H, d, J = 8.0Hz), 7.01 (1H, t, J = 7.9Hz), 7.17 (1H, d, J = 8.3Hz), 7.24-7.49 (9H, m), 8.38 (2H, s).
10 Example 305 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(5-methylpyridin2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.71 g) as a starting material, 5-hydroxy-N- dihydrochloride (6-isopropylpyridin-3– il) –N - ({1 - [(5–
15 methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.62 g).
MS (ESI) m / z: 496 [MH] +
1H-NMR (DMSO-d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.33-1.55 (1H, m), 1.71-1.97 (3H, m) , 2.43 (3H, s), 2.36-2.59 (2H, m), 3.29-3.64 (2H, m) ‚4.62-4.91 (2H, m), 5 , 67 (2H, s), 6.49 (1H, d, J = 7.7Hz), 6.65 (1H, d, J = 7.9Hz), 6.88 (1H, t, J = 7, 8Hz), 7.28–7.41 (2H, m), 7.72–7.96 (2H, m), 8.12–8.29 (2H, m), 8.63–8.80 ( 2H, m).
Example 306 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1, hydrochloride 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 6-5 chloromethyl-3-methoxypyridine (0.47g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridine-) was obtained 3-yl) - N - ({1 - [(5-methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.63 g ).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.41-1.57 (1H, m), 1.76-2.09 (3H, m), 2 , 61–2.82 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.68–3.77 (1H, m), 3.84 (3H, s), 4 , 65 (1H, d, J = 14.5Hz), 4.84 (1H, d, J = 14.5Hz), 5.03 (2H, s), 5.33 (2H, s), 6.54 (1H, d, J = 7.7Hz), 6.71 (1H, d, J = 8.1Hz), 6.95–7.05 (2H, m), 7.11–7.19 (2H, m), 7.25–7.47 (8H, m), 8.25
10 (1H, d, J = 2.9Hz), 8.37 (1H, d, J = 2.4Hz).
Example 307 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6– isopropylpyridin-3-yl) -N - ({1 - [(5-methoxypyridin-2-yl)) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide 15 (0.61 g) as starting material, 5-hydroxy-N- (6-isopropylpyridine dihydrochloride) was obtained –3 – il) –N - ({1 - [(5– methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen – 1-carboxamide (0.46 g).
MS (ESI) m / z: 512 [MH] +
1H – NMR (DMSO – d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.37–1.54 (1H, m), 1.71–1.95 (3H, m) , 2.36-2.60 (2H, m), 3.31-3.65 (2H, m), 3.89 (3H, s), 4.67-4.90 (2H, m), 5 , 49 (2H, s), 6.49 (1H, d, J = 7.6Hz), 6.65 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 20 7 , 8Hz), 7.24 (1H, d, J = 8.8Hz), 7.29–7.42 (1H, m), 7.71–7.96 (3H, m), 8.13–8 , 29 (1H, m), 8.44 (1H, d, J = 2.7Hz), 8.70-8.84 (1H, m).
Example 308 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 2-chloromethyl-6-methylpyridine (0.43g) as starting materials, 5-benzyloxy-N- (6- isopropylpyridin – 3 – il) –N– image 1
5 ({1 - [(6-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.75 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.56 (1H, m), 1.77-2.10 (3H, m), 2 , 55 (3H, s), 2.62-2.83 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.58-3.68 (1H, m), 4 , 66 (1H, d, J = 1.4Hz), 4.86 (1H, d, J = 14.7Hz), 5.03 (2H, s), 5.37 (2H, s) 6.54 ( 1H, d, J = 7.8Hz), 6.64–6.75 (2H, m), 6.94–7.08 (2H, m), 7.18 (1H, d, J = 8.1Hz ), 7.25–7.55 (9H, m), 8.39 (1H, d, J = 2.4Hz).
10 Example 309 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N- (6-methylpyridin-2-yl) methyl] pyrazole-4 –Il} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.74 g) as a starting material, 5-hydroxy-N dihydrochloride (6-isopropylpyridin-3-yl) was obtained - N - ({1 - [(6 – methylpyridin–
15 2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.63 g).
MS (ESI) m / z: 496 [MH] +
1H – NMR (DMSO – d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.32–1.53 (1H, m), 1.70–1.99 (3H, m) , 2.34–2.58 (2H, m), 2.72 (3H, s), 3.15–3.34 (1H, m), 3.45–3.62 (1H, m), 4 , 72 (1H, d, J = 15.6Hz), 4.83 (1H, d, J = 14.7Hz), 5.68 (2H, s), 6.48 (1H, d, J = 7, 5Hz), 6.63 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 7.07 (1H, d, J = 8.1Hz), 7, 29–7.48 (1H, m), 7.61–8.32 (5H,
20 m), 8.57–8.74 (1H, m).
Example 310 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 2–
(chloromethyl) -4-methylpyridine (0.53 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) - N - ({1 - [(4-methylpyridin-2–) il) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.67 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.75-2.08 (3H, m), 2 , 31 (3H, s), 2.60–2.82 (2H, m), 3.08 (1H, sept, J = 6.9H2), 3.57–3.69 (1H, m), 4 , 67 (1H, d, J = 14.4Hz), 4.85 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.36 (2H, s), 6.55 (1H, d, J = 7.5Hz), 6.72 (1H, d, J = 7.8Hz), 6.80 (1H, s), 6.93–7.06 (2H, m), 7 , 13-7.50 (9H, m), 8.33- 8.46 (2H, m).
Example 311 image 1
Through reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N– (6–
10 isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0 , 67 g) as a starting material, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4– methylpyridin-2-yl) methyl] pyrazol-4 dihydrochloride was obtained -Yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.57 g).
MS (ESI) m / z: 496 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.35–1.51 (1H, m), 1.70–1.97 (3H, m) , 2.36–2.62 (5H, m), 3.19–3.39
15 (1H, m), 3.45-3.64 (1H, m), 4.71 (1H, d, J = 14.0Hz), 4.85 (1H, d, J = 14.1Hz), 5.69 (2H, s), 6.49 (1H, d, J = 7.7Hz), 6.64 (1H, d, J = 7.9Hz), 6.87 (1H, t, J = 7 , 8Hz), 7.25-7.47 (2H, m), 7.63-8.20 (4H, m), 8.62-8.80 (2H, m).
Example 312 image 1
Through reaction and treatment in the same manner as in Example 82 using 1– (tert–
20-butyloxycarbonyl) -4- (hydroxymethyl) pyrazole (1.41 g) and 5-benzyloxy-8-fluoro-N- (6-isopropylpyridin-3-yl) –1,2,3,4- tetrahydronaphthalen-1-carboxamide (2.83 g) as starting materials, 5-benzyloxy-8-fluoro-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1 hydrochloride was obtained, 2,3,4-tetrahydronaphthalen-1-carboxamide (1.62 g). Melting point: 194.7 ° C.
Example 313 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-8-fluoro-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.79 g) and 2– (chloromethyl) pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-8– was obtained fluoro – N– (6-isopropylpyridin– 3-yl) –N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 69 g). image6
1H-NMR (CDCl3) δ: 1.32 (6H, d, J = 6.9Hz), 1.43-1.58 (1H, m), 1.65-2.02 (3H, m), 2 , 55–2.82 (2H, m), 3.10 (1H, sept, J = 6.9Hz), 3.60–3.70 (1H, m), 4.57 (1H, d, J = 14.6Hz), 4.87 (1H, d, J = 14.6Hz), 5.00 (2H, s), 5.41 (2H, s), 6.61– 6.77 (2H, m) , 6.90 (1H, d, J = 7.9Hz), 7.14-7.48 (10H, m), 8.59-8.43 (1H, d, J = 2.4Hz), 8, 53–8.60 (1H, m).
Example 314 image 1
10 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-8-fluoro- N- (6-isopropylpyridin-3-yl) -N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g) as starting material, 8-fluoro-5-hydroxy-N- dihydrochloride was obtained (6– isopropylpyridin-3-yl) -N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g).
MS (ESI) m / z: 500 [MH] +
15 1H – NMR (DMSO – d6) δ: 1.32 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.63–1.92 (3H, m ), 2.33-2.60 (2H, m), 3.26-3.44 (1H, m), 3.50-3.65 (1H, m), 4.60 (1H, d, J = 14.7Hz), 4.87 (1H, d, J = 15.0Hz), 5.64 (2H, s), 6.58-6.78 (2H, m), 7.23 (1H, d , J = 7.8Hz), 7, 36 (1H, s), 7.64–7.87 (3H, m), 8.00–8.13 (1H, m), 8.19–8.36 (1H, m), 8.44-8.58 (1H, m), 8.78 (1H, d, J = 5.1Hz).
Example 315 image2
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 3- (benzyloxy) -6- (chloromethyl) pyridine (0.81g) as starting materials, 5-benzyloxy-N- was obtained ({1 - [(5– (benzyloxy) pyridin-2-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen– 1-carboxamide
25 (0.75 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.37-1.54 (1H, m), 1.77-2.07 (3H, m), 2 , 60–2.80 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4.65 (1H, d, J = 14.7Hz), 4.84 (1H, d, J = 14.7Hz), 5.02 (2H, s), 5.09 (2H, s), 5.33 (2H, s), 6.54 (1H, d, J = 7.5Hz), 6.71 (1H, d, J = 8.1Hz), 6.98 (2H, t, J = 8.3Hz), 7.13–7.48 ( 15H, m), 8.32 (1H, d, J = 2.7Hz), 8.37 (1H, d, J = 2.4Hz).
Example 316 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - ({1 - [(5– (benzyloxy) pyridiri-2-yl) methyl] pyrazol-4-yl} methyl ) –N– (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide 5 (0.74 g) as starting material, 5-hydroxy-N dihydrochloride was obtained ( {1 - [(5-hydroxypyridin-2-yl) methyl] pyrazol- 4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.57 g).
MS (ESI) m / z: 498 [MH] +
1H – NMR (DMSO – d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.70–1.97 (3H, m) , 2.33-2.63 (2H, m), 3.26-3.67 (2H, m), 4.62-4.93 (2H, m), 5.56 (2H, s), 6 , 48 (1H, d, J = 7.6Hz), 6.65 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 10 7.28–7 , 44 (2H, m) ,. 7.68–7.95 (3H, m), 8.08–8.23 (1H, m), 8.37 (1H, d, J = 2.7Hz), 8.67–8.83 (1H , m).
Example 317 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 2–
As chloromethyl-5-ethylpyridine (0.58 g) as starting materials, 5-benzyloxy-N - ({1 - [(5-ethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) was obtained - N– (6-isopropylpyridin-3-yl) -1,2,3,4-1-carboxamide (0.75 g).
1H-NMR (CDCl3) δ: 1.23 (3H, t, J = 7.6Hz), 1.30 (6H, d, J = 6.9Hz.), 1.37-1.55 (1H, m ), 1.77-2.07 (3H, m), 2.63 (2H, q, J = 7.6Hz), 2.65-2.82 (2H, m), 3.08 (1H, sept , J = 6.9Hz), 3.58-3.68 (1H, m), 4.66 (1H, d, J = 14.5Hz), 4.85 (1H, d, J = 14.5Hz) , 5.03 (2H, s), 5.37 (2H, s), 6.55 (1H, d, J = 7.7Hz), 6.71 (1H, d, 8.0Hz), 6.91 (1H, d, J = 8.0Hz), 7.01 (1H,
20 t, J = 8.2Hz), 7.17 (1H, d, J = 8.4Hz), 7.25–7.50 (9H, m), 8.38 (1H, d, J = 2, 3Hz), 8.40 (1H, d, J = 1.9Hz).
Example 318 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N - ({1 - [(5-ethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.75 g) as starting material, N - ({1 - [(5 –Ethylpyridin – 2-yl) methyl} pyrazol-4-yl} methyl) –5 – hydroxy-N– image 1
5 (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.61 g).
MS (ESI) m / z: 510 [MH] +
1H – NMR (DMSO – d6) δ: 1.22 (3H, t, J = 7.5Hz), 1.29 (6H, d, J = 6.9Hz), 1.32–1.53 (1H, m), 1.70–1.97 (3H, m), 2.33– 2.57 (2H, m), 2.74 (2H, q, J = 7.5Hz), 3.20–3, 37 (1H, m), 3.43-3.63 (1H, m), 4.62-4.90 (2H, m), 5.63 (2H, s), 6.48 (1H, d, J = 7.5Hz), 6.64 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz), 7.28 (1H, d, J = 8.1Hz ), 7.32–7.42 (1H, m), 7.65–
10 7.91 (2H, m), 8.02–8.27 (2H, m), 8.57–8.77 (2H, m).
Example 319 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methylj-1 hydrochloride, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 2–
As chloromethyl-3-methylpyridine (0.53 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- ({1– [3-methylpyridirin-2-yl) was obtained methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide.
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.54 (1H, m), 1.12-2.07 (3H, m), 2 , 30 (3H, s), 2.59-2.79 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.56-3.66 (1H, m), 4 , 63 (1H, d, J = 14.4Hz), 4.81 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.42 (2H, s), 6.54 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 6.93–7.03 (1H, m), 7.09–7.19 (2H, m), 7.23-7.50 (9H, m),
20 8.36 (1H, d, J = 2.1Hz), 8.42 (1H, dd, J = 1.2.4.8Hz).
Example 320 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(3-methylpyridin-2– il) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.74 g) as a starting material, 5-hydroxy-N dihydrochloride was obtained (6-Isopropylpyridin-3-yl) -N - ({1– [(3-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.65 g). image 1
MS (ESI) m / z: 496 [MH] +
1H – NMR (DMSO – d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.32–1.52 (1H, m), 1.70–1.97 (3H, m) , 2.30 (3H, s), 2.38–2.60 (2H, m), 3.17 – З, 33 (1H, m), 3.43–3.60 (1H, m), 4 , 60–4.86 (2H, m), 5.70 (2H, s), 6.46 (1H, d, J = 7.5Hz), 6.63 (1H, d, J = 7.8Hz) , 6.87 (1H, t, J = 7.8Hz), 7.23-7.37 (1H, m), 7.58-8.09 (4H, m), 8.25 (1H, d, J = 7.8Hz), 8.54-8.70 (2H, m).
Example 321 image4
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-8-fluoro-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) hydrochloride methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.81 g) and 2-chloromethyl-4-methylpyridine (0.54 g) as starting materials, 5-benzyloxy-8-fluoro was obtained –N– (6– isopropylpyridin-3-yl) –N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen– 1-carboxamide
15 (0.77 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.43-1.57 (1H, m), 1.67-2.03 (3H, m), 2 , 31 (3H, s), 2.57-2.84 (2H, m), 3.09 (1H, Sept, J = 6.9Hz), 3.60-3.72 (1H, m), 4 , 58 (1H, d, J = 14.4Hz), 4.67 (1H, d, J = 14.4Hz), 5.00 (2H, s), 5.36 (2H, s), 6.62 –6.77 (3H, m), 7.02 (1H, d, J = 4.8Hz), 7.19 (1H, d, J = 8.1Hz), 7.24–8.07 (8H, m), 8.35-8.45 (2H, m).
Example 322 image2
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-8-fluoro- N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridine) 2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) as starting material, 8-fluoro-5-hydroxy dihydrochloride was obtained –N– (6– isopropylpyridin-3-yl) –N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen– 1-carboxamide
25 (0.64 g).
MS (ESI) m / z: 514 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.56 (1H, m), 1.61–1.93 (3H, m) , 2.33–2.59 (5H, m), 3.18–3.37 (1H, m), 3.50–3.63 (1H, m), 4.59 (1H, d, J = 14.7Hz), 4.84 (1H, d, J = 14.7Hz), 5.68 (2H, s), 6.60-6.77 (3H, m), 7.26 (1H, s) , 7.36 (1H, m), 7.63–8.05 (4H, m), 8.41–8.53 (1H, m), 8.73 (1H, d, J = 6.0Hz) .
Example 323 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 2-cloprometyl-4-trifluoromethylpyridine (0.67g) as starting materials, 5-benzyloxy-N- (6 –Isopropylpyridin– image 1
5 3-yl) -N - ({1 - [(4-trifluoromethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.79 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.40-1.57 (1H, m), 1.75-2.07 (3H, m), 2 , 59–2.81 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.59–3.68 (1H, m), 4.69 (1H, d, J = 14.7Hz), 4.85 (1H, d, J = 14.7Hz), 5.03 (2H, s), 5.48 (2H, s), 6.54 (1H, d, J = 7, 8Hz), 6.72 (1H, d, J = 8.1H2), 7.00 (1H, t, J = 7.8Hz), 7.10-7.47 (10H, m), 7.55 ( 1H, s), 8.42 (1H, d, J = 2.4Hz), 8.76 (1H, d, J = 5.1Hz).
10 Example 324 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) as a starting material, 5-hydroxy-N- dihydrochloride (6-isopropylpyridine) was obtained 3 – il) –N–
15 ({1 - [(4-trifluoromethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.63 g).
MS (ESI) m / z: 550 [MH] +.
1H-NMR (DMSO-d6) δ: 1.29 (6H, d, J = 6.9Hz), 1.35-1.53 (1H, m), 1.68-1.95 (3H, m) , 2.35–2.59 (2H, m), 3.16–3.34 (1H, m), 3.44–3.62 (1H, m), 4.63–4.92 (2H, m), 5.53 (2H, s), 6.46 (1H, d, J = 7.5Hz), 6.63 (1H, d, J = 7.8Hz), 6.85 (1H, t, J = 7.8Hz), 7.28–7.42 (2H, m), 7.60–8.06 (4H, m), 8.58–8.75 (1H, m), 8.84 ( 1H, d, J = 5.1Hz).
Example 325 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 5-butyl-2-chloromethylpyridine (0.66 g) as starting materials, 5-benzyloxy-N - ({ 1 - [(5-Butylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0 , 76 g). image 1
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.2Hz), 1.21-1.68 (11H, m), 1.78-2.07 (3H, m), 2 , 59 (2H, t, J = 7.2Hz.), 2.67-2.79 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57-3.67 (1H, m), 4.66 (1H, d, J = 14.4Hz), 4.85 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.34 (2H , s), 6.55 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 6.89 (1H, d, J = 7.8Hz), 7 , 01 (1H, t, J = 7.8Hz), 7.17 (1H, d, J = 8.1Hz), 7.24-7.48 (10H, m), 8.38 (1H, s) .
Example 326 image4
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(5-butylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -N - (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) as starting material, N - ({1 - [(5-butylpyridine dihydrochloride) –2 – yl) methyl] pyrazol – 4-yl} methyl) –5– hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.62 g ).
15 MS (ESI) m / z: 538 [MH] +
1H – NMR (DMSO – d6) δ: 0.90 (3H, t, J = 7.2Hz), 1.18–1.63 (11H, m), 1.71–1.97 (3H, m) , 2.37-2.60 (2H, m), 2.70 (2H, t, J = 7.2Hz), 3.13-3.32 (1H, m), 3.43-3.61 ( 1H, m), 4.72 (1H, d, J = 13.5Hz), 4.82 (1H, d, J = 14.7Hz), 5.59 (2H, s), 6.47 (1H, d, J = 7.5Hz), 6.63 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz), 7.21 (1H, d, J = 8 , 1Hz), 7.29-7.42 (1H, m), 7.58-8.19 (4H, m), 8.55-8.72 (2H, m).
20 Example 327 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 3-chloromethyl-2,6-dimethoxypyridine (0.56 g) as starting materials, 5-benzyloxy-N - ({1 - [(2,6–
Dimethoxypyridin-3-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38-1.55 (1H, m), 1.76-2.08 (3H, m), 2 , 60–2.81 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 3.90 (3H, s), 3 , 94 (3H, s), 4.63 (1H, d, J = 14.4Hz), 4.80 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.15 (2H, s), 6.27 (1H, d, J = 8.1Hz), 6.53 (1H, d, J = 7.8Hz), 6.72 (1H, d, J = 8.1Hz) , 7.01 (1H, t, J = 7.8Hz), 7.16
30 (1H, d, J = 8.1Hz), 7.23-7.44 (9H, m), 8.37 (1H, d, J = 2.4Hz).
Example 328 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1– [(2,6-dimethoxypyridin-3-yl) methyl] pyrazol-4-yl} methyl) –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1– 5 carboxamide (0.68 g) as starting material, N - ({1 - [( 2,6-dimethoxypyridin-3-yl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.16 g).
MS (ESI) m / z: 542 [MH] +
1H-NMR (DMSO-d6) δ: 1.26 (6H, d, J = 6.9Hz), 1.30-1.50 (1H, m), 1.69-1.95 (3H, m) , 2.32–2.59 (2H, m), 3.07–3.26 (1H, m), 3.40–3.57 (1H, m), 3.85 (3H, s), 3 , 88 (3H, s), 4.58-4.85 (2H, m), 5.12 (2H, s), 6.35 (1H, d, J = 8.1Hz), 6.43
10 (1H, d, J = 7.5Hz), 6.62 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7.7Hz), 7.26 (2H, d , J = 8.1Hz), 7.43-7.62 (2H, m), 7.75-7.92 (1H, m), 8.43-8.63 (1H, m).
Example 329 image 1
Through reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N– (6–
15 isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.20 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as starting materials, 5- benzyloxy-N - [(2-ethylthiazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.30 g).
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.38 (3H, t, J = 7.5Hz), 1.45-1.57 (1H, m) , 1.83-2.08 (3H, m), 2.60-2.81 (2H, m), 3.01 (2H, q, J = 7.5Hz), 3.07 (1H, sept, J = 6.9Hz), 3.68-3.78 (1H, m), 4.88 (1H, d, J = 14.7Hz), 5.02 (2H, s),
20 5.09 (1H, d, J = 14.7Hz), 6.63 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 7.03 ( 1H, t, J = 7.8Hz), 7.10 (1H, s), 7.20 (1H, d, J = 8.1Hz), 7.23-7.45 (5H, m), 7, 60 (1H, dd, J = 2.7, 8.4Hz), 8.47 (1H, d, J = 2.4Hz).
Example 330 image 1
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - [(2-25 ethylthiazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.28 g) as starting material, N - [(2-ethylthiazol-4-yl) methyl] -5-hydroxy-N- hydrochloride was obtained ( 6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.85 g).
MS (ESI) m / z: 436 [MH] +
1 H-NMR (NMR-d 6) δ: 1.24-1.57 (10H, m), 1.73-2.00 (3H, m), 2.32-2.60 (2H, m), 2 , 98 (2H, q, J = 7.4Hz), 3.19-3.45 (1H, m), 3.52-3.70 (1H, m), 4.80-5.11 (2H, m), 6.40–6.58 (1H, m), 6.63 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz) 7.30–8 , 02 (2H, m), 8.22-8.48 (1H, m), 8.80-8.93 (1H, m).
Example 331 image 1
By reaction and treatment in the same manner as in Example 271 using 5– hydrochloride
10 benzyloxy-N– (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 4– Chloromethyl-2-ethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N - ({1 - [(2-ethylthiazol-4-yl) methyl] pyrazol-4-yl} methyl) -N - (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.37 (3H, t, J = 7.5Hz), 1.41-1.57 (1H, m) , 1.77-2.08 (3H, m), 2.60-2.80 (2H, m), 3.01 (2H, q, J = 7.5H2), 3.09 (1H, sept, J = 6.9Hz), 3.59-3.68 (1H, m), 4.66 (1H, d, J = 14.4Hz), 4.84 (1H, d,
15 J = 14.7Hz), 5.03 (2H, s), 5.26 (2H, s), 6.55 (1H, d, J = 7.8Hz), 6.72 (1H, d, J = 8.1Hz), 6.82 (1H, s), 7.03 (1H, t, J = 7.8Hz), 7.18 (1H, d, J = 8.4Hz), 7.22–7 , 50 (8H, m), 8.38 (1H, d, J = 2.4Hz).
Example 332 image 1
Through reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1 - [(2–
Ethylthiazol-4-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.655g) as the material of Starting, N - ({1 - [(2-ethylthiazol-4-yl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1 hydrochloride was obtained , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.56 g).
MS (ESI) m / z: 516 [MH] +
1 H-NMR (DMSO-d 6) δ: 1.18-1.52 (10H, m), 1.70-1.97 (3H, m), 2.34-2.60 (2H, m), 2 , 95 (2H, q, J = 7.5Hz), 3.18–
25 3.39 (1H, m), 3.45-3.62 (1H, m), 4.60-4.88 (2H, m), 5.32 (2H, s), 6.47 (1H , d, J = 7.5Hz), 6.63 (1H, d, J = 7.8Hz), 6.87 (1H, t, J = 7.8Hz), 7.14 (1H, s), 7 , 22–7.38 (1H, m), 7.57–7.81 (2H, m) ‚7.97–8.13 (1H, m), 8.60–8.88 (1H, m) .
Example 333 By reaction and treatment in the same manner as in Example 82 using 1– (tert-butyloxycarbonyl) -4- (hydroxymethyl) pyrazole (1.74 g) and N– (6-isopropylpyridin-3– il) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.15 g) as starting materials, N- (6-isopropylpyridin-3-yl) -N- [(pyrazole-4) hydrochloride was obtained -Yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.99 g). Melting point: 217.3 ° C image 1
1H-NMR (CDCl3) δ: 1.36 (6H, d, J = 6.9Hz), 1.42-1.60 (1H, m), 1.75-2.00 (3H, m), 2 , 55-2.80 (2H, m), 3.52 (1H, sept, J = 6.9Hz), 3.60-3.77 (1H, m), 4.70-5.02 (2H, m), 6.98–7.18 (4H, m), 7.85 (2H, s), 8.60 (1H, d, J = 8.7Hz), 8.33–8.53 (1H, m), 8.98 (1H, d, J = 2.1Hz).
Example 334 image4
To a solution of N- (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide hydrochloride (0.99 g) in methylene chloride (10 mL) tetra-n-butylammonium hydrogen sulfate (0.82 g), 2-chloromethyl-4-methylpyridine hydrochloride (0.86 g) and 1 mol / L of aqueous solution of sodium hydroxide (24.0 mL). The mixture was stirred at room temperature for one day. The reaction mixture was divided into water and chloroform.
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N- (6-isopropylpyridin-3-yl) - N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazole –4 – yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide. This compound was dissolved in ethyl acetate and 4 moles / L of HCl / dioxane (2.4 mL) was added. The precipitated solid was collected by filtration to give N- (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridin-2-yl) meti] pyrazol-4-yl} methyl) - dihydrochloride.
20 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.61 g).
MS (ESI) m / z: 480 [MH] +
1H-NMR (DMSO-d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.38-1.60 (1H, m), 1.72-2.00 (3H, m) , 2.50 (3H, s), 2.57–2.80 (2H, m), 3.23–3.42 (1H, m), 3.53–3.68 (1H, m), 4 , 60–4.94 (2H, m), 5.45 (2H, s), 6.95–7.20 (5H, m), 7.27–7.43 (1H, m), 7.60 –7.93 (3H, m), 8.01–8.22 (1H, m), 8.40 (1H, d, J = 2.7Hz), 8.67–8.85 (1H, m) .
Example 335 By reaction and treatment in the same manner as in Example 334 using N- (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1 hydrochloride, -1 2,3,4-tetrahydronaphthalen-1-carboxamide (0.95 g) and 2-chloromethyl-5-methoxypyridine (0.83 g) as starting materials, N- (6-isopropylpyridin-3-yl dihydrochloride) was obtained ) –N - ({1– [(5-methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.97 g). image 1
MS (ESI) m / z: 496 [MH] +
1H – NMR (DMSO – d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.37–1.59 (1H, m), 1.77–2.02 (3H, m) , 2.46-2.82 (5H, m), 3.21-3.42 (1H, m), 3.52-3.71 (1H, m), 4.60-4.98 (2H, m), 5.70 (2H, s), 6.98–7.17 (4H, m), 7.28–7.52 (2H, m), 7.75 (2H, d, J = 5, 4Hz), 7.85–8.00 (1H, m), 8.09–8.26 (1H, m), 8.74 (2H, d, J = 6.0Hz).
Example 336 image4
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] –1.2 , 3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 6-chloromethyl-2– (dimethylamino) pyridine (0.46 g) as starting materials, 5-benzyloxy-N - ({1– [(6-dimethylaminopyridin-2-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.43 g).
1 H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.39-1.63 (1H, m), 1.77-2.08 (3H, m), 2.60–2.83 (2H, m), 3.05 (6H, s), 3.08 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4.66 (1H, d, J = 14.4Hz), 4.85 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.22 (2H, s), 6, 19 (1H, d, J = 7.2Hz), 6.40 (1H, d, J = 8.4Hz), 6.55 (1H, d, J = 7.5Hz), 6.71 (1H, d , J = 8.1Hz), 7.01 (1H, t, J = 8.0Hz), 7.16 (1H, d, J = 8.4Hz), 7.23–7.44 (8H, m) , 7.51 (1H, s), 8.40 (1H, d, J = 2.1Hz).
Example 337 image2
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - ({1 - [(6- dimethylaminopyridin-2-yl) methyl] pyrazol-4-yl} methyl) -N - (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.43 g) as starting material, N - ({1 - [(6-dimethylaminopyridine dihydrochloride) –2– il) methyl] pyrazol-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.30 g).
25 MS (ESI) m / z: 525 [MH] +
1H – NMR (DMSO – d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.33–1.51 (1H, m), 1.70–1.96 (3H, m) , 2.35–2.60 (2H, m), 3.15–3.32 (1H, m), 3.17 (6H, m), 3.43–3.64 (1H, m), 4 , 72 (1H, d, J = 14.1Hz), 4.81 (1H, d, J = 14.4Hz), 5.46 (2H, s), 6.09 (1H, d, J = 7, 2Hz), 6.46 (1H, d, J = 7.5Hz), 6.63 (1H, d, J = 7.8Hz), 6.82-6.97 (2H, m), 7.30– 7.43 (1H, m), 7.57-7.85 (3H, m), 7.90-8.07 (1H, m), 8.55-8.68 (1H, m).
Example 338 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78g) and 3- (dimethylamino) benzyl chloride (0.51g) as starting materials, 5-benzyloxy-N- ( {1– [3– image 1
5 (dimethylaminophenyl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.46 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.39-1.55 (1H, m), 1.75-2.07 (3H, m), 2 , 58–2.80 (2H, m), 2.93 (6H, s), 3.08 (1H, sept, J = 6.9Hz), 3.57–3.67 (1H, m), 4 , 61 (1H, d, J = 14.4Hz), 4.84 (1H, d, J = 14.7Hz), 5.03 (2H, s), 5.20 (2H, s) 6.47– 6.59 (3H, m), 6.62–6.75 (2H, m), 6.95–7.04 (1H, m), 7.11–7.45 (10H, m), 8, 38 (1H, d, J = 2.4Hz).
10 Example 339 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - ({1– [3– (dimethylaminophenyl) methyl] pyrazol-4-yl} methyl) –N– (6– isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.46 g) as starting material, N - ({1– [3– (dimethylaminophenyl) methyl] pyrazole dihydrochloride was obtained –4 – il} methyl) -
15 5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.33 g).
MS (ESI) m / z: 524 [MH] +
1H-NMR (DMSO-d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.33-1.50 (1H, m), 1.67-1.93 (3H, m) , 2.33–2.57 (2H, m), 3.00 (6H, s), 3.11–3.31 (1H, m), 3.42–3.63 (1H, m), 4 , 60–4.86 (2H, m), 5.28 (2H, s), 6.45 (1H, d, J = 7.8Hz), 6.63 (1H, d, J = 7.8Hz) , 6.75–6.90 (2H, m), 7.17–7.41 (4H, m), 7.57–7.75 (2H, m), 7.85–8.03 (1H, m), 8.53-8.71 (1H, m).
Example 340 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 2- (dimethylamino) benzyl chloride (0.51 g) as starting materials, 5-benzyloxy-N- ( {1 - [(2– (dimethylamino) phenyl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide image 1
5 (0.43 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.36-1.56 (1H, m), 1.68-2.07 (3H, m), 2 , 66 (6H, s), 2.65-2.81 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57-3.67 (1H, m), 4 , 64 (1H, d, J = 14.4Hz), 4.84 (1H, d, J = 14.4Hz), 5.02 (2H, s), 5.40 (2H, s), 6.52 (1H, d, J = 7.8Hz), 6.71 (1H, d, J = 8.1Hz), 6.88 (1H, d, J = 6.6Hz), 6.94 7.06 (2H , m), 7.16 (2H, d, J = 8.1Hz), 7.22-7.45 (9H, m), 8.38 (1H, d, J = 2.4Hz).
10 Example 341 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - ({1 - [(2– (dimethylamino) phenyl) methyl] pyrazol-4-yl} methyl) -N– (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.43 g) as starting material, N - ({1 - [(2 - (dimethylamino) dihydrochloride was obtained. ) phenyl) methyl] pyrazol-4-yl} methyl) -
15 5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.32 g).
MS (ESI) m / z: 524 [MH] +
1H – NMR (DMSO – d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.31–1.52 (1H, m), 1.70–1.96 (3H, m) , 2.33-2.59 (2H, m), 3.08 (6H, s), 3.15-3.33 (1H, m), 3.44-3.61 (1H, m), 4 , 62–4.87 (2H, m), 5.68 (2H, s), 6.46 (1H, d, J = 7.5Hz), 6.63 (1H, d, J = 7.8Hz) 6.87 (1H, d, J = 7.8Hz), 7.00 (1H, d, J = 7.2Hz), 7.27–7.51 (3H, m), 7.60–8.05 (4H m), 8.57-8.70 (1H, m).
20 Example 342 image 1
By reaction and treatment in the same manner as in Example 82 using N- (4-isopropylphenyl) -8- nitrochroman-4-carboxamide (4.1 g) and 1- (tert-butyloxycarbonyl) -4- (hydroxymethyl) pyrazole (2.4 g) as starting materials, N- (4-isopropylphenyl) -8-nitro-N - [(pyrazol-4-yl) methyl] chroman-4-carboxamide (2.9 g).
1 H NMR (CDCl 3) δ: 1.27 (6H, d, J = 6.9Hz), 1.90-2.25 (2H, m), 2.85-3.05 (1H, m), 3.60–3.85 (2H, m), 4.05–4.25 (1H, m), 4.50-4.70 (1H, m), 4.72 (1H, d, J = 14 , 4Hz), 4.80 (1H, d, J = 14.4Hz), 6.87 (1H, t, J = 7.9Hz), 7.00–7.15 (3H, m), 7.20 –7.35 (2H, m), 7.49 (2H, s), 7.70 (1H, d, J = 1.4Hz).
Example 343 By reaction and treatment in the same manner as in Example 271 using N- (4-isopropylphenyl) -8- nitro-N - [(pyrazol-4-yl) methyl] chroman-4-carboxamide ( 2.9 g) and ethyl iodide (1.1 mL) as starting material, N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -8-nitrochroman-4 was obtained –Carboxamide (2.9 g). image 1
1H-NMR (CDCl3): 1.27 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 72Hz), 1.90-2.05 (1H, m), 2, 10-2.20 (1H, m), 2.85-3.05 (1H, m), 3.70-3.80 (1H, m), 4.13 (2H, q, J = 7.2Hz ), 4.05-4.25 (1H, m), 4.50-4.65 (1H, m), 4.64 (1H, d, J = 14.1Hz), 4.75 (1H, d , J = 14.1Hz), 6.87 (1H, t, J = 7.8Hz), 6.95–7.10 (3H, m), 7.20–7.40 (4H, m), 7 , 65–7.75 (1 H, m).
Example 344 image 1
To a mixed solvent of ethanol (43 mL) and water (18 mL) were added iron (0.43 g) and ammonium chloride (0.06 g), and a solution of N - [(1-ethylpyrazole-4 -Il) methyl] -N- (4-isopropylphenyl) -8-nitrochroman-4-carboxamide (0.9 g) in ethanol (10 mL) was added dropwise with heating and stirring at 50 ° C – 70 ° C . After stirring at 50 ° C – 70 ° C for 3 h, the reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on
15 silica gel column to give 8-amino-N - [(1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (0.66 g).
1H – NMR (CDCl3) δ: 1.27 (6H, d, J = 6.9Hz), 1.45 (3H, t, J = 7.3Hz), 1.85-2.00 (1H, m) , 2.10–2.25 (1H, m), 2.85–3.00 (1H, m), 3.60–3.80 (3H, m), 4.00–4.12 (2H, q, J = 7.3Hz), 4.45-4.55 (1H, m), 4.60 (1H, d, J = 14.4Hz), 4.81 (1H, d, J = 14.4Hz ), 6.30 (1H, d, J = 7.5Hz), 6.50–6.56 (1H, m), 6.63 (1H, t, J = 7.6Hz), 6.95–7 , 40 (6H, m).
20 Example 345 image 1
By reaction and treatment in the same manner as in Example 82 using 4-benzyloxy-N- (2,4-dimethoxyphenyl) indan-1-carboxamide (0.96 g) and 1– (tert-butyloxycarbonyl) –4– (hydroxymethyl) pyrazole (0.47 g) as starting materials, 4-benzyloxy-N– (2,4-dimethoxyphenyl) -N - [(pyrazol-4-yl) methyl] indan – 1– carboxamide
25 (0.43 g). Through the reaction and treatment in the same manner as in Example 271 using this compound (0.43 g) and ethyl iodide (0.28 mL), 4-benzyloxy-N- (2,4– dimethoxyphenyl) -N - [(1-ethylpyrazol-4-yl) methyl] indan-1-carboxamide (0.36 g). Through reaction and treatment in the same manner as in Example 17 using this compound (0.36 g), N- (2,4-dimethoxyphenyl) -N - [(1-ethylpyrazol-4-yl) was obtained ) methyl) -4- hydroxyindan-1-carboxamide (0.21 g).
30 MS (ESI) m / z: 422 [MH] + 1H-NMR (CDCl3) δ: 1.44 (3H, t, J = 7.2Hz), 2.00-2.50 (2H, m), 2.55-280 (1H, m), 2.90-3.20 (1H, m), 3.55-4.40 (8H, m), 4.11 (2H, q, J = 7.2Hz ), 5.00–5.25 (1H, m), 5.90–7.50 (9H, m).
Example 346 image 1
5 By reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.41 g) and [(1-ethylpyrazole] 4-yl) methyl] (4-isopropylphenyl) amine (0.51 g) as starting materials, N - [(1-ethylpyrazol-4-yl) methyl] -7-fluoro-N- (4-isopropylphenyl) was obtained ) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.33 g).
1H-NMR (CDCl3) δ: 1.26 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.46 (3H, t, J = 7.2Hz) , 1.80–2.15 (3H, m), 2.55–3.05
10 (3H, m), 3.60-3.75 (1H, m), 4.14 (2H, q, J = 7.2Hz), 4.59 (1H, d, J = 14.4Hz), 4.83 (1H, d, J = 14.4Hz), 6.55–6.65 (1H, m), 6.75–6.85 (1H, m), 6.95–7.10 (3H , m), 7.20-7.40 (2H, m), 7.31 (1H, s) 7.43 (1H, s).
Example 347 image 1
By reaction and treatment in the same manner as in Example 12 using 8-cyanochroman acid–
15 4-carboxylic (0.7 g) and [(1-ethylpyrazol-4-yl) methyl] (4-isopropylphenyl) amine (0.84 g) as starting materials, 8-cyary-N - [( 1-ethylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide (1.2 g).
1H – NMR (CDCl3) δ: 1.27 (6H, d, J = 7.0Hz), 1.45 (3H, t, J = 7.4Hz), 1.85-2.20 (2H, m) , 2.85-3.05 (1H, m), 3.70-3.80 (1H, m), 4.05-4.25 (1H, m), 4.12 (2H, q, J = 7.4Hz), 4.63 (1H, d, J = 14.3Hz), 4.75 (1H, d, J = 14.3Hz), 4.50-4.70 (1H, m), 6, 85 (1H, t, J = 7.7Hz), 7.00–7.15 (3H, m), 7.20–7.50 (5H, m).
20 Example 348 image 1
By reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -8-methyl-1,2,3,4-tetrahydronaphthalen-1– carboxamide (1.75 g) and 1– (tert-butyloxycarbonyl) -4- (hydroxymethyl) pyrazole (0.84 g) as starting materials, 5-benzyl-N- (6-isopropylpyridin-3-yl) was obtained –8 – methyl – N–
[[(Pyrazole-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.22 g).
MS (ESI) m / z: 495 [MH] + 1H-NMR (CDCl3) δ: 1.33 (6H, d, J = 6.9Hz), 1.50-1.80 (2H, m), 1 , 82–2.10 (2H, m), 2.05 (3H, s), 2.45–2.60 (1H, m), 2.80–3.20 (2H, m), 3.50 –3.60 (1H, m), 4.57 (1H, d, J = 14.5Hz), 4.86 (1H, d, J = 14.5Hz), 5.01 (2H, s), 6 , 68 (1H, d, J = 8.3Hz), 6.88 (1H, d, J = 8.2Hz), 7.20–7.55 (9H, m), 8.45 (1H, d, J = 2.4Hz).
Example 349 image5
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -8-methyl-N - [(pyrazole-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.5 g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.36 g) as starting materials, 5-benzyloxy-N- ( 6 – isopropylpyridin – 3– yl) –N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –8 – methyl – 1,2,3,4-tetrahydronaphthalen– 1-carboxamide (0.45 g).
10 1H-NMR (CDCl3) δ: 1.33 (6H, d, J = 6.9Hz), 1.55-1.75 (2H, m), 1.80-2.00 (2H, m), 2.03 (3H, s), 2.31 (3H, s), 2.45-2.60 (1H, m), 2.85-3.00 (1H, m), 3.02-3, 20 (1H, m), 3.50–3.60 (1H, m), 4.54 (1H, d, J = 14.5Hz), 4.82 (1H, d, J = 14.5Hz), 5.01 (2H, s), 5.35 (2H, s), 6.67 (1H, d, J = 8.3Hz), 6.79 (1H, s), 6.87 (1H, d, J = 8.3Hz), 7.02 (1H, d, J = 4.8Hz), 7.15–7.50 (9H, m), 8.41 (1H, d, J = 5.0Hz), 8.46 (1H, d, J = 2.4Hz).
Example 350 image3
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridin-2-yl)) methyl] pyrazol-4-yl} methyl) -8-methyl-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.45 g) as starting materials, 5-hydroxy-N dihydrochloride was obtained ( 6-isopropylpyridin-3-yl) - N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –8-methyl – 1,2,3,4-tetrahydronaphthalen– 1-carboxamide (0.27 g).
20 MS (ESI) m / z: 510 [MH] +
1H – NMR (DMSO – d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.40–2.05 (4H, m), 1.92 (3H, s) 2.20– 2.70 (5H, m), 3.10-3.25 (1H, m), 3.40-3.50 (1H, m), 4.60 (1H, d, J = 14.4Hz), 4.75 (1H, d, J = 14.4Hz), 5.60 (2H, s), 6.54 (1H, d, J = 7.2Hz), 6.70 (1H, d, J = 8 , 1Hz), 7.17 (1H, brs), 7.34 (1H, brs), 7.50-7.95 (4H, m), 8.51 (1H, brs), 8.67 (1H, d, J = 5.7Hz).
Example 351 image6
By reaction and treatment in the same manner as in Example 142 using 2-ethyl-5-hydroxymethyl- 4-methylthiazole (0.63 g) and 5-benzyloxy-N- (6-isopropylpyrin-3-yl ) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.8 g) as
starting materials, 5-benzyloxy-N - [(2-ethyl-4-methylthiazol-5-yl) methyl] -N- (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen was obtained -1-carboxamide (1.3 g). MS (ESI) m / z: 540 [MH] + Example 352 image5
By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - [(2-ethyl-4-methylthiazol-5-yl) methyl] -N- (6-isopropylpyridin-3– il) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.3 g) as starting material, N - [(2-ethyl-4-methylthiazol-5-yl) methyl] hydrochloride was obtained - 5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g).
10 MS (ESI) m / z: 450 [MH] +
1H – NMR (DMSO – d6) δ: 1.26 (6H, d, J = 6.9Hz), 1.26 (3H, t, J = 7.5Hz), 1.30–1.50 (1H, m), 1.70-2.00 (3H, m), 1.94 (3H, s), 2.35-2.60 (2H, m), 2.94 (2H, q, J = 7, 5Hz), 3.10–3.25 (1H, m), 3.40–3.60 (1H, m), 4.92 (1H, d, J = 14.6Hz), 5.04 (1H, d, J = 14.6Hz), 6.45 (1H, d, J = 7.5H2), 6.63 (1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7 , 8Hz), 7.56 (1H, d, J = 8.1Hz), 7.75-7.90 (1H, m), 8.52 (1H, brs).
15 Example 353 image 1
By reaction and treatment in the same manner as in Example 142 using 2-ethyl-5-hydroxymethyl- 4-trifluoromethylthiazole (0.63 g) and 5-benzyloxy-N- (6-isopropylpyridin-3-yl ) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.2 g) as starting materials, 5-benzyloxy-N - [(2-ethyl-4-trifluoromethylthiazol-5-yl) meti] ) –N– (6–
20 isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.4 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.40 (3H, t, J = 7.5Hz), 1.45-1.65 (1H, m) 1.80–2.10 (3H, m), 2.65–2.80 (2H, m), 3.02 (2H, q, J = 7.5Hz), 2.95–3.20 (1H , m), 3.65-3.80 (1H, m), 5.04 (2H, s), 5.19 (2H, s), 6.59 (1H, d, J = 7.8Hz), 6.75 (1H, d, J = 7.8Hz), 7.08 (1H, t, J = 7.8Hz), 7.20-7.45 (7H, m), 8.37 (1H, d , J = 2.4Hz).
Example 354 image6
By reaction and treatment in the same manner as in Example 133 using 5-benzyloxy-N - [(2-ethyl-4-trifluoromethylthiazol-5-yl) methyl] -N- (6-isopropylpyridin-3– il) -1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.4 g)
As a starting material, N - [(2-ethyl-4-trifluoromethylthiazol-5-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4– was obtained tetrahydronaphthalen-1-carboxamide (0.22 g). Melting point: 164.0 ° C.
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 7.0Hz), 1.40 (3H, t, J = 7.6Hz), 1.45-1.70 (1H, m) , 1.80-2.20 (3H, m), 2.50-2.75 (2H, m), 3.03 (2H, q, J = 7.6Hz), 3.00-3.20 ( 1H, m), 3.65–3.80 (1H, m), 5.19 (2H, s), 5.58 (1H, s), 6.45-6.60 (2H, m), 6 , 93 (1H, t, J = 7.8Hz), 7.20-7.50 (2H, m), 8.37 (1H, d, J = 2.4Hz).
Example 355 image 1
To a solution of 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.35 g) in dimethylformamide 2-Chloro-N, N-dimethylethylamine hydrochloride (0.12 g) was added and
10 sodium hydride (0.035 g) and the mixture was stirred for one day. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue obtained was reacted and treated in the same manner as in Example 17 to give N - ({1– [2– (dimethylamino) ethyl] pyrazol-4-yl} methyl) –5– hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.18 g). Melting point: 92 ° C.
15 Example 356 image 1
By reaction and treatment in the same manner as in Example 17 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 -Tetrahydronaphthalen-1-carboxamide (0.36 g) as a starting material, 5-hydroxy-N- (4-isopropylphenyl) -N - [(pyrazole-4-yl) methyl] -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.14 g).
20 Melting point: 247 ° C.
Example 357 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] 1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.41 g) and isopropyl iodide (0.16
25 mg) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(1-isopropylpyrazol-4-yl) methyl] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide was obtained (0.47 g). Through the reaction and treatment of this compound in the same manner as in Example 17, 5-hydroxy-N- (4-isopropylphenyl) -N - [(1-isopropylpyrazol-4-yl) methyl] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.22 g). Melting point: 185 ° C.
Example 358 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (0.50 mg) and bromocyclopentane
5 (0.12 mL) as starting materials, 5-benzyloxy-N - [(1-cyclopentylpyrazol-4-yl) methyl] -N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen was obtained –1 – carboxamide (0.54 g). Through the reaction and treatment of this compound in the same manner as in Example 17, N - [(1-cyclopentylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-isopropylphenyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.27 g). Melting point: 173 ° C.
Example 359 image4
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 -Tetrahydronaphthalen-1-carboxamide (0.52 g) and methyl iodide (0.073 mL) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(1-methylpyrazole-4-yl ) methyl] –1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.49 g). Through the reaction and treatment of this compound of the
In the same manner as in Example 17, 5-hydroxy-N- (4-isopropylphenyl) -N - [(1-methylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1- was obtained carboxamide (0.33 g). Melting point: 215 ° C.
Example 360 image 1
Through reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N– (4–
20 isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.50 g) and 1-bromopropane (0.1 mL) as starting materials , 5-benzyloxy-N- (4-isopropylphenyl) -N - [(1-propylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.52 g) was obtained. Through the reaction and treatment of this compound in the same manner as in Example 17, 5-hydroxy-N- (4-isopropylphenyl) -N - [(1-propylpyrazol-4-yl) methyl] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.31 g). Melting point: 161 ° C.
Example 361 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N– (4– image 1
isopropylphenyl) –N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.12 g) and ethyl bromoacetate
(0.31 mL), 2– (4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl) -N– (4–
5 isopropylphenyl) amino] methyl} pyrazol-1-yl) ethyl acetate (0.66 g). This compound was dissolved in ethanol (20 mL) and 1
mol / L of aqueous sodium hydroxide solution (1.22 mL). The mixture was stirred at room temperature for 1 h.
To the reaction mixture was added 1 mol / L hydrochloric acid (1.22 mL), and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is
evaporated. Through the reaction and treatment of the residue obtained in the same manner as in Example 17 10 (0.58 g), 2– (4 - {[N– (5-benzyloxy-1,2,3) acid was obtained , 4 – tetrahydronaphthalen – 1 – ylcarbonyl) –N– (4–
isopropylphenyl) amino] methyl} pyrazol-1-yl) acetic acid (0.23 g). Melting point: 180–182 ° C.
Example 362 image 1
2– (4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl) -N- (4-isopropylphenyl) amino] methyl} pyrazole-1-yl) acetate
Ethyl (1.0 g) was dissolved in tetrahydrofuran solution: ethanol (1: 2) (10 mL), and lithium chloride (0.30 g) and sodium borhydride (0.27 g) were added. The mixture was stirred at room temperature for 3 h. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue obtained (0.91 g) was reacted and treated in the same manner as in Example 17 to give 5-hydroxy-N - {[1– (2-hydroxyethyl) pyrazole-4– il] methyl} –N– (4-isopropylphenyl) –1,2,3,4–
Tetrahydronaphthalen-1-carboxamide (0.25 g). Melting point: 110-114 ° C.
Example 363 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (1.02 g) and 1 – bromo – 3– (2–25 oxanyloxy) propane (0.45 mL) as starting materials, 5-benzyloxy-N– (4-isopropylphenyl) was obtained –N - ({1– [3– (2-oxanyloxy) propyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.65 g) This compound was dissolved in methanol (30 mL) and 4 moles / L of HCl / dioxane (0.1 mL) was added. The mixture was stirred at room temperature for 2 h. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate (2 mL). The reaction mixture was concentrated under reduced pressure and divided into water and ethyl acetate. The organic layer was washed with
30 saturated brine and dried over magnesium sulfate. The solvent was evaporated. By reaction and treatment of the residue obtained (0.94 g) in the same manner as in Example 105, 5-hydroxy-N - {[1– (3-hydroxypropyl) pyrazol-4-yl] methyl} -N was obtained - (4-Isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.58 g).
1H-NMR (CDCl3) δ: 2.48 (6H, d, J = 6.9Hz), 1.41-1.44 (1H, m), 1.82-1.98 (5H, m), 2 , 57 (2H, brs), 2.92 (1H, sept, J = 6.9Hz), 3.48-3.52 (2H, m), 3.68-4.19 (2H, t, J = 6.2Hz), 4.57 (1H, d, J = 14.3Hz), 4.83 (1H, d, J = 14.3Hz), 6.40 (2H, t, J = 8. 7Hz), 6.80 (1H, t, J = 7.8Hz), 7.07 (2H, d, J = 8.1Hz), 7.22–7.26 (2H, m), 7.34 (1H, s ), 7.47 (1H, s), 8.14 (1H, brs).
Example 364 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 -Tetrahydronaphthalen-1-carboxamide (0.33 g) and (bromomethyl) cyclohexane (0.142 mL) as starting materials, 5-benzyloxy-N - {[1- (cyclohexylmethyl) pyrazole-4-yl] methyl} - N– (4–
10 isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.26 g). Through the reaction and treatment of this compound in the same manner as in Example 105, N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} –5– hydroxy-N– (4– isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.18 g).
1H – NMR (DMSO – d6) δ: 0.84–0.92 (2H, m), 1.11–1.44 (12H, m), 1.63–1.77 (6H, m), 1 , 91–1.99 (1H, m), 2.43–2.52 (2H, m), 2.89 (1H, sept, J = 6.9Hz), 3.50–3.55 (1H, m), 3.86 (2H, d, J = 7.2Hz), 4.65 (2H, s), 6.40 (1H, d, J = 7.8Hz),
15 6.59 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 7.8Hz), 7.12 (2H, d, J = 8.4Hz). 7.21 (1H, s), 7.28 (2H, d, J = 8.4Hz), 7.41 (1H, s).
Example 365 image 1
Through reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N– (4–
20 isopropylphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.37 g) and 3- (chloromethyl) thiophene (0.21 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - {[1– (3-thienylmethyl) pyrazol-4-yl] methyl} - 1,2,3,4-tetrahydronaphthalen-1– was obtained carboxamide (0.16 g). Through the reaction and treatment of this compound (0.11 g) in the same manner as in Example 133, 5-hydroxy-N- (4-isopropylphenyl) -N - {[1– (3–) thienylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.054 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.38-1.45 (1H, m), 1.76-2.01 (3H, m), 2.55–2.60 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.67–3.72 (1H, m), 4.67 (1H, d, J = 14.4Hz), 4.79 (1H, d, J = 14.4Hz), 5.23 (2H, s), 6.33 (1H, d, J = 7.8Hz), 6.38 (1H , d, J = 7.8Hz), 6.74 (1H, t, J = 7.8Hz), 6.94-6.96 (1H, m), 7.04 (2H, d, J = 8, 1Hz), 7.11-7.12 (1H, m), 7.20-7.30 (3H, m), 1.41 (2H, s), 7.53 (1H, brs). Example 366 image 1
By reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.98 g) and 1– (tert-butoxycarbonyl) –4– (hydroxymethyl) pyrazole (1.83 g) as starting materials, 5-benzyloxy-N- (4-methoxyphenyl) –N - [(pyrazole-4-yl) methyl was obtained ] –1,2,3,4– tetrahydronaphthalen – 1-carboxamide (1.74 g).
MS (ESI) m / z: 468 [MH] +
Example 367 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-methoxyphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide (0.56 g) and 4-fluorobenzyl chloride
10 (0.172 mL) as starting materials, 5-benzyloxy-N - {[1– (4-fluorobenzyl) pyrazol-4-yl] methyl} -N- (4-methoxyphenyl) -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.60 g). Through the reaction and treatment of this compound in the same manner as in Example 133, N - {[1– (4-fluorobenzyl) pyrazol-4-yl] methyl} –5– hydroxy-N– ( 4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.42 g). Melting point: 143-146 ° C.
Example 368 image3
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (4-methoxyphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4 -Tetrahydronaphthalen-1-carboxamide (0.62 g) and ethyl iodide (0.13 mL) as starting materials, 5-benzyloxy-N - [(1-ethylpyrazole-4-yl) methyl] -N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.55 g). Through the reaction and treatment of this compound (0.40 g) of
In the same manner as in Example 133, N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1 was obtained –Carboxamide (0.30 g). Melting point: 211-213 ° C.
Example 369 image 1
Through reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N– (4–
Methoxyphenyl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.56 g) and (bromomethyl) cyclohexane (0.20 mL) as materials Starting, 5-benzyloxy-N - {[1- (cyclohexylmethyl) pyrazol-4-yl] methyl} -N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 55 g). By reaction and treatment in the same manner as in Example 133 using this compound (0.45 g), N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} -5-hydroxy was obtained –N– (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.36 g).
1H – NMR (DMSO – d6) δ: 0.84–0.92 (2H, m), 1.12–1.23 (3H, m), 1.32–1.46 (3H, m), 1 , 63–1.75 (6H, m), 1.90–1.94 (1H, m), 2.40–2.56 (2H, m), 3.53–3.58 (1H, m) , 3.74 (3H, s), 3.83 (2H, d, J = 10.8Hz), 4.60 (1H, d, J = 14.7Hz), 4.66 (1H, d, J = 14.7Hz), 6.40 (1H, d, J = 7.8Hz), 6.62 (1H, d, J = 7.8Hz), 6.86 (1H, t, J = 78Hz), 6, 93–6.96 (2H, m), 7.10–7.13 (2H, m) 7.20 (1H, s), 7.41 (1H, s), 9.19 (1H, s).
Example 370 image 1
By reaction and treatment in the same manner as in Example 271 using 5– hydrochloride
10 benzyloxy-N– (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.77 g) and 4– (chloromethyl) pyridine (0.49 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (4-pyridylmethyl) pyrazole-4-yl] was obtained methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.67 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (4–) dihydrochloride was obtained pyridylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.58
15 g)
MS (ESI) m / z: 482 [MH] +
1H – NMR (DMSO – d6) δ: 1.28 (6H, d, J = 6.9Hz), 1.35–1.43 (1H, m), 1.80–2.00 (3H, m) , 2.38–2.55 (2H, m), 3.22–3.28 (1H, m), 3.53 (1H, brs), 4.73 (1H, d, J = 14.3Hz) , 4.84 (1H, d, J = 14.3Hz), 5.68 (2H, s), 6.47 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz), 6.87 (1H, d, J = 7.8Hz), 7.43 (1H, s), 7.57 (2H, d, J = 6.6Hz) 7.66–7.69 (1H, m), 7.83 (1H, s), 8.00
20 (1H, brs), 8.61 (1H, brs), 8.89 (2H, d, J = 6.6Hz).
Example 371 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.77 g) e
From 1– (2-chloroethyl) piperidine hydrochloride (0.55 g) as starting materials, 5-benzyloxy-N– (6– isopropylpyridin-3-yl) –N - {[1– (2-piperidinoethyl) was obtained ) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (2–) dihydrochloride was obtained piperidinoethyl) pyrazol-4-yl] methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.54).
30 MS (ESI) m / z: 502 [MH] +
1H-NMR (DMSO-d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.32-1.40 (1H, m), 1.65-1.91 (7H, m) , 2.47-2.52 (3H, m), 2.81-2.86 (2H, m), 3.18-3.57 (5H, m), 4.61 (2H, d, J = 6.6Hz), 4.63-4.87 (2H, m), 5.10 (2H, brs), 6.49 (1H, d, J = 7.8Hz), 6.66 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 7.36 (1H, brs), 7.76 (2H, brs), 8.15 (1H, brs), 8 , 68 (1H, brs), 11.1 (1H, brs).
Example 372 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) and (bromomethyl) cyclohexane (0.25 mL) as starting materials, 5-benzyloxy-N - {[1– (cyclohexylmethyl) ) pyrazole– image 1
5-4-yl] methyl} -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.86 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} -5-hydroxy-N- hydrochloride was obtained ( 6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.63 g).
MS (ESI) m / z: 487 [MH] +
10 1H-NMR (DMSO-d6) δ: 0.83-1.91 (21H, m), 2.46-2.52 (2H, m), 3.23 (1H, brs), 3.52 ( 1H, brs), 3.86 (2H, d, J = 7.1Hz), 4.74 (2H, brs), 6.45 (1H, d, J = 7.8Hz), 6.63 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 7.26 (1H, brs), 7.49 (1H, brs), 7.65 (1H, brs) , 7.93 (1H, brs), 8.61 (1H, brs).
Example 373 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] - hydrochloride] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) and 1-bromoheptane (0.28.3 mL) as starting materials, 5-benzyloxy-N - [(1-heptylpyrazole) was obtained 4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.86 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - [(1-heptylpyrazol-4– hydrochloride) was obtained
20 il) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.62 g).
MS (ESI) m / z: 489 [MH] +
1H – NMR (DMS0 – d6) δ: 0.82–0.87 (3H, m), 1.10–1.43 (15H, m), 1.63–1.91 (5H, m), 2 , 46–2.54 (2H, m), 3.31 (1H, brs), 3.54 (1H, brs), 4.02 (2H, t, J = 6.9Hz), 4.72–4 , 77 (2H, m), 6.47 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7, 8Hz), 7.27 (1H, brs) 7.55 (1H, brs), 7.74 (1H, brs), 8.03 (1H, brs), 8.68 (1H, brs).
Example 374 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) and 3-chloromethyl-5,6-dihydroimidazo [2,1-b] thiazole hydrochloride (0.38 g) as materials game, was obtained 5– image 1
5 benzyloxy-N - ({1 - [(5,6-dihydroimidazo [2,1-b] thiazol-3-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl ) –1,2,3,4– tetrahydronaphthalen – 1 – carboxamide (0.92 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - ({1 - [(5,6-dihydroimidazo [2,1-b] thiazole-3-yl-dihydrochloride) ) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.50 g).
MS (ESI) m / z: 529 [MH] +
10 1H – NMR (DMSO – d6) δ: 1.28 (6H, d, J = 6.8Hz), 1.34-1.44 (1H, m), 1.80–1.91 (3H, m ), 2.46-2.55 (2H, m), 3.21 (1H, brs), 3.51 (1H, brs), 4.11-4.29 (4H, m), 4.66– 4.81 (2H, m), 5.35 (2H, m), 6.45 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz), 6, 81–6.91 (2H, m), 7.37 (1H, brs), 7.59–7.61 (1H, m), 7.74 (1H, brs), 7.93 (1H, brs) , 8.85 (1H, brs), 9.98 (1H, brs).
Example 375 image3
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide (0.72 g) and (bromomethyl) cyclopropane (0.174 mL) as starting materials, 5-benzyloxy-N - {[1– (cyclopropylmethyl) pyrazole was obtained –4 – yl] methyl} –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.80 g).
By reaction and treatment of this compound in the same manner as in Example 139, N - {[1– (cyclopropylmethyl) pyrazol-4-yl] methyl} -5-hydroxy-N- (6 -Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.58 g).
MS (ESI) m / z: 445 [MH] +
1H – NMR (DMSO – d6) δ: 0.26–0.30 (2H, m), 0.45 (0.51 (2H, m), 1.12–1.20 (1H, m), 1 , 32 (6H, d, J = 6.9Hz), 1.40-1.50
25 (1H, m), 1.81-1.91 (3H, m), 2.47-2.51 (2H, m), 3.34 (1H, brs), 3.55 (1H, brs) , 3.91 (2H, d, J = 6.9Hz), 4.76 (2H, brs), 6.49 (1H, d, J = 7.8Hz), 6.65 (1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7.8Hz), 7.28 (1H, brs), 7.59 (1H, brs), 7.79 (1H, brs), 8.07 (1H, brs), 8.70 (1H, brs).
Example 376 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) and 4– (2-chloroethyl) morpholine hydrochloride (0.33 g) as starting materials, 5-benzyloxy-N- was obtained {[1– (2– image 1
5 morpholinoethyl) pyrazol-4-yl] methyl} -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.69 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N - {[1– (2-morpholinoethyl) pyrazol-4-yl] methyl} -N hydrochloride was obtained - (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.34 g).
MS (ESI) m / z: 504 [MH] +
10 1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.9Hz), 1.40–1.50 (1H, m), 1.81–1.91 (3H, m ), 2.43–2.54 (2H, m), 3.05 (1H, brs), 3.24 (1H, brs), 3.52–3.57 (4H, m), 3.81– 3.89 (4H, m), 4.58-5.20 (6H, m), 6.48 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz ), 6.90 (1H, t, J = 7.8Hz), 7.35 (1H, brs), 7.47-7.73 (2H, m), 8.05 (1H, brs), 8, 63 (1H, brs), 11.7 (1H, brs).
Example 377 image 1
To a solution of 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide hydrochloride ( 0.72 g) in dimethylformamide (5 mL), triethylamine (0.23 mL) and cyclohexanecarbonyl chloride (0.22 mL) were added, and the mixture was stirred at room temperature for one day. The reaction mixture was divided into water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography.
20 to give 5-benzyloxy-N - {[1– (cyclohexylcarbonyl) pyrazol-4-yl] methyl} -N- (6-isopropylpyridin-3-yl) –1,2,3,4- tetrahydronaphthalen-1-carboxamide (0.67 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - {[1– (cyclohexanecarbonyl) pyrazol-4-yl] methyl} –5– hydroxy-N– hydrochloride was obtained ( 6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.23 g).
MS (ESI) m / z: 501 [MH] +
25 1H-NMR (DMSO-d6) δ: 1.15-2.00 (20H, m), 2.43 (2H, brs), 2.58-2.64 (1H, m), 3.40– 3.44 (1H, m), 3.66 (1H, brs), 4.73–7.89 (2H, m), 6.89 (1H, d, J = 7.8Hz), 7.01 ( 1H, d, J = 7.8Hz), 7.16 (1H, t, J = 7.8Hz), 7.57-7.66 (2H, m), 7.86-7.89 (2H, m ), 8.25–8.26 (1H, m), 8.87 (1H, brs).
Example 378 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide (0.83 g) and 3– (chloromethyl) thiophene (0.27 g) as starting materials, 5-benzyloxy-N - {[1– (3 – thienylmethyl) pyrazole – 4– image 1
5-yl] methyl} -N- (6-isopropylpyridin) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.48 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (3–) hydrochloride was obtained thienylmethyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.39 g).
MS (ESI) m / z: 487 [MH] +
1H – NMR (DMSO – d6) δ: 1.30 (6H, d, J = 6.8Hz), 1.42 (1H, m), 1.79–1.91 (3H, m), 2.46 –2.51 (2H, m), 3.30 (1H, brs),
10 3.53-3.57 (1H, m), 4.76 (2H, m), 5.26 (2H, s), 6.45 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz), 6.87-6.94 (2H, m), 7.24-7.28 (2H, m), 7.49-7.52 (1H, m) , 7.61 (1H, brs), 7.73 (1H, brs), 8.02 (1H, brs), 8.68 (1H, brs).
Example 379 image 1
By reaction and treatment in the same manner as in Example 271 using 5– hydrochloride
15 benzyloxy-N– (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g) and 4– (chloromethyl) -2-methylthiazole (0.55 g) as starting materials, 5-benzyloxy-N - ({1 - [(2-methylthiazol-4-yl) methyl] pyrazol-4-yl} methyl) was obtained –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.73 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(2 –Methylthiazol – 4-yl) methyl] pyrazol – 4-yl} methyl) –1,2,3,4–
Tetrahydronaphthalen-1-carboxamide (0.62 g).
MS (ESI) m / z: 502 [MH] +
1H-NMR (DMSO-d6) δ: 1.33 (6H, d, J = 6.9Hz), 1.41-1.50 (1H, m), 1.83-1.91 (3H, m) , 2.41-2.50 (2H, m), 2.63 (3H, s), 3.40-3.45 (1H, m), 3.57 (1H, brs), 4.70-4 , 85 (2H, m), 5.31 (2H, s), 6.49 (1H, d, J = 7.8Hz), 6.66 (1H, d, J = 7.8Hz), 6.88 (1H, d, J = 7.8Hz), 7.19 (1H, s), 7.32 (1H, brs), 7.67-7.70 (1H, m), 7.87-7.89 (1H, m), 8.21 (1H, brs), 8.80 (1H,
25 brs).
Example 380 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide (0.83 g) and 1– bromobutane (0.322 mL) as starting materials, 5-benzyloxy-N - [(1-butylpyrazole-4-yl ) methyl] –N– (6– image 1
5 isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.66 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - [(1-butylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-opropylpyridine) hydrochloride was obtained –3 – yl) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide (0.41 g).
MS (ESI) m / z: 447 [MH] +
1H – NMR (DMSO – d6) δ: 0.82–0,, 84 (3H, m), 1.07–1.20 (2H, m), 1.35 (6H, d, J = 6.9Hz ), 1.40-1.51 (1H, m), 1.62-1.92
10 (5H, m), 2.47-2.52 (2H, m), 3.43-3.57 (2H, m), 3.99-4.06 (2H, m), 4.70– 5.20 (2H, m), 6.50 (1H, d, J = 7.7Hz), 6.68 (1H, d, J = 7.7Hz), 6.89 (1H, t, J = 7 , 7Hz), 7.33 (1H, brs), 7.60 (1H, brs), 7.92-7.95 (1H, m), 8.25 (1H, brs).
Example 381 image 1
By reaction and treatment in the same manner as in Example 271 using 5– hydrochloride
15 benzyloxy-N– (6-isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydrnaphthalen-1-carboxamide (0.83 g) and isobromide of butyl (0.326 mL) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- {[1– (2-methylpropyl) pyrazol-4-yl] methyl} -1 was obtained, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.16 g). Through the reaction and treatment of this compound in the same manner as in Example 19, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (2–) hydrochloride was obtained methylpropyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.11 g).
20 MS (ESI) m / z: 447 [MH] +
1H – NMR (DMSO – d6) δ: 0.75 (6H, d, J = 6.9Hz), 1.29 (6H, d, J = 6.9Hz), 1.35– 1.47 (1H, m), 1.81–1.94 (3H, m), 2.46–2.52 (3H, m), 3.29 (1H, brs), 3.50–3.60 (1H, m) , 3.83 (2H, d, J = 6.9Hz), 4.76 (2H, brs), 6.47 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 7.24-7.31 (1H, m), 7.51 (1H, brs), 7.74 (1H, brs) , 8.02 (1H, brs), 8.67 (1H, brs).
Example 382 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.83 g) and 1-brouro-3-methylbutane (0.359 mL) as starting materials, 5-benzyloxy-N- (6-isopropylpyridine) –3 – yl) –N– {[1– (3-methylbutyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.60 g). Through the reaction and the image 1
5 treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (3-methylbutyl) pyrazole-4– hydrochloride was obtained il] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.45 g).
MS (ESI) m / z: 461 [MH] +.
1H – NMR (DMSO – d6) δ: 0.85 (6H, d, J = 6.6Hz), 1.34 (6H, d, J = 6.9Hz), 1.43– 1.54 (1H, m), 1.56–1.63 (2H, m), 1.85–, 192 (3H, m), 2.43–2.52 (3H, m), 3.41–3.65 (2H , m), 4.02-4.08 (2H, m), 4.70-5.20 (2H, m), 6.49 (1H, d, J = 10 7.8Hz), 6.67 ( 1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7.8Hz), 7.22-7.31 (1H, m), 7.61 (1H, brs), 7, 90–7.92 (1H, m), 8.22 (1H, brs), 8.81 (1H, brs).
Example 383 image 1
Through reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N– (6–
Methoxypyridin-3-yl) –1,2,3,4– tetrahydronaphthalen-1-carboxamide (20.0 g) and 1– (tert-butoxycarbonyl) –4– (hydroxymethyl) pyrazole (12.0 g), se obtained 5-benzyloxy-N- (6-methoxypyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide hydrochloride (18.8 g ).
MS (ESI) m / z: 469 [MH] +
1H-NMR (DMSO-d6) δ: 1.38-1.49 (1H, m), 1.75-1.82 (2H, m), 1.90-2.00 (1H, m), 2 , 52–2.55 (2H, m), 3.57 (1H, t, J =
20 6.8Hz), 3.84 (3H, s), 4.71 (2H, s), 5.08 (2H, s), 6.59-6.62 (1H, m), 6.83– 6.90 (2H, m), 7.02–7.07 (1H, m), 7.31–7.46 (7H, m), 7.60–7.64 (1H, m), 8, 04 (1H, d, J = 2.4Hz).
Example 384 image 1
By reaction and treatment in the same manner as in Example 83 using 5– hydrochloride
Benzyloxy-N- (6-methoxypyridin-3-yl) -N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.94.8) and bromide of benzyl (0.285 mL) as starting materials, 5-benzyloxy-N - [(1-benzylpyrazol-4-yl) methyl] -N- (6-methoxypyridin-3-yl) -1,2,3, 4-tetrahydranaphthalen-1-carboxamide (0.31 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - [(1-benzylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-methoxypyridine) hydrochloride was obtained –3 – yl) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide (0.087 g).
30 MS (ESI) m / z: 469 [MH] +
1H-NMR (DMSO-d6) δ: 1.36-1.43 (1H, m), 1.75-1.79 (2H, m), 1.86-2.00 (1H, m), 2 , 43–2.57 (2H, m), 3.49–3.55 (1H, m) 3.85 (3H, s), 4.68 (2H, s), 5.28 (2H, s) , 6.40 (1H, d, J = 7.8Hz), 6.60 (1H, d, J = 7.8Hz), 6.82-6.88 (2H, m), 7.09 (2H, d, J = 6.5Hz), 7.25–7.36 (4H, m), 7.57–7.62 (2H, m), 8.01 (1H, d, J = 2.4Hz), 9.20 (1H, brs).
Example 385 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-methoxypyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.9.4 g) and 2- (chloromethyl) pyridine hydrochloride (0.33 g) as starting materials, 5-benzyloxy-N- was obtained (6 – methoxypyridin– image 1
5 3-yl) -N - {[1– (2-pyridylmethyl) pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.28 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-methoxypyridin-3-yl) -N - [(1– (2–) pyridylmethyl) pyrazol-4-yl) methyl-1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.085 g).
MS (ESI) m / z: 470 [MH] +.
10 1H-NMR (DMSO-d6) δ: 1.35-1.43 (1H, m) 1.74-1.80 (2H, m), 1.87-1.95 (1H, m), 2 , 43–2.56 (2H, m), 3.50–3.55 (1H, m), 3.85 (3H, s), 4.65–5.00 (3H, m), 5.51 (2H, m), 6.43 (1H, d, J = 7.8Hz), 6.61 (1H, d, J = 7.8Hz), 6.83-6.90 (2H, m), 7 , 03 (1H, d, J = 7.8Hz), 7.34 (1H, s), 7.55 (1H, t, J = 6.3Hz), 7.64 (1H, dd, J = 2, 7, 8.7Hz), 7.73 (1H, s), 8.00–8.07 (2H, m), 8.66-8.67 (1H, m).
Example 386 image3
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N - [(pyrazol-4-yl) methyl] -N- (6-methoxypyridin-3-yl) -1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.936 g) and 4- (trifluoromethyl) benzyl chloride (0.592 mL) as starting materials, 5-benzyloxy-N- (6-methoxypyridin-3-yl) was obtained ) –N - {[1– (4-trifluoromethylbenzyl) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.25
20 g) Through the reaction and treatment of this compound in the same manner as in Example 133, 5-hydroxy-N- (6-methoxypyridin-3-yl) -N - {[1– (4-trifluoromethylbenzyl) was obtained pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.53 g). Melting point: 199–200 ° C.
Example 387 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N - [(pyrazol-4-yl) methyl) -N- (6-methoxypyridin-3-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.70 g) and 2– (2-chloroethyl) pyridine (0.42 g) as starting materials, 5-benzyloxy-N- (6– methoxypyridin-3-yl) -N - ({1– [2– (2-pyridyl) ethyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.45 g ). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-methoxypyridin-3-yl) -N- ({1– [2–) dihydrochloride was obtained (2-Pyridyl) ethyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.31 g).
5 MS (ESI) m / z: 484 [MH] +
1H-NMR (DMSO-d6) δ: 1.37-1.41 (1H, m), 1.71-1.77 (2H, m), 1.87-1.92 (1H, m), 2 , 44-2.52 (2H, m), 3.47-3.57 (3H, m), 3.86 (3H, s), 4.54-4.68 (4H, m) 6.40 ( 1H, d, J = 7.7Hz), 6.63 (1H, d, J = 7.7Hz), 6.86-6.91 (2H, m), 7.12 (1H, s), 7, 53–7.58 (2H, m), 7.72 (1H, d, J = 8.0Hz), 7.86–7.90 (1H, m), 7.94 (1H, d, J = 2 , 5Hz), 8.38-8.41 (1H, m), 8.81 (1H, d, J = 4.9Hz).
10 Example 388 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.83) and 2– (2-chloroethyl) pyridine (0.42 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridine) 3 – il) –N - ({1–
[2– (2-Pyridyl) ethyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.56 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N- ({1– [2–) dihydrochloride was obtained (2-Pyridyl) ethyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.41 g).
MS (ESI) m / z: 496 [MH] +
20 1H-NMR (DMSO-d6) δ: 1.32 (6H, d, J = 6.9Hz), 1.37-1.46 (1H, m), 1.79-1.92 (3H, m ), 2.44–2.56 (2H, m), 3.34 (1H, brs), 3.51–3.60 (1H, m), 3.58 (2H, t, J = 6.6Hz ), 4.61 (2H, t, J = 6.6Hz), 4.73-4.78 (2H, m), 6.46 (H, d, J = 7.8Hz), 6.66 (1H , d, J = 7.8Hz), 6.90 (1H, t, J = 7.8Hz), 7.20 (1H, brs), 7.61 (1H, brs), 7.76 (2H, d , J = 7.7Hz), 7.86–7.92 (1H, m), 8.04 (1H, brs), 8.46 (1H, t, J = 7.7Hz), 8.63 (1H , brs), 8.82 (1H, d, J = 5.0Hz).
Example 389 image6
By reaction and treatment in the same manner as in Example 83, using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] - hydrochloride] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.96 g) and dodecyl bromide (0.719 mL) as starting materials, 5-benzyloxy-N - [(1-dodecylpyrazol-4-yl) was obtained methyl] - N– (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.29 g). Through the reaction and treatment of this compound in the same manner as in Example 139, N - [(1- dodecylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridine) hydrochloride was obtained –3 – yl) –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide (0.54 g).
MS (ESI) m / z: 559 [MH] +
1H – NMR (DMSO – d6) δ: 0.82–0.87 (3H, m), 1.12–1.45 (19H, m), 1.32 (6H, d, J = 6.9Hz) , 1.64–1.73 (2H, m), 1.82– 1.92 (3H, m), 2.40–2.56 (2H, m), 3.30–3.40 (1H, m), 3.55 (1H, brs), 4.02 (2H, t, J = 6.7Hz), 4.74-4.82 (2H, m), 6.48 (1H, d, J = 7.8Hz), 6.66 (1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7.8Hz), 7.28 (1H, brs), 7.56 (1H, brs), 7.78 (1H, brs), 8.07 (1H, brs), 8.72 (1H, brs).
Example 390 image 1
10 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- (pyrazole-4-yl) methyl-1 hydrochloride, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.96 g) and nonyl bromide (0.57 mL) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) was obtained - N - [(1– nonylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.20 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N- hydrochloride (6–
15 isopropylpyridin-3-yl) -N - [(1-nonylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.81 g).
MS (ESI) m / z: 517 [MH] +
1H-NMR (DMSO-d6) δ: 0.85 (3H, t, J = 6.6Hz), 1.12-1.45 (13H, m), 1.31 (6H, d, J = 6, 9Hz), 1.68 (2H, tt, J = 6.9Hz), 1.81-1.91 (3H, m), 2.40-2.55 (2H, m), 3.33 (1H, brs), 3.54 (1H, brs), 4.02 (2H, t, J = 6.9Hz), 4.69-4.81 (2H, m), 6.47 (1H, d, J = 7.8Hz), 6.65 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 7.27 (1H, brs), 7.55 (1H, brs), 7.76 (1H, brs), 8.05
20 (1H, brs), 8.69 (1H, brs).
Example 391 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (3.26 g) and 7-25 ethyl bromoheptanoate (2.0 mL) as starting materials, 7– (4 - {[N– (5– benzyloxy – 1,2,3,4– tetrahydronaphthalene – 1-ylcarbonyl) –N– (6-isopropylpyridin-3-yl) amino] methyl} pyrazol-1-yl) ethyl heptanoate (4.25 g).
MS (ESI) m / z: 637 [MH] + Example 392 image 1
7– (4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-yl-carbonyl) -N- (6-isopropylpyridin-3-yl) amino] methyl} pyrazole-1–
5 il) ethyl heptanoate (2.0 g) was dissolved in ethanol (100 mL) and 1 mol / L of aqueous sodium hydroxide solution (6.60 mL) was added. The mixture was stirred at room temperature for 1 h. To the reaction mixture was added 1 mol / L hydrochloric acid (6.60 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give acid 7– (4 - {[N– (5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1–
10 -carbonyl) -N- (6-isopropylpyridin-3-yl) amino] methyl} pyrazol-1-yl) heptanoic acid (1.80 g). Through the reaction and treatment of this compound in the same manner as in Example 139, 7– (4– {[N– (5-hydroxy-1,2,3,4-tetrahydronaphthalen) acid hydrochloride was obtained 1-ylcarbonyl) -N- (6-isopropylpyridin-3-yl) amino] methyl} pyrazol-1-yl) heptanoic acid (0.84 g).
MS (ESI) m / z: 519 [MH] +
15 1H – NMR (DMSO – d6) δ: g: 1.13–1.51 (7H, m), 1.32 (6H, d, J = 6.8Hz), 1.64–1.73 (2H , m), 1.80–1.99 (3H, m), 2.18 (2H, t, J = 7.2Hz), 2.40–2.57 (2H, m), 3.36 (1H , brs), 3.55 (1H, brs), 4.02 (2H, t, J = 6.9Hz), 4.68-4.81 (2H, m), 6.48 (1H, d, J = 7.8Hz), 6.65 (1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7.8Hz), 7.28 (1H, brs), 7.56 (1H , brs), 7.80 (1H, brs) 8.08 (1H, brs), 8.74 (1H, brs).
Example 393 image2
By reaction and treatment in the same manner as in Example 256 using 7– (4 - {(N– (5– benzyloxy – 1,2,3,4-tetrahydronaphthalen – 1-ylcarbonyl) –N– ( Ethyl 6-isopropylpyridin-3-yl) amino] methyl) pyrazol-1-yl) heptanoate (2.2 g) as starting material, 5-benzyloxy-N - {[1– (7-hydroxyheptyl) pyrazole was obtained –4 – yl] methyl} –N– (6– isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.30 g). Through reaction and treatment
25 of this compound in the same manner as in Example 139, 5-hydroxy-N - {[1– (7-hydroxyheptyl) pyrazol-4-yl] methyl} -N- (6-isopropylpyridin-3) hydrochloride was obtained -Il) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.48 g).
MS (ESI) m / z: 505 [MH] + 1H-NMR (DMSO-d6) δ: 1.04-1.40 (15H, m), 1.64-1.73 (2H, m), 1 , 85–1.91 (3H, m), 2.50–2.52 (2H, m), 3.36 (2H, t, J = 6.4Hz), 3.36 – З, 40 (1H, m), 3.56 (1H, brs), 4.02 (2H, t, J = 6.4Hz), 4.79 (2H, brs), 6.48 (1H, d, J = 7.8Hz) , 6.66 (1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7.8Hz), 7.29 (1H, brs), 7.57 (1H, brs), 7 , 85 (1H, brs) 8.13 (1H, brs), 8.77 (1H, brs).
Example 394 image5
To a solution of ethylene glycol monobutyl ether (1 mL) and triethylamine (1.6 mL) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.88 mL) under ice cooling and the mixture was stirred at room temperature for one day. The reaction mixture was divided into water and chloroform, washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue obtained and 5-benzyloxy-N- (6-isopropylpyridin-3-yl) hydrochloride -
10 N - [(pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.0 g) was reacted and treated in the same manner as in Example 83 to give 5-benzyloxy-N - {[1– (2-butoxyethyl) pyrazol-4-yl] methyl} -N- (6- isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.58 g).
MS (ESI) m / z: 581 [MH] +
Example 395 image3
By means of the reaction and treatment. In the same manner as in Example 139 using 5-benzyloxy-N - {[1– (2-butoxyethyl) pyrazol-4-yl] methyl} -N- (6-isopropylpyridin- 3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.58 g) as a starting material, N - {[1– (2-butoxyethyl) pyrazole-4-yl] hydrochloride was obtained methyl} -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.25 g).
20 MS (ESI) m / z: 491 [MH] +
1H – NMR (DMSO – d6) δ: 0.82 (3H, t, J = 7.3Hz), 1.15–1.24 (2H, m), 1.29 (6H, d, J = 6, 6Hz), 1.36–1.43 (3H, m), 1.81–1.91 (3H, m), 2.41–2.51 (2H, m), 3.21–3.32 ( 1H, m), 3.32 (2H, t, J = 6.6Hz), 3.53 (1H, brs), 3.65 (2H, t, J = 5.4Hz), 4.18 (2H, t, J = 5.4Hz), 4.70-4.77 (2H, m), 6.47 (1H, d, J = 7.8Hz), 6.63 (1H, d, J = 7.8Hz ), 6.89 (1H, t, J = 7.8Hz), 7.27 (1H, brs), 7.55 (1H, brs), 7.68 (1H, brs), 7.96 (1H, brs), 8.63 (1H, brs).
Example 396 By reaction and treatment in the same manner as in Example 394 using diethylene glycol monomethyl ether (1 mL) and 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4 –Il) methyl] –1,2,3,4– tetrahydronaphthalen-1-carboxamide (1.0 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N- ({1– [2– (2-methoxyethoxy) ethyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g). image 1
MS (ESI) m / z: 583 [MH] +
Example 397 image 1
Through reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N– (6–
10 isopropylpyridin-3-yl) -N - ({1– [2– (2-methoxyethoxy) ethyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) As a starting material, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1– [2– (2-methoxyethoxy) ethyl] pyrazol-4-yl} methyl hydrochloride was obtained ) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.20 g).
MS (ESI) m / z: 493 [MH] +.
1H – NMR (DMSO – d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.40 (1H, m) 1.81–1.91 (3H, m) 2.51 (2H , m), 3.19 (3H, s), 3.28-3.32
15 (1H, m), 3.36-3.39 (2H, m), 3.44-3.47 (2H, m), 3.48-3.52 (1H, m), 3.70 ( 2H, t, J = 5.4Hz), 4.19 (2H, t, J = 5.4Hz), 4.71-4.78 (2H, m), 6.49 (1H, d, J = 7 , 8Hz), 6.64 (1H, d, J = 7.8Hz), 6.89 (1H, t, J = 7.8Hz), 7.28 (1H, brs), 7.58 (1H, brs ), 7.76 (1H, brs), 8.04 (1H, brs), 8.70 (1H, brs).
Example 398 By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalep-1-carboxylic acid (0.56 g) and (4-isopropylphenyl) [(6-morpholinopyridin-3-yl) methyl] amine (0.62 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - [(6-morpholinopyridin-3-yl) was obtained methyl] –1,2,3,4– tetrahydronaphthalen – 1-carboxamide (0.90 g). image 1
1H-NMR (CDCl3) δ: 1.21 (6H, d, J = 6.9Hz), 1.31-1.51 (1H, m), 1.73-2.09 (3H, m), 2 , 49–2.70 (2H, m), 2.90 (1H, sept, J = 6.9Hz), 3.49 (4H, t, J = 5.0Hz), 3.68–3.79 ( 1H, m), 3.83 (4H, t, J = 4.8Hz), 4.73 (1H, d, J = 14.1Hz), 4.86 (1H, d, J = 14.1Hz), 5.03 (2H, s), 6.55–6.65 (2H, m), 6.71 (1H, d, J = 8.1Hz), 6.97–7.10 (3H, m), 7.17–7.45 (7H, m), 7.69 (1H, dd, J = 2.1, 8.7Hz), 7.93 (1H, d, J = 2.1Hz).
Example 399 image4
By reaction and treatment in the same manner as in Example 105 using 5-benzyloxy-N- (4-isopropylphenyl) -N - [(6-morpholinopyridin-3-yl) methyl] –1,2,3 , 4-tetrahydronaphthalen-1-carboxamide (0.88 g) as starting material, 5-hydroxy-N- (4-isopropylphenyl) -N - [(6-morpholinopyridin-3-yl) methyl] -1 was obtained, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.51 g).
1 H NMR (CDCl3) δ: 1.21 (6H, d, J = 6.9Hz), 1.32-1.51 (1H, m), 1.73-2.08 (3H, m), 2.49-2.69 (2H, m), 2.88 (1H, sept, J = 6.9Hz), 3.36-3.58 (4H, m), 3.69-3.90 (5H , m), 4.78 (1H, d, J = 14.2Hz), 4.85 (1H, d, J = 14.2Hz), 6.34 (1H, d, J = 7.9Hz), 6 , 46 (1H, d, J = 7.7Hz), 6.62 (1H, d, J = 8.8Hz), 6.78 (1H, t, J = 7.8Hz), 7.02 (2H, d, J = 7.9Hz), 7.20 (2H, d, J = 8.3Hz), 7.59 (1H, dd, J = 2.1, 8.7Hz), 7.93 (1H, d , J = 2.0Hz), 7.90–8.38 (1H, brs).
Example 400 image2
By reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.56 g) and (4-isopropylphenyl) - { [6– (2-Methoxyethoxy) pyridin-3-yl] methyl} amine (0.60 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) -N - {[6– (2 -Methoxyethoxy) pyridin-3-yl-3-methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.52g).
1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.9Hz), 1.40-1.59 (1H, m), 1.77-2.10 (3H, m), 2.67-2.79 (2H, m), 2.90 (1H, sept, J = 6.9Hz), 3.45 (3H, s), 3.68-3.81 (3H, m), 4.39-4.50 (2H, m), 4.78 (1H, d, J = 14.1Hz), 4.89 (1H, d, J = 14.1Hz), 5.03 (2H, s ), 6.61 (1H, d, J = 7.8Hz), 6.72 (1H, d, J = 8.1Hz), 6.77 (1H, d, J = 8.7Hz), 6.98 (2H, d, J = 8.4Hz), 7.06 (1H, t, J = 8.1Hz), 7.17-7.44 (7H, m), 7.61 (1H, dd, J = 2.4, 8.4Hz), 7.86 (1H, d, J = 2.4Hz).
Example 401 By reaction and treatment in the same manner as in Example 17 using 5-benzyloxy-N- (4-isopropylphenyl) -N - {[6– (2-methoxyethoxy) pyridin-3-yl] methyl } –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.88 g) as a starting material, 5-hydroxy-N- (4-isopropylphenyl) -N - {[6– (2-methoxyethoxy) ) pyridin-3-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.35 g). Melting Point: 153 ° C image 1
Example 402 image 1
To a solution of N - ({1 - [(4-fluorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6– tetrahydronaphthalen-1-carboxamide
(0.55 g) in chloroform (10 mL) m-chloroperbenzoic acid (0.29 g) was added and the mixture was stirred at temperature
10 room for 2 h. The reaction mixture was divided into water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. and the residue was purified by silica gel column chromatography to give N- ({1 - [(4-fluorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropyl) hydrochloride –1 – oxidopyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.13 g).
MS (ESI) m / z: 515 [MH] +
1 H NMR (CDCl 3) δ: 1.31 (6H, d, J = 6.9Hz), 1.38-1.57 (1H, m), 1.78-2.05 (3H, m), 2.48-2.67 (2H, m), 3.57-3.80 (2H, m), 4.61 (1H, d, J = 14.7Hz), 4.82 (1H, d, J = 15.0Hz), 5.23 (2H, s), 6.33 (1H, d, J = 7.8Hz), 6.49 (1H, d, J = 7.8Hz), 6.80 (1H , t, J = 8.0Hz), 6.95–7.10 (3H, m), 7.13–7.29 (4H, m), 7.42 (2H, d, J = 2.1Hz) , 8.15–8.30 (1H, brs).
Example 403 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (4-isopropylphenyl) -N- [(pyrazol-4-yl) methyl] -1,2,3, 4-tetrahydronaphthalen-1-carboxamide (0.62 g) and 2– (chloromethyl) -4-methylpyridine hydrochloride (0.46 g) as starting materials, 5-benzyloxy-N- (4-isopropylphenyl) was obtained - N - ({1– [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.53 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.35-1.53 (1H, m), 1.75-2.08 (3H, m), 2 , 30 (3H, s), 2.60–2.80 (2H, m), 2.91 (1H, sept, J = 6.9Hz), 3.65–3.77 (1H, m), 4 , 65 (1H, d, J = 14.4Hz), 4.85 (1H, d, J = 14.4Hz), 5.02 (2H, s), 5.37 (2H, s), 6.58 (1H, d, J = 7.8Hz), 6.70 (1H, d, J = 8.1Hz), 6.76 (1H, s), 6.92–7.09 (4H, m 7.17 –7.51 (9H, m), 8.41 (1H, d, J = 4.8Hz).
Example 404 image 1
By reaction and treatment in the same manner as in Example 133 using 5-benzyloxy-N- (4-isopropylphenyl) -N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazole) 4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.53 g) as a starting material, 5-hydroxy-N- (4-isopropylphenyl) -N- ({1 - [(4-methylpyridine-2-yl) methyl] pyrazole-4–
10-yl} methyl – 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.50 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.35-2.08 (4H, m), 2.30 (3H, s), 2.49-2 , 68 (2H, m), 2.91 (1H, sept, J = 6.9Hz), 3.64-3.76 (1H, m), 4.68 (1H, d, J = 14.4Hz) , 4.83 (1H, d, J = 14.4Hz), 5.03–5.18 (1H, brs), 5.38 (2H, s), 6.45 (2H, t, J = 7, 8Hz), 6.73–6.86 (2H, m), 6.98–7.12 (3H, m), 7.18–7.32 (2H, m), 7.46 (1H, s) , 7.50 (1H, s), 8.42 (1H, d, J = 5.1Hz).
15 Example 405 image 1
By reaction and treatment in the same manner as in Example 402 using 5-hydroxy-N- (4-isopropylphenyl) -N- ({1– [4-methylpyridin-2-yl] methyl} pyrazole-4 –Il) methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.50 g) as starting material, 5-hydroxy-N- (4-isopropylphenyl) -N - ({1– [(4-methyl-1-oxidopyridin-2-yl) methyl] pyrazole–
20 4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.16 g).
1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.9Hz), 1.35-1.52 (1H, m), 1.76-2.07 (3H, m), 2 , 27 (3H, s), 2.52-2.67 (2H, m), 2.92 (1H, sept, J = 6.9Hz), 3.66-3.80 (1H, m), 4 , 69 (1H, d, J = 14.5Hz), 4.88 (1H, d, J = 14.5Hz), 5.56 (2H, s), 6.43 (2H, d, J = 7, 9Hz), 6.51 (1H, d, J = 1.6Hz), 6.78 (1H, t, J = 7.8Hz), 7.00–7.17 (3H, m), 7.20– 7.31 (2H, m), 7.54 (1H, s), 7.58 (1H, s), 8.18 (1H, d, J = 6.6Hz).
Example 406 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl hydrochloride ] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 5-chloromethyl-2-ethoxypyridine (0.51 g) as starting materials, 5-benzyloxy-N - ({ 1 - [(6 – ethoxypyridin – 3– image 1
5-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.67 g).
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.38 (3H, t, J = 7.1Hz), 1.39-1.57 (1H, m) , 1.78-2.08 (3H, m), 2.60-2.80 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.57-3.67 ( 1H, m), 4.35 (2H, q, J = 7.1Hz), 4.59 (1H, d, J = 14.4Hz), 4.83 (1H, d, J = 14.4Hz) 5 , 03 (2H, s), 5.17 (2H, s), 6.49 (1H, d, J = 7.8Hz), 6.65–6.77 (2H, m), 7.01 (1H , t, J = 8.0Hz), 7.17 (1H, d, J = 8.4Hz), 7.22–7.48 (9H, m), 8.04 (1H, d, J = 2, 4Hz), 8.36 (1H, d, J = 2.4Hz).
10 Example 407 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - ({1 - [(6- ethoxypyridin-3-yl) methyl] pyrazol-4-yl} methyl) -N - (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronatalen-1-carboxamide (0.66 g) as starting material, N - ({1 - [(6-ethoxypyridine) dihydrochloride was obtained –3 – il) methyl] pyrazol – 4-yl} methyl) –5 – hydroxy–
15 N– (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.54 g).
MS (ESI) m / z: 526 [MH] +
Example 408 By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] hydrochloride] –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.65 g) and 6– chloromethyl-2-morpholinopyridine (0.29 g) as starting materials, 5-benzyloxy-N– (6– isopropylpyridin-3-yl) -N - ({1 - [(6-morpholinopyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0, 44 g). image 1
1H-NMR (CDCl3) δ: 1.30 (6H, d, J = 6.9Hz), 1.39-1.57 (1H, m), 1.77-2.08 (3H, m), 2 , 60–2.81 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.49 (4H, t, J = 4.8Hz), 3.58–3.69 ( 1H, m), 3.80 (4H, t, J = 5.0Hz), 4.66 (1H, d, J = 14.4Hz), 4.85 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.23 (2H, s), 6.28 (1H, d, J = 7.2Hz), 6.46-6.58 (2H, m), 6.71 ( 1H, d, J = 8.1Hz), 7.00 (1H, t, J = 7.8Hz), 7.18 (1H, d, J = 8.4Hz), 7.25–7.51 (9H , m), 8.39 (1H, d, J = 2.4Hz).
Example 409 image4
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6– isopropylpyridin-3-yl) -N - ((1 - [(6-morpholinopyridin-2-yl) methyl] pyrazol-4-yl) methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.44 g) as a starting material, 5-hydroxy-N- (6-isopropylpyridine dihydrochloride) was obtained 3-yl) -N- ({1 - [(6-morpholinopyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.30 g ).
15 MS (ESI) m / z: 567 [MH] +
1H-NMR (DMSO-d6) δ: 1.30 (6H, d, J = 6.9Hz) 1.34-1.52 (1H, m), 1.68-1.93 (3H, m), 2.34-2.58 (2H, m), 3.20-3.70 (10H, m), 5.30 (2H, s), 6.13 (1H, d, J = 7.2Hz), 6.47 (1H, d, J = 7.8Hz), 6.64 (1H, d, J = 7.8Hz), 6.78-6.90 (2H, m), 7.27-7.44 (1H, m), 7.61 (1H, t, J = 7.8Hz), 7.67-7.83 (2H, m), 7.97-8.17 (1H, m), 8.61 –8.80 (1H, m).
Example 410 image2
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and 5-chloromethyl-2– (2-methoxyethoxy) pyridine (0.61 g) as starting materials, 5-benzyloxy-N- was obtained (6– isopropylpyridin-3-yl) –N - [(1 - {[6– (2-methoxyethoxy) pyridin-3-yl] methyl} pyrazol-4-yl) methyl] –1,2,3,4– tetrahydronaphthalen – 1–
Carboxamide (0.77 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.40-1.57 (1H, m), 1.75-2.05 (3H, m), 2 , 60–2.80 (2H, m), 3.08 (1H, sept, J = 6.9Hz), 3.39–3.49 (3H, m), 3.55–3.65 (1H, m), 3.68–3.78 (2H, m), 4.42–4.51 (2H, m), 4.59 (1H, d, J = 14.7Hz), 4.83 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.17 (2H, s), 6.49 (1H, d, J = 7.8Hz), 6.72 (1H, d, J = 8.1Hz), 6.80 (1H, t, J = 9.3Hz), 7.01 (1H, t, J = 7.8Hz), 7.17 (1H, d, J = 8.4Hz ), 7.24–7.48 (9H, m), 8.03 (1H, d, J = 2.4Hz), 8.37 (1H, d, J =
30 2.4Hz).
Example 411 By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - [(1 - {[6– (2-methoxyethoxy) ) pyridin-3-yl] methyl} pyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.76 g) as starting material, 5-hydroxy dihydrochloride was obtained N– (6 – isopropylpyridin – 3 – yl) –N– image 1
5 [(1– [6– (2-methoxyethoxy) pyridin-3-yl] methyl} pyrazol-4-yl] methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.55 g).
MS (ESI) m / z: 556 [MH] +
1H-NMR (DMSO-d6) δ: 1.31 (6H, d, J = 6.9Hz), 1.34-1.53 (1H, m), 1.68-1.93 (3H, m) 2.35–2.60 (2H, m), 3.29–3.67 (7H, m), 4.29–4.39 (2H, m), 4.63–4.90 (2H, m ), 5.22 (2H, s), 6.45 (1H, d, J = 7.6Hz), 6.64 (1H, d, J = 7.8Hz), 6.77-6.90 (2H , m), 7.22–7.38 (1H, m), 7.55 (1H, dd, J = 2.4, 8.5Hz), 7.60–7.89 (2H, m), 8 , 00–8.16 (2H, m), 8.67–8.82 (1H,
10 m)
Example 412 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1 hydrochloride , 2,3,4 – tetгahidronaftalen – 1 – carboxamide (0.78 g) and 6–
15 Chloromethyl-2-methoxypyridine (0.47 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) - N - ({1 - [(6-methoxypyridin-2-yl) ) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.44 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.40-1.60 (1H, m), 1.77-2.08 (3H, m), 2 , 61–2.82 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.60–3.70 (1H, m), 3.88 (3H, s), 4 , 66 (1H, d, J = 14.7Hz), 4.86 (1H, d, J = 14.4Hz), 5.03 (2H, s), 5.28 (2H, s), 6.53 (2H, t, J = 6.6Hz), 6.64 (1H, d, J = 8.4Hz), 6.71 (1H, d, J = 8.1Hz), 7.00 (1H, t, J = 7.8Hz), 7.18 (1H, d, J =
20 8.4Hz), 7.25–7.56 (9H, m), 8.39 (1H, d, J = 2.1Hz).
Example 413 By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1 - [(6-methoxypyridin-2– il) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.43 g) as starting material, 5-hydroxy-N dihydrochloride was obtained (6– isopropylpyridin – 3 – yl) –N - ({1 - [(6– image 1
5-methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.34g).
MS (ESI) m / z :. 512 [MH] +
1H – NMR (DMSO – d6) δ: 1.27 (6H, d, J = 6.9Hz), 1.31–1.53 (1H, m), 1.69–1.99 (3H, m) , 2.34-2.60 (2H, m), 3.13-3.32 (1H, m), 3.43-3.62 (1H, m), 3.80 (3H, s), 4 , 65–4.90 (2H, m), 5.29 (2H, s), 6.39 (1H, d, J = 7.2Hz), 6.46 (1H, d, J = 7.8Hz) , 6.62 (1H, d, J = 7.8Hz), 6.73 (1H, d, J = 8.4Hz), 6.86 (1H, t, J = 7.8Hz), 7.25– 7.44 (1H, m), 7.55–8.05 (4H, m),
10 8.49-8.73 (1H, m).
Example 414 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl]) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.78 g) and
As isopropyl iodide (0.30 mL) as starting materials, 5-benzyloxy-N - [(1-isopropylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1 was obtained, 2,3,4-tetrahydronaphthalen-1-carboxamide (0.68 g).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.9Hz), 1.39-1.58 (7H, m), 1.78-2.07 (3H, m), 2 , 62–2.83 (2H, m), 3.09 (1H, sept, J = 6.9Hz), 3.58–3.68 (1H, m), 4.47 (1H, sept, J = 6.6Hz), 4.58 (1H, d, J = 14.7Hz), 4.90 (1H, d, J = 14.4Hz), 5.03 (2H, s), 6.52 (1H, d, J = 7.8Hz), 6.72 (1H, d, J = 8.1Hz), 7.02 (1H, t, J = 7.8Hz), 7.19 (1H, d, J = 8 , 1Hz), 7.25–7.47
20 (8H, m), 8.38 (1H, d, J = 2.4Hz).
Example 415 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - [(1– isopropylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1 , 2,3,4-tetrahydronaphthalen-1-carboxamide (0.67 g) as starting material, 5-hydroxy-N - [(1-isopropylpyrazol-4-yl) methyl] -N- (6– isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.52 g).
MS (ESI) m / z: 433 [MH] +
1H-NMR (DM50-d6) δ: 1.22-1.60 (13H, m), 1.72-1.98 (3H, m), 2.36-2.64 (2H, m), 3 , 21–3.63 (2H, m), 4.30–5.07 (3H, m), 6.46 (1H, d, J = 7.6Hz), 6.63 (1H, d, J = 7.8Hz), 6.88 (1H, t, J = 7.8Hz), 7.20–7.37 (1H, m), 7.47-7.63 (1H, m), 7.68– 7.87 (1H, m), 7.97-8.13 (1H, m), 8.59-8.80 (1H, m).
Example 416 image 1
By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl) methyl ] (6-isopropylpyridin-3-yl) amine (0.54 g) as starting materials, N - [(4-dimethylaminophenyl) methyl] -N- (6-isopropylpyridin-3-yl) –1,2,3,4–
10 tetrahydronaphthalen-1-carboxamide (0.13 g).
MS (ESI) m / z: 458 [MH] +
1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.9Hz), 1.40-1.65 (1H, m), 1.80-2.10 (3H, m), 2 , 50–2.85 (2H, m), 2.93 (6H, s), 3.00–3.15 (1H, m), 3.55–3.65 (1H, m), 3.69 (3H, s), 4.60 (1H, d, J = 13.8Hz), 5.07 (1H, d, J = 13.8Hz), 6.48 (1H, d, J = 2.4Hz) , 6.55–6.75 (3H, m), 6.90–7.30 (5H, m), 8.29 (1H, d, J = 2.4Hz).
15 Example 417 image 1
By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - [(pyrazol-4-yl) methyl] –1.2 , 3,4-tetrahydronaphthalen-1-carboxamide (0.96 g) and 2– (chloromethyl) thiophene (0.25 g) as starting material, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) ) –N - {[1– (2–
Thienylmethyl) pyrazol –– 4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.95 g). Through the reaction and treatment of this compound in the same manner as in Example 133, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (2-thienylmethyl) was obtained pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.41 g). Melting point: 125–129 ° C
Example 418 By reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1 , 2,3,4-tetrahydronaphthalen-1-carboxamide (1.44 g) and 2-chloro-5- (chloromethyl) thiophene (0.79 g) as starting materials, 5-benzyloxy-N - ({ 1 - [(5-chlorothiophene-2-yl) methyl] pyrazol-4-yl} methyl) -N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1 , 37 g). Through the reaction and treatment of this compound in the same manner as in Example 133, N - ({1 - [(5-chlorothiophene-2-yl) methyl] pyrazol-4-yl} methyl) - 5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.37 g). Melting point: 98–101 ° C image 1
Example 419 image4
By means of the reaction and treatment of diethylene glycol monobutyl ether (1.0 mL) and 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - [(pyrazole-4-yl) methyl] –1,2, 3,4-tetrahydronaphthalen-1-carboxamide (0.96 g) in the same manner as in Example 394, 5-benzyloxy-N - ({1– [2– (2-butoxyethoxy) ethyl] pyrazole-4) was obtained -Yl} methyl) -N- (6-isopropylpyridin-3-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.94 g).
15 MS (ESI) m / z: 625 [MH] +
Example 420 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - ({1– [2– (2-butoxyethoxy)) ethyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.94 g) as a starting material, N - ({1– [2– (2-hydrochloride) –Butoxyethoxy) ethyl] pyrazol-4-yl} methyl) -5-hydroxy-N– image 1
5 (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.48 g).
MS (ESI) m / z 535 [MH] +
1H – NMR (DMSO – d6) δ: 0.85 (ЗH, t, J = 7.2Hz), 1.21–1.48 (11H, m), 1.80–1.85 (3H, m) , 2.51 (2H, brs), 3.26 (2H, t, J = 6.5Hz), 3.42-3.58 (6H, m), 3.71 (2H, t, J = 5, 2Hz), 4.20 (2H, t, J = 5.2Hz), 4.73-4.82 (2H, m), 6.50 (1H, d, J = 7.1Hz), 6.67 ( 1H, d, J = 7.7Hz), 6.90 (1H, t, J = 7.7Hz), 7.32 (1H, brs), 7.61 (1H, brs), 7.92 (1H, brs), 8.21 (1H, brs),
10 8.81 (1H, brs).
Example 421 image 1
By means of the reaction and treatment of diethylene glycol monoethyl ether (1.5 mL) and 5-benzyloxy-N- (6-isopropylpyridi-p-З-il) –N - [(pyrazole-4-yl) methyl] –1,2, 3,4-tetrahydronaphthalen-1-carboxamide (0.72 g) in the same manner as in Example 394, 5-benzyloxy-N - ({1– [2– (2-ethoxyethoxy) ethyl] pyrazole) was obtained 4-yl} methyl) -N- (6-isopropylpyridin-3-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.89 g).
MS (ESI) m / z: 597 [MH] +
Example 422 By reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - ({1– [2– (2-ethoxyethoxy) ethyl] pyrazol-4-yl} methyl) -N - (6-Isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.00 g) as a starting material, 5-hydroxy-N - hydrochloride ({1– [ 2– (2-ethoxyethoxy) ethyl] pyrazol-4-yl} methyl) –N– (6– image 1
5 isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.15 g).
MS (ESI) m / z: 507 [MH] +
1H – NMR (DMSO – d6) δ: 1.06 (3H, t, J = 7.0Hz), 1.32 (1H, d, J = 6.8Hz), 1.43–1.48 (1H, m), 1.81-1.91 (3H, m), 2.50 (2H, brs), 3.34-3.55 (8H, m), 3.70 (2H, t, J = 5, 3Hz), 4.19 (2H, t, J = 5.3Hz), 4.71-4.79 (2H, m), 6.48 (1H, d, J = 7.7Hz), 6.65 ( 1H, d, J = 7.7Hz), 6.90 (1H, t, J = 7.7Hz), 7.29 (1H, brs), 7.59 (1H, brs), 7.79 (1H, brs), 8.08 (1H, brs),
10 8.72 (1H, brs).
Example 423 image 1
By reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxylic acid (0.64 g) and (4-isopropylphenyl) - { [4– (2,2,2-Trifluoroethoxy) phenyl] methyl} amine (1.0 g) as 15 starting materials, N- (4-isopropylphenyl) -7-methoxy-N - {[4– ( 2,2,2-trifluoroethoxy) phenyl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.58 g). Melting point: 125-127 ° C.
Example 424 image 1
Through reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N– (6–
20 methoxypyridin-3-yl) -N - [(pyrazole-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.94g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.71 g) as starting materials, 5-benzyloxy-N- (6-methoxypyridin-3-yl) -N- ({1 - [(4-methylpyridin-2-yl) methyl] pyrazole-4 was obtained -Yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.90 g).
1H-NMR (CDCl3) δ: 1.39-1.57 (1H, m), 1.76-2.12 (3H, m), 2.31 (3H, s), 2.61-2.82 (2H, m), 3.62-3.82 (1H, m), 3.93 (3H, s), 4.65 (1H, d, J = 14.4Hz), 4.84 (1H, d , J = 14.4Hz), 5.03 (2H, s), 5.36 (2H, s), 6.55 (1H, d, J = 7.8Hz), 6.68– 6.83 (3H , m), 6.95–7.07 (8H, m), 7.98 (1H, d, J = 2.4Hz), 8.41 (1H, d, J = 5.1Hz).
Example 425 image5
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6- methoxypyridin-3-yl) -N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1, –2,3,4-tetrahydronaphthalen-1-carboxamide (0.90 g) as starting material, 5-hydroxy-N- dihydrochloride (6-methoxypyridine) –3 – il) –N - ({1 - [(4– methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen – 1-carboxamide (0.67 g).
10 MS (ESI) m / z: 484 [MH] +
1H-NMR (DMSO-d6) δ: 1.22-1.51 (1H, m), 1.80-2.00 (3H, m), 2.35-2.62 (5H, m), 3 , 47–3.57 (1H, m), 3.84 (3H, s), 4.67 (1H, d, J = 14.6Hz), 4.76 (1H, d, J = 14.7Hz) , 5.71 (2H, s), 6.45 (1H, d, J = 7.7Hz), 6.63 (1H, d, J = 7.8Hz), 6.80–6.92 (2H, m), 7.24 (1H, s), 7.38 (1H, s, 7.70 (1H, dd, J = 2.6, 8.7Hz), 7.77 (1H, d, J = 5 , 8Hz), 7.85 (1H, s), 8.07 (1H, d, J = 2.4Hz), 8.74 (1H, d, J = 5.9Hz).
15 Example 426 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6– methoxypyridin-3-yl) -N - [(pyrazol-4-yl) methyl] –1.2 , 3,4-tetrahydronaphthalen-1-carboxamide (0.94 g) and 2-chloromethyl-5-methylpyridine hydrochloride (0.71 g) as starting materials, 5-benzyloxy-N- (6-methoxypyridine) was obtained 3 – il) –N–
20 ({1 - [(5-methylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.94 g).
1H-NMR (CDCl3) δ: 1.39-1.57 (1H, m), 1.76-2.12 (3H, m), 2.31 (3H, s), 2.61-2.82 (2H, m), 3.62 – З, 82 (1H, m), 3.93 (3H, s), 4.65 (1H, d, J = 14.4Hz), 4.84 (1H, d , J = 14.4Hz), 5.03 (2H, s), 5.35 (2H, s), 6.54 (1H, d, J = 7.7Hz), 6.64– 6.77 (2H , m), 6.88 (1H, d, J = 8.0Hz), 7.01 (1H, t, J = 7.9Hz), 7.23–7.52 (9H, m), 7.97 (1H, d, J = 2.5Hz), 8.38 (1H, d, J = 1.7Hz).
Example 427 By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N- (6- methoxypyridin-3-yl) -N - ({1 - [(5-methylpyridin-2 -Tetrahydronaphthalen-1-carboxamide (0.94 g) as a starting material, 5-hydroxy-N- (6-methoxypyridin-3-yl) dihydrochloride was obtained - N - ({1 - [(5-methylpyridin-2 –Il) methyl] pyrazol – 4-yl} methyl) - image 1
5 1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.73 g).
MS (ESI) m / z: 484 [MH] +
1H-NMR (DMSO-d6) δ: 1.30-1.52 (1H, m), 1.68-1.98 (3H, m), 2.33-2.57 (5H, m), 3 , 45–3.57 (1H, m), 3.85 (3H, s), 4.66 (1H, d, J = 15.0Hz), 4.74 (1H, d, J = 14.7Hz) , 5.61 (2H, s), 6.43 (1H, d, J = 7.5Hz), 6.62 (1H, d, J = 7.8Hz), 6.79-6.93 (2H, m), 7.22 (1H, d, J = 8.1Hz), 7.34 (1H, s), 7.65 (1H, dd, J = 2.7, 8.7Hz), 7.79 ( 1H, s), 8.02–8.18 (2H,
10 m), 8.68 (1H, s).
Example 428 image 1
By reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N- (6– methoxypyridin-3-yl) -N - [(pyrazol-4-yl) methyl] –1.2 , 3,4-tetrahydronaphthalen-1-carboxamide (0.94 g) and 6-chloromethyl-2–
15 (dimethylamino) pyridine (0.68 g) as starting materials, 5-benzyloxy-N - ({1 - [(6- (dimethylamino) pyridin-2-yl) methyl] pyrazol-4-yl} methyl was obtained ) –N– (6-methoxypyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.31 g).
1H-NMR (CDCl3) δ: 1.38-1.67 (1H, m), 1.73-2.07 (3H, m), 2.61-2.82 (2H, m), 3.04 (6H, s), 3.59-3.72 (1H, m), 3.93 (3H, s), 4.64 (1H, d, J = 14.4Hz), 4.83 (1H, d , J = 14.4Hz), 5.03 (2H, s) 5.21 (2H, s), 6.18 (1H, d, J = 7.2Hz), 6.40 (1H, d, J = 8.4Hz), 6.54 (1H, d, J = 7.5Hz), 6.62-6.76 (2H, m), 7.01 (1H, t, J = 8.0Hz), 7, 21–7.52 (9H, m), 7.99 (1H, d, J =
20 2.4Hz).
Example 429 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - ({1 - [(6- (dimethylamino) pyridinium-2-yl) methyl] pyrazol-4-yl} methyl –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide (0.31 g) as material
Starting, N - ({1 - [(6 - (dimethylamino) pyridin-2-yl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6– methoxypyridin-3–) dihydrochloride was obtained il) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.20 g).
MS (ESI) m / z: 5.13 [MH] +
1H-NMR (DMSO-d6) δ: 1.30-1.50 (1H, m), 1.68-2.00 (3H, m), 2.34-2.58 (2H, m), 3 , 17 (6H, s), 3.30–3.78 (1H, m), 3.84 (3H, s), 4.67 (1H, d, J = 14.8Hz), 4.74 (1H , d, J = 14.7Hz), 5.45 (2H, s), 6.06 (1H, d, J = 7.1Hz), 6.43 (1H, d, J = 7.6Hz), 6 , 61 (1H, d, J = 7.8Hz), 6.80-6.97 (3H, m), 7.35 (1H, s), 7.60-7.81 (3H, m), 8 , 06 (1H, d, J = 2.4Hz).
Example 430 image 1
By reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N– (5–
10 methylpyridin-2-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (1.43 g) and 5-chloromethyl-2-ethyl-4-methylthiazole (0.68 g) as starting materials, 5-benzyloxy-N - [(2-ethyl-4-methylthiazol-5-yl) methyl] -N- (5-methylpyridin-2-yl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide was obtained (0.92 g).
1H-NMR (CDCl3) δ: 1.33 (3H, t, J = 7.5Hz), 1.40-1.57 (1H, m), 1.75-2.12 (6H, m), 2 , 36 (3H, s), 2.66-2.80 (2H, m), 2.92 (2H, q, J = 7.6Hz), 3.68-3.81 (1H, m), 5 , 03 (2H, s), 5.10 (1H, d, J = 15.0Hz), 5.17 (1H, d, J = 15.0Hz), 6.72 (1H,
15 d, J = 3.3Hz), 6.75 (1H, d, J = 2.7Hz), 6.88-7.00 (1H, m), 7.07 (1H, t, J = 8, 0Hz), 7.25–7.52 (6H, m), 8.40 (1H, d, J = 2.1Hz).
Example 431 image 1
By reaction and treatment in the same manner as in Example 101 using 5-benzyloxy-N - [(2–
Ethyl-4-methylthiazol-5-yl) methyl) -N- (5-methylpyridin-2-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.92g) as starting material, N - [(2-ethyl-4-methylthiazol-5-yl) methyl] -5-hydroxy-N- (5-methylpyridin-2-yl) -1,2,3,4-tetrahydronaphthalen-1 hydrochloride was obtained -Carboxamide (0.57 g).
MS (ESI) m / z: 422 [MH] +
1H-NMR (DMSO-d6) δ: 1.30 (3H, t, J = 7.5Hz), 1.35-1.50 (1H, m) 1.73-1.99 (3H, m), 2.16 (3H, s), 2.34 (3H, s),
25 2.42-2.58 (2H, m), 3.10 (2H, q, J = 7.5Hz), 3.62-2.77 (1H, m), 5.03 (2H, s) , 6.44 (1H, d, J = 7.6Hz), 6.43 (1H, d, J = 7.7Hz), 6.85 (1H, t, J = 7.8Hz), 7.40 ( 1H, d, J = 8.0Hz), 7.80 (1H, dd, J = 2.1, 8.1Hz), 8.42 (1H, d, J = 2.3Hz).
Example 432 By reaction and treatment in the same manner as in Example 142 using 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide ( 0.53 g) and 2– (2-butoxyethoxy) –5– (hydroxymethyl) pyridine (0.30 g) as starting materials, 5-benzyloxy-N - {[6– (2-butoxyethoxy) pyridine– was obtained 3-yl) methyl} -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.40 g). image 1
MS (ESI) m / z: 608 [MH] +
Example 433 image 1
By means of the reaction and treatment in the same manner as in Example 139 using 5-benzyloxy-N - {[6– (2-butoxyethoxy) pyridin-3-yl] methyl} -N- (6-isopropylpyridin-3 –Il) –1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.40 g) as a starting material, N - {[6– (2-butoxyiethoxy) pyridin-3-yl] methyl was obtained } –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen-1-carboxamide (0.10 g).
MS (ESI) m / z: 518 [MH] +
1H – NMR (CDCl3) δ: 0.92 (3H, t, J = 7.2Hz), 1.30 (6H, d, J = 6.9Hz), 1.20–2.15 (8H, m) , 2.50–2.70 (2H, m), 3.00–3.20 (1H, m), 3.54 (2H, t, J = 6.6Hz), 3.60–3.70 ( 1H, m), 3.75–3.85 (2H, m), 4.40-4.50 (2H, m), 4.83 (1H, d, J = 14.1Hz), 15 4.90 (1H, d, J = 14.1Hz), 6.35-6.50 (2H, m, 6.75-6.90 (2H, m), 7.19 (1H, d, J = 8.4Hz ), 7.25–7.35 (1H, m), 7.61 (1H, dd, J = 2.4, 8.4Hz), 7.85 (1H, d, J = 2.4Hz), 8 , 34 (1H, d, J = 2.4Hz).
Example 434 image 1
Through reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N– (6–
20 isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide (2.05 g) and 4-chloromethyl-1- (2,2,2-trifluoroethyl) pyrazole (1.02 g) as starting materials, 5-benzyloxy-N- (6-isopropylpyridin-3-yl) -N - {[1– (2,2,2- trifluoroethyl) pyrazol-4-yl] methyl} -1.2 , 3,4-tetrahydronaphthalen-1-carboxamide (1.70, g).
MS (ESI) m / z: 563 [MH] +
1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 7.2Hz), 1.40-1.65 (1H, m), 1.75-2.10 (3H, m), 2 , 60–2.85 (2H, m), 3.00–3.20 (1H,
25 m), 3.60–3.70 (1H, m), 4.55–4.75 (3H, m), 4.87 (1H, d, J = 14.4Hz), 5.03 (2H , s), 6.51 (1H, d, J = 7.8Hz), 6.73 (1H, d, J = 7.8Hz), 7.04 (1H, t, J = 7.8Hz), 7 , 15–7.60 (9H, m), 8.39 (1H, d, J = 2.4Hz).
Example 435 By reaction and treatment in the same manner as in Example 17 using 5-benzyloxy-N- (6- isopropylpyridin-3-yl) -N - {[1– (2,2,2-trifluoroethyl) ) pyrazol-4-yl] methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.81 g) as a starting material, 5-hydroxy-N- (6-isopropylpyridin-3-yl) was obtained ) –N - {[1– (2,2,2-trifluoroethyl) pyrazol-4-yl) methyl} -1,2,3,4-tetrahydronaphthalen-1-carboxamide (0.23 g). Melting point: 127.7 ° C image 1
MS (ESI) m / z: 473 [MH] + 1H-NMR (CDCl3) δ: 1.29 (6H, d, J = 6.3Hz), 1.35-1.55 (1H, m), 1 , 75–2.10 (3H, m), 2.50–2.70 (2H, m), 3.00–3.20 (1H,
m), 3.60–3.70 (1H, m), 4.55–4.75 (3H, m), 4.85 (1H, d, J = 14.5Hz), 6.35–6, 45 (2H, m), 6.82 (1H, t, J = 7.8Hz), 6.91 (1H, brs), 7.20–7.55 (4H, m), 8.40 (1H, d, J = 2.3Hz). Formulation Example 1 The compound of the present invention (5.0 mg) is completely kneaded with lactose (9.8 mg), corn starch (45
mg) and hydroxypropylcellulose (3 mg) in a kneader. The kneaded product is passed through a 200 mesh screen, dried at 50 ° C and passed through a 24 mesh screen. Talc (3 mg) and magnesium stearate (1 mg) are mixed and, using a mallet of 9 mm in diameter, 200 mg tablets are obtained. These tablets may be coated with sugar or coated with film, if necessary.
Pharmaceutical preparation example 1 Tablets containing the following ingredients were produced by a conventional method. Ingredients per compound tablet of Example 4 10 mg lactose 125 mg corn starch 75 mg talc 4 mg magnesium stearate 1 mg total weight 215 mg Example of pharmaceutical preparation 2 Capsules containing the following ingredients were produced by a conventional method. Ingredients per compound tablet of Example 4 10 mg lactose 165 mg corn starch 20 mg talc 5 mg total weight of one capsule 200 mg Example of pharmaceutical preparation 3 An ointment containing the following ingredients was produced by a conventional method. Ingredients compound dose of Example 4 0.2 g white petrolatum 97.8 g liquid paraffin 2 g total weight 100 g Pharmaceutical preparation example 4 An injection containing the following ingredients was produced by a conventional method. Ingredients dose
compound of Example 4 0.2 g
0.9 g sodium chloride
distilled water for injection appropriate amount
total weight 100 g
5 Example of pharmaceutical preparation 5
An ophthalmic drop containing the following ingredients was produced by a conventional method.
Ingredients
compound of Example 4 0.1 g
0.3 g sodium chloride
10 sterile purified water appropriate amount
total weight 100 g
The superior pharmacological effect of the compound of the formula (1) is verified by means of a series of the following tests.
Test example 1: C5a receptor ligation test
The ligation inhibitory action of the C5a receptor and the test compound was evaluated by a ligation assay of the receptor comprising reacting a human cell line U-937 (human histiocytic lymphoma line), which expresses the C5a receptor with ( 125I) –C5a human (Amersham Pharmacia Biotech) on a MultiScreen (MILLIPORE). The U-937 cells were first stimulated with 1 mM of cyclic dibutyryl AMP (dcAMP, SIGMA) for 2 days to express the C5a receptor (dcAMP-U937 cell), and suspended in a buffer of
20 ligation [50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% bovine albumin (BSA, SIGMA), 0.02% NaN3 (pH 7.2)], and stored at - 80 ° C The ligation assay was started by adding 1 x 105 cells / 50 µl of dcAMP-U937 cell suspension dissolved immediately before using, 25 µL of a test compound (obtained by dissolving the test compound in N, N– dimethylformamide to a final concentration of 10 mmol / L, and solution with ligation buffer), and 25 µL of (125I) -C5a solution (final concentration 200 pM),
25 to each cavity of the MultiScreen. For the calculation of non-specific ligation, cavities were prepared containing an unlabeled C5a (final concentration 20 nM) or ligation buffer instead of the test compound. After incubation at 4 ° C for two hours, the suction filtration was repeated four times and the addition of 300 µL of ligation buffer to remove the non-binding portion. After drying the MultiScreen, the radioactivity in the filter was measured by a gamma counter.
The coefficient (% inhibition) of the inhibition of ligation of C5a by the test compound was calculated for which the following formula was used based on the count value obtained without adding the test compound as Total, and the value of count obtained with the addition of unlabeled C5a as No, and the count value obtained with the addition of the test compound as Test.
% inhibition = 100 - [(Test – No) / (Total – No)] x 100
In addition, the concentration (IC50 value) of the test compound was calculated, at which the ligation of human [125I] -C5a is inhibited by 50%, by the method of two interpolations. In this evaluation system, the C50 value of the compound of Example 4 was 104 nmol / L.
Test example 2: action on the increase in intracellular Ca2 + concentration of neutrophils stimulated by C5a
40 A fraction of human peripheral venous blood neutrophils was taken separately by Lympholyte-poly (Cedarlane), and suspended in Hank's balanced salt solution (HBSS, Hansk's Balanced Salt Solution, GIBCO BRL) supplemented with 1% of FBS (fetal bovine serum, fetal bovine serum). Next, Fura 2-AM (5 μM final concentration, DOJINDO) was added to the neutrophil fraction (5 x 106 cells / mL), and the mixture was incubated at 37 ° C for 40 min. The cells were washed by centrifugation and suspended to a concentration of 1 x 106
45 cells / mL. The concentration of intracellular Ca2 + was measured by a spectrophotofluorimeter (CAF-110, JASCO Corporation), and calculated from the ratio (Ex340 value / Ex380 value) of fluorescent intensities at 500 nm after excitation at 340 nm and 380 nm , the former being the Ex340 value, and the latter being the Ex380 value. To be specific, a suspension of neutrophils (450 µL, 1 x 10 6 cells / mL) was dispensed in a cuvette having a stir bar 5 minutes before the measurement, and the suspension was heated to 37 ° C. Then it
50 placed the cuvette on the CAF – 110 set at 37 ° C, and the measurement was started. Immediately afterwards, 50 µL of a solution of the test compound was added. Approximately 45 seconds later, 5 µL of recombinant human C5a (final concentration 100 pmol / L) was added, and the measurement was continued for approximately one minute. Then Triton X-100 (0.2% final concentration) was added and the cells dissolved, and the sb2 value, which was then the Ex340 value, and the Rmax value, which was then the Ex340 / Ex380 value, were measured. Next, EGTA (final concentration 3 mmol / L) was added, and the sf2 value was measured, which
5 then was the Ex340 value, and the Rmin value, which was then the Ex340 / Ex380 value. From these measurement results, the intracellular Ca2 + concentration was calculated using the following formula:
C2 + concentration (Ex340 value / Ex380 value) –value x 224 x (sf2 / sb2) Rmin)
intracellular (nmol / L) (Rmax value - (Ex340 value / value
= Ex380)
In the formula, the Ex340 / Ex380 value is the value at each continuous point throughout the entire measurement period.
The coefficient (% inhibition) of the inhibition of the increase in intracellular Ca2 + concentration of neutrophils stimulated by C5a by the test compound was calculated by the following formula, in which the
10 peak value of the increase in the concentration of intracellular Ca2 + derived by C5a if addition of the test compound is Max, the peak value of the intracellular Ca2 + concentration without addition of the test compound and without stimulation with C5a is Min, and the peak value of the increase in the concentration of intracellular Ca2 + derived by C5a with the addition of the test compound is Assay.
% inhibition = 100 - [(Test – Min) / (Max – Min)] x 100
On the other hand, by means of the two interpolation method, the concentration (IC50 value) of the test compound at which the increase in intracellular Ca2 + concentration of neutrophils stimulated by C5a is inhibited by 50% was calculated.
The IC50 value of the compound of Example 4 was 5 nmol / L. On the other hand, the addition of the compound of Example 4 (3 μmol / L) did not induce an increase in intracellular Ca2 + and no agonist action was found.
20 Test example 3: action of neutrophils stimulated by C5a on the production of species that react to oxygen
A fraction of neutrophils was taken separately from human peripheral venous blood for which Lympholyte-poly (Cedarlane) was used, and suspended in Hank's balanced salt solution (HBSS, Hansk's Balanced Salt Solution, GIBCO BRL) containing 1% FBS (fetal bovine serum, fetal bovine serum) and 1 mmol / L of luminol 25 (Wako Pure Chemical Industries, Ltd.). The reactive oxygen species were measured by a luminometer (MicroLumat, Berthold) for a 96-well plate. That is, 1 x 106 cells / 150 µL of neutrophil suspension and 25 µL of a test compound solution (obtained by dissolving the test compound in N, N-dimethylformamide to a final concentration of 10 mmol / L and dilution with HBSS supplemented with 1% FBS) were added to a cavity that was placed in a MicroLumat set at 37 ° C, and allowed to stand for approximately five minutes. Then 25 µL of C5a (final concentration 3 nmol / L) was added and a luminescence produced by the reaction of the luminol with the oxygen reactive species was measured, over a time interval of 15 minutes. The coefficient (% inhibition) of the inhibition of the production of oxygen reactive species in the neutrophils stimulated by C5a by the test compound was calculated, using the following formula, in which the peak value of the production of the reactive species to oxygen derived by C5a, without addition
35 of the test compound is Max, the peak value of the production of the reactive oxygen species without the addition of the test compound and without the stimulation of C5a is Min, and the peak value of the production of reactive oxygen species derived by C5a With the addition of the test compound is Test:
% inhibition = 100 - [(Test – Min) / (Max – Min)] x 100
On the other hand, using the two interpolations method, the concentration (IC50 value) of the compound was calculated
40 test at which the increase in the concentration of oxygen reactive species in neutrophils stimulated by C5a is inhibited by 50%.
The IC50 value of the compound of Example 4 was 10 nmol / L.
Test example 4: action on the ability to migrate from neutrophils stimulated by C5a
A fraction of human peripheral venous blood neutrophils was taken separately by Lympholyte-poly
45 (Cedarlane), and was suspended in RPMI 1640 medium (GIBCO BRL) supplemented with 0.1% FBS (fetal bovine serum, fetal bovine serum). To this fraction of neutrophils (5 x 106 cells / mL), Calcein-AM (5 µM final concentration, FUNAKOSHI) was added, and the mixture was incubated at 37 ° C for 30 minutes. The cells were washed by centrifugation and suspended to a concentration of 1 x 10 6 cells / mL. Migration was evaluated by adding neutrophils to chemotaxicell (pore size: 3 μM, KURABO), and the neutrophils that were measured were measured.
50 migrated out of chemotaxicell. Then, the neutrophil suspension and the test compound solution (200 µl of each of them, were added into the chemotaxicell and incubated at 37 ° C, 5% CO2 for 90 minutes. After the reaction was completed. , the chemotaxicell was removed after shaking well and 100 µl of cell lysate solution (10% SDS, 0.01 mol / L HCl) was added .. The fluorescent intensity of each cavity was measured by Cyto Fluor II (Ex: 485, Em: 530) The coefficient (percentage inhibition) of the migration inhibition of neutrophils stimulated by C5a by the test compound was calculated by the following formula, in which the fluorescence intensity of the migrating neutrophils due to the stimulation of C5a is Max, the fluorescence intensity of the neutrophils that migrated without addition of the test compound and without stimulation by C5a is Min, and the fluorescence intensity of the neutrophils q What migrated by stimulation of C5a with the addition of the test compound is Test:
% inhibition = 100 - [(Min test) / (Max test)] x 100
On the other hand, using the two interpolations method, the concentration (IC50 value) of the test compound in which the migration of neutrophils stimulated by C5a was inhibited by 50% was calculated.
The IC50 value of the compound of Example 4 was 100 nmol / L.
Test Example 5: C5a-induced neutrophil depletion action in monkeys
The test compound is administered intravenously, subcutaneously or orally to cynomolgus monkeys. Next, human C5a (SIGMA) is administered. Peripheral neutrophil counts are performed over time, and the suppressive action by the test compound on the decrease in peripheral neutrophil count is evaluated.
Test example 6: action on collagen-induced arthritis in monkeys
Intradermally, type II collagen (purchased from Collagen Research Center) is inoculated twice in the back of cynomolgus monkeys, together with Freund H37Rv complete adjuvant (purchased from Waco Pure Chemical Industries, Ltd.), on the first day of the test and on day 21. The test compound is administered orally from day 22 to day 33 after inoculation. Swelling of the four joints of the limbs is observed according to scores between 0 (no changes) and 3 (edema in the five toes). The total swelling score of each monkey's joints is shown by the total scores of four members.
Test example 7: toxicity test
In a single toxicity test per administration, the test compound is administered to male and female SD rats (at a rate of three per group) and cynomolgus monkeys (one per group), and toxicity is evaluated based on the presence and absence of incidence of death, general condition and body weight as indices. In a repeated administration toxicity test, the compound is administered repeatedly to male and female SD rats (at the rate of 6 per group) and male and female cynomolgus monkeys (at the rate of 2 per group) for two weeks, and the Repeated administration toxicity of the test compound based on the general condition, body weight, diet intake, hematological tests, blood biological tests, organ weight and autopsy (which includes the pathological test of the tissues) as indexes.
Test example 8: evaluation of bioavailability in the rat
The test compound is administered intravenously and orally to male SD rats (at the rate of five per group), and blood is drawn over time. By using high performance liquid chromatography, the concentration of the drug in plasma is measured. Bioavailability (BA) is calculated using the following formula:
((AUC by oral administration) / (AUC by intravenous administration))) x ((intravenous administration dose / (oral administration dose)) x 100 (%)
AUC: plasma concentration - area below the time curve
Industrial applicability
The compound of the formula (1) of the present dimension, one of its optically active forms and one of its pharmaceutically acceptable salts have an antagonistic action of the C5a receptor and are useful as an agent for the prevention and treatment of diseases or syndromes due to inflammation caused by C5a [eg, autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease and serious organic lesions (for example, pneumonia, nephritis, hepatitis and pancreatitis and the like) due to the activation of leukocytes caused by ischemic reperfusion, trauma, burns, surgical invasion and the like]. In addition, it is useful as an agent for the prevention or treatment of infectious diseases caused by bacteria or viruses that invade through a C5a receptor.
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Claims (24)

1. An amide derivative represented by the formula (1) image 1 where R1, R2 and R3 are the same or different and each is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylalkyl group, acyloxy group that optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group which optionally has substituents, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoi group which optionally has substituents or haloalkyl group or any two of R1, R2 and R3 in combination with the adjacent carbon atom can form a ring, a, b, c, d and e are each carbon atom or 1 or 2 of a, b, c, d and e are nitrogen atoms (provided that the nitrogen atom here can be attached with amine oxide oxygen atom and the rest they are carbon atoms, R4, R5 and R6 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally has substituents, aryloxy group, arylalkyl group, acyloxy group that optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group which optionally has substituents, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoi group which optionally has substituents, haloalkyl group or haloalkyloxy group, A is cycloalkyl group that optionally has substituents, aryl group that optionally has substituents or heteroaryl group that optionally has substituents, W1 and W2 are the same or different and each is a bond or alkylene (Cn) that optionally has substituents, where n is an integer from 1 to 3, X is an oxygen atom or sulfur atom, Y is a bond, oxygen atom, –CO–, –N (R7) -, where R7 is hydrogen atom or alkyl group that optionally has substituents, –SOm–, where m is an integer from 0 to 2 , –CON (R8) -, where R8 is hydrogen atom or alkyl group that optionally have substituents or –N (R9) CO–, where R9 is hydrogen atom or alkyl group that optionally has substituents), Z is alkylene group that optionally has substituents and Optional substituents are selected from alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, alkoxy group, aryloxy group, arylalkyl group, acyloxy group, halogen atom, hydroxyl group, group nitro, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, acylamino group, sulfamoyl group, haloalkyl group, haloalkyloxy group , oxo group (provided that, when replacing a divalent nitrogen atom, it forms amine oxide), tetrahydropyran-2-yloxy, R13O (CH2) jO (CH2) kO (CH2) 10-, R13O (CH2) jO (CH2) kO–, R13O (CH2) jO–, R13O (CH2) jO (CH2) kO (CH2) l–, R13O (CH2) jO (CH2) k–, R13O (CH2) j–, where j, kyl are each one, independently, an integer from 2 to 10, R13 is hydrogen atom, alkyl group, g rupo cycloalkyl, aryl group, heteroaryl group, arylalkyl group, heteroarylalkyl group or haloalkyl group, one of its optically active forms or one of its pharmaceutically acceptable salts. 2. The amide derivative according to claim 1, wherein, in formula (1), R1, R2 and R3 are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, group carboxyl, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl group, a, b, c, d and a are each carbon atom or 1 or 2 of a, b, c, d and e are nitrogen atoms and the rest are carbon atoms, R4, R5 and R6 are the same or different and each is hydrogen atom, alkyl group that optionally has substituents, alkenyl group that optionally has substituents, alkynyl group that optionally has substituents, cycloalkyl group, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, group carboxyl, tetrazolyl group, oxadiazolyl group, sulfamoyl group or hahoalkyl group, A is cycloalkyl group, aryl group that optionally has substituents or heteroaryl group that optionally has substituents, W1 and W2 are the same or different and each is a bond or alkylene (Cn) that optionally has substituents, where n is an integer from 1 to 3, X is an oxygen atom or sulfur atom, Y is a bond, oxygen atom, –CO–, –N (R7) -, where R7 is hydrogen atom or alkyl group that optionally has substituents, –SOm–, where m is an integer from 0 to 2 , -CON (R8) -, where R8 is hydrogen atom or alkyl group that optionally has substituents or -N (R9) CO-, where R9 is hydrogen atom or alkyl group that optionally has substituents, Z is an alkylene group that optionally has substituents, one of its optically active forms or one of its pharmaceutically acceptable salts and the optional substituents are defined as in item 1 above.

3.

 The amide derivative according to claim 2, wherein a, b, c, d and c in the formula (1) are all carbon atoms, one of its optically active forms or one of its pharmaceutically acceptable salts.

Four.

 The amide derivative according to claim 1, wherein R1, R2 and R3 in formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group, one of its optically active forms or one of its pharmaceutically acceptable salts.

5.

 The amide derivative according to claim 1, wherein R1, R2 and R3 in the formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group which it has 2 to 4 carbon atoms, one of its optically active forms or one of its pharmaceutically acceptable salts.

6.

 The amide derivative according to claim 1, wherein R1, R2 and R3 in formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or a methoxy group, one of its optically active forms or one of its pharmaceutically acceptable salts.

7.

 The amide derivative according to claim 1, wherein R4, R5 and R6 in formula (1) are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group, haloalkyl group or haloalkyloxy group and wherein the optional substituents are defined according to claim 1, one of its optically active forms or one of its pharmaceutically acceptable salts.

8.

 The amide derivative according to claim 1, wherein R4, R5 and R6 in formula (1) are the same or different and each is a hydrogen atom, alkyl group that optionally has substituents, alkoxy group that optionally has substituents, acyloxy group which optionally has substituents, halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group or haloalkyl group and wherein the optional substituents are defined as in claim 1, one of its forms optically active or one of its pharmaceutically acceptable salts.

9.

 The amide derivative according to claim 1, wherein Z of the formula (1) is –CH2–,

one of its optically active forms or one of its pharmaceutically acceptable salts.

10.

 The amide derivative according to claim 1, wherein A of the formula (1) is an aryl group that optionally has substituents or heteroaryl group that optionally has substituents and wherein the optional substituents are defined as in claim 1, one of its optically active forms or one of

5 its pharmaceutically acceptable salts. 11. The amide derivative according to claim 1, wherein A of the formula (1) is a phenyl group that optionally has substituents, pyridyl group that optionally has substituents, pyrazolyl group that optionally has substituents, thiazolyl group that optionally has substituents , oxazolyl group that optionally has substituents or thienyl group that optionally has substituents and wherein the substituents Optional are defined as in claim 1, one of its optically active forms or one of its pharmaceutically acceptable salts. 12. The amide derivative according to claim 1, wherein A of the formula (1) is a phenyl group that optionally has substituents or a nitrogen-containing heterocyclic group selected from the group consisting of the following formulas (Aa) - ( Ac) image 1 fifteen wherein R 10 is a hydrogen atom, an alkyl group that optionally has substituents, an alkenyl group that optionally has substituents, an alkynyl group that optionally has substituents, a cycloalkyl group, an alkoxy group that optionally has substituents, an acyloxy group that optionally has substituents, a halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group, 20 amino group, alkylamino group, dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl group and wherein the optional substituents are defined as claim 1, one of its optically active forms or a pharmaceutically acceptable salt thereof. 13. The amide derivative according to claim 1, wherein X of the formula (1) is an oxygen atom, one of its optically active forms or one of its pharmaceutically acceptable salts.

14.

 The amide derivative according to claim 1, wherein –W1 – Y – W2– of the formula (1) is - (CH2) 2–, - (CH2) 3– or - (CH2) 2O,

one of its optically active forms or one of its pharmaceutically acceptable salts.

fifteen.

 The amide derivative according to claim 1, wherein R1, R2 and R3 of the formula (1) are the same or

30 different and each one is hydrogen atom, alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms, a, b, c, d and e are each carbon atom or b or d is a nitrogen atom and the rest are carbon atoms, R4, R5 and R6 are the same or different and each one is hydrogen atom, methoxy group, halogen atom or hydroxyl group, 35 Z is –CH2–, A is a phenyl group that optionally has substituents or nitrogen-containing heterocyclic group selected from the group consisting of the following formulas (Aa ') - (Ae') xxxxxx image 1 wherein R10a, R11 and R12 are the same or different and each is a hydrogen atom, an alkyl group that Optionally it has substituents, cycloalkyl group which optionally has substituents, aryl group which optionally has substituents; heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, alkoxy group that optionally it has substituents, aryloxy group, arylalkyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, alkylthio group, amino group, alkylamino group, dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) lO–, where j, kyl are each, independently, an integer from 2 to 10, R13 is hydrogen atom, alkyl group that optionally has 5 substituents, cycloalkyl group that optionally has substituents, aryl group that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents or haloalkyl group or R13O (CH2) jO (CH2) kO–, where j, k and R13 are as defined above, R10b is a hydrogen atom, alkyl group that optionally has substituents, cycloalkyl group that optionally has substituents, gru po 10 aryl that optionally has substituents, heteroaryl group that optionally has substituents, arylalkyl group that optionally has substituents, heteroarylalkyl group that optionally has substituents, haloalkyl group, haloalkyloxy group, R13O (CH2) jO (CH2) kO (CH2) l–, in where j, k, l and R13 are as defined above or R13O (CH2) O (CH2) k–, where j, k and R13 are as previously defined, X is an oxygen atom, 15 –W1 – Y – W2– is - (CH2) 2 - or - (CH2) 3 and wherein the optional substituents are defined as in claim 1, one of its optically active forms or one of its pharmaceutically acceptable salts. 16. The amide derivative according to any one of claims 1 to 15, wherein the amide derivative is selected from the group consisting of 20 N - [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) - 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-ethylphenyl) indan-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N - (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3, 4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) chroman-4-carboxamide, 25 N - [(4-dimethylaminophenyl) methyl] –5-hydroxy-N– (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -6-methoxyindan-1-carboxamide, N- [ (1-ethylpyrazol-4-yl) methyl] –N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphtal en-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (4-isopropylphenyl) -6-methoxychroman-4-carboxamide, N - [(1,3-dioxaindan-5-yl) methyl] - N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, 30 N - [(4-dimethylaminophenyl) methyl] -4-hydroxy-N- (4-isopropylphenyl) indan –1 – carboxamide, N - [(1-ethylpyrazol-4-yl) methyl) –5-hydroxy-N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide and N - ((1-ethylpyrazol-4-yl) methyl) -4-hydroxy-N- (4-isopropylphenyl) indan-1-carboxamide, one of its optically active forms or one of its pharmaceutically acceptable salts. 17. The amide derivative according to claim 1, wherein the amide derivative is 35 N - [(1-ethylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, one of its forms optically active or one of its pharmaceutically acceptable salts. 18. The amide derivative according to any one of claims 1 to 15, wherein the amide derivative is selected from the group consisting of N - [(2,6-dimethoxypyridin-3-yl) methyl] -5-hydroxy –N– (4-isopropylphenyl) –1,2,3,4-tetrahydronaphthalen – 1-carboxamide, 40 5-hydroxy-N– (4-isopropylphenyl) –N - [(6-phenoxypyridin-3-yl) methyl) –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide, N - [(6-dimethylaminopyridin-3-yl) methyl] –5-hydroxy-N– (4-isopropylphenyl) –1,2,3,4– tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-ethoxy-N– (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(5-ethylthiophene-2-yl) methyl ] –N– (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -7-fluoro-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-bromophenyl) -N - [(4 –Dimethylaminophenyl) methyl] –7 – fluoro – 1,2,3,4-tetrahydronaphthalen – 1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –8-fluoro-5-hydroxy-N– (4-isopropylphenyl) –1,2,3,4 – tetrahydronaphthalen – 1-carboxamide, N - [(2,6-dimethoxypyridin-3-yl) methyl] –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1, 2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1 –Carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) –N - [(6-methoxypyridin-3-yl) –methyl – 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N– [(2,4-dimethylthiazol-5-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4– butylphenyl) –N - [(4 – dimet ilaminophenyl) methyl] –5-hydroxy – 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –7-methoxy-N– (4-methoxyphenyl) –1,2, 3,4-tetrahydronaphthalen-1-carboxamide, N- (4-chlorophenyl) -N - [(4-dimethylaminophenyl) methyl] -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- [ (4-dimethylaminophenyl) methyl] –7-methoxy-N– (4-methylphenyl)] - 1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] –N– (4 -Ethoxyphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-bromophenyl) -N - [(4-dimethylaminophenyl) methyl] –7-methoxy – 1,2,3 , 4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4-methylaminophenyl) methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [( 4-dimethylaminophenyl) methyl] -5-hydroxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4-isopropylphenyl) -N - [(2 –Methyl thiazol-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-bromophenyl) -N - [(4-dimethylaminophenyl) methyl] –5-hydroxy-1,2, 3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N- (2-tolylmethyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2, 4-dichlorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4 –Nitrophenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(3-tolyl) methyl] –1,2,3,4 –Tetrahydronaphthalen – 1 – carboxamide, N– (4-isopropylphenyl) –7 – methoxy-N - [(4-tolyl) methyl] –1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide, N - [(2– fluorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-fluorophenyl) methyl] -N- (4-isopropylphenyl) - 7 – methoxy – 1,2,3,4 – tetrahydronaphthalen– 1-carboxamide, N - [(2,4-dimethylphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) –7 – methoxy – N - [(2-methoxyphenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-chlorophenyl) methyl] –N– (4-isopropylphenyl) –7 –Methoxy – 1,2,3,4 – tetrahydronaphthalen – 1 – carboxamide, N - [(2,4 – difluorophenyl) methyl] –N– (4-isopropylphenyl) –7 – methoxy – 1,2,3,4– tetrahydronaphthalen-1-carboxamide, N - [(2,6-difluorophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4 -Ethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(4– oxacroman – 6-yl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(2,3-dimethoxyphenyl) methyl] –N– (4-isopropylphenyl) –7-methoxy – 1, 2,3,4-tetrahydronaphthalen-1-carboxamide, N– [(2,4-dimethoxyphenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(2-Trifluoromethylphenyl) methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) –7-methoxy-N - [(4-trifluoromethylphenyl) methyl] –1,2 , 3,4-tetrahydronaphthalen-1-carboxamide, N - [(2-bromophenyl) methyl] -N- (4-isopropylphenyl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, N- (4-isopropylphenyl) -7-methoxy-N - [(2,3,4-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4-isopropylphenyl) –N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(1-benzylpyrazol-4-yl) methyl] - 5-hydroxy-N– (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - {[ 1– (2-pyridylmethyl) pyrazole – 4 yl] methyl} -1,2,3,4-tetrahydronaphthalen-1- carboxamide, 5 N - ({1 - [(4-fluorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen– one- carboxamide, N - ({1 - [(4-chlorophenyl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen - 10 1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methoxyphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, N - ({1 - [(4-bromophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4– tetrahydronaphthalen – 1– carboxamide, 15 N - ({1 - [(3-chlorophenyl) methyl] pyrazol-4-yl) methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen– 1– carboxamide, N - ({1 - [(2-chlorophenyl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4 –Tetrahidronaftalen – 1– carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylphenyl) methyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen -one- 20 carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(5-methylpyridin-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [( 5– methoxypyridin-2-yl) methyl] pyrazol-4-yl} methyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (6-isopropylpyridin-3-yl) -N - ({1 - [(6-methylpyridine-2-yl) methyl-1-yl] -pyrazol-4-yl) -methyl) –1,2,3,4– tetrahydronaphthalen-1-carboxamide, 25 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-methylpyridine-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3, 4– tetrahydronaphthalen – 1-carboxamide, 8-fluoro-5-hydroxy-N– (6-isopropylpyridin-3-yl) –N - {[1– (2-pyridylmethyl) pyrazol-4-yl] methyl} –1, 2,3,4 – tetrahydronaphthalen – 1– carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(4-trifluoromethylpyridin-2-yl) methyl] pyrazol-4-yl} methyl) –1,2,3 ,4- Tetrahydronaphthalen-1-carboxamide, N - ({1 - [(6-dimethylaminopyridin-2-yl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4 - tetrahydronaphthalen-1-carboxamide, N - ({1– [3– (dimethylaminophenyl) methyl] pyrazol-4-yl} methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2, 3.4– tetrahydronaphthalen-1-carboxamide, 35 N - [(2-ethyl-4-trifluoromethylthiazol-5-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-benzyloxy-N– (4-isopropylphenyl) -N - [(1-isopropylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N- (4– isopropylphenyl) –N - [(1-methylpyrazol-4-methyl] –1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-benzyloxy-N- (4-isopropylphenyl) –N - [(1-propylpyrazole– 4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 40 N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} -5-hydroxy-N- (4-isopropylphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N - (4-Isopropylphenyl) –N - {(1– (3-thienylmethyl) pyrazol-4-yl] methyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (4– fluorobenzyl) pyrazol-4-yl] methyl} -5-hydroxy-N- (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(1-ethylpyrazole-4-yl) methyl ] –5 – hydroxy-N– (4-methoxyphenyl) –1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - {(1– (cyclohexylmethyl) pyrazol-4-yl] methyl) –5-hydroxy– N– (4-methoxyphenyl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (2-piperidinoethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N - {[1– (cyclohexylmethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N - [(1-Heptylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (3-thienylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(2-methylthiazol-4-yl) methyl] pyrazol-4-yl} methyl) –1,2,3,4 –Tetrahidronaftalen– 1-carboxamide, N - [(1-Butylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (3-methylbutyl) pyrazol-4-yl) methyl] –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N - [(1-benzylpyrazol-4-yl) methyl] -5-hydroxy-N- (6-methoxypyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1– [2– (2-pyridyl) ethyl] pyrazol-4-yl} methyl – 1,2,3,4-tetrahydronaphthalen– one- carboxamide, N - [(1-dodecylpyrazi-4-yl) methyl] -5-hydroxy-N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - [(1-nonylpyrazol-4-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - {[1– (2-Butoxyethyl) pyrazol-4-yl] methyl} –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1– [2– (2-methoxyethoxy) ethyl] pyrazol-4-yl} methyl) –1,2,3,4-tetrahydronaphthalen -one- carboxamide, 5-hydroxy-N– (4-isopropylphenyl) -N - [(6-morpholinopyridin-3-yl) methyl] -1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (4-isopropylphenyl) -N - ({1 - [(4-methylpyridin-2-yl) methyl] pyrazol-4-yl) methyl) –1,2,3,4-tetrahydronaphthalen – 1 - carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - ({1 - [(6-morpholinopyridin-2-yl) methyl] pyrazol-4-yl) methyl) –1,2,3,4 - tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {(1 - [(6-methoxypyridin-2-yl) methyl] -pyrazol-4-yl) methyl} –1,2,3, 4- tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N - [(1-isopropylpyrazol-4-yl) methyl] -N- (6-isopropylpyridin-3-yl) -1,2,3,4-tetrahydronaphthalen-1-carboxamide, N - [(4-dimethylaminophenyl) methyl] -N- (6-isopropylpyridin-3-yl) -7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide, 5-hydroxy-N– (6-isopropylpyridin-3-yl) -N - {[1– (2-thienylmethyl) pyrazol-4-yl] methyl} –1,2,3,4-tetrahydronaphthalen – 1– carboxamide, N - ({1 - [(5-chlorothiophene-2-yl) methyl] pyrazol-4-yl} methyl) -5-hydroxy-N- (6-isopropylpyridin-3-yl) –1,2,3,4 –Tetrahidronaftalen– 1-carboxamide, 5-benzyloxy-N - ({1– [2– (2-butoxyethoxy) ethyl] pyrazol-4-yl) methyl) –N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen -one- carboxamide, N - ({1– [2– (2-Butoxyethoxy) ethyl] pyrazol-4-yl) methyl) –5-hydroxy-N– (6-isopropylpyridin-3-yl) –1,2,3,4-tetrahydronaphthalen -one- carboxamide and N - ({1– [2– (2-ethoxyethoxy) ethyl] pyrazol-4-yl} methyl) -N– (6-isopropylpyridin-3-yl) –5-hydroxy – 1,2,3,4-tetrahydronaphthalen -one- carboxamide, one of its optically active forms or one of its pharmaceutically acceptable salts.

19.

 A pharmaceutical composition comprising the amide derivative or any of claims 1 to 18, one of its optically active forms or one of its pharmaceutically acceptable salts and a pharmaceutically acceptable additive.

twenty.

 A drug comprising the amide derivative of any one of claims 1 to 18, one of its optically active forms or one of its pharmaceutically acceptable salts as an active ingredient for use in the prevention and therapy of a disease selected from an autoimmune disease. , sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis,

5 heart attack, cerebral infarction, psoriasis, Alzheimer's disease or severe organic injury due to leukocyte activation caused by reperfusion due to ischemia, trauma, burn or surgical invasion.

twenty-one.

 The drug according to claim 20, wherein the autoimmune disease is rheumatism or systemic lupus erythematosus.

22

 A C5a receptor antagonist comprising the amide derivative according to any of the

10 claims 1 to 18, one of its optically active forms or one of its pharmaceutically acceptable salts in the form of an active ingredient. 23. The C5a receptor antagonist according to claim 22 for use in combination with an agent for the prevention or treatment of an autoimmune disease, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis heart attack heart attack Brain, psoriasis, Alzheimer's disease or severe organic injury due to leukocyte activation caused by reperfusion due to ischemia, trauma, burn or surgical invasion. 24. A drug combined with an agent for the prevention or treatment of an autoimmune disease, sepsis, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis, heart attack, cerebral infarction, psoriasis, Alzheimer's disease or severe organic injury due 20 to a leukocyte activation caused by reperfusion due to ischemia, trauma, burn or surgical invasion, which comprises the amide derivative of any of items 1 to 18 above, one of its optically active forms or one of its pharmaceutically acceptable salts in form of an active ingredient.