HU211894A9 - Benzo-fused lactams promote release of growth hormone - Google Patents

Description

The growth hormone secreted by the pituitary gland stimulates the growth of all tissues within the body that are able to grow. In addition, growth hormone exerts the following effects on metabolic processes:

1. Increases the rate of protein synthesis in all cells.

2. Reduces carbohydrate utilization in cells.

3. Enhance mobilization and utilization of free fatty acids for energy production.

Changes in growth hormone secretion can cause various diseases, such as dwarfism.

There are several ways to release growth hormone. Examples of triggers include chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin and insulin-induced hypoglycemia, as well as certain processes such as sleep and exercise that induce growth. hormone release from the pituitary gland through various effects on the hypothalamus. These may include, for example, reducing the secretion of somatostatin or increasing the secretion of known growth hormone releasing factor (GRF) or unknown endogenous growth hormone releasing hormones, or a combination thereof.

Increased growth hormone levels are usually achieved by administering exogenous growth hormone or by stimulating growth hormone production and / or release. In both cases, the peptide nature of the substance requires administration by injection. Growth hormone was originally extracted from the pituitary glandular body. This is a costly procedure and carries the risk that any disease associated with the pituitary gland used can spread with growth hormone. Recombinant growth hormone, which does not involve the transmission of disease, has recently been developed but remains expensive and can only be administered by injection or nasal spray.

Compounds that stimulate the release of endogenous growth hormone have also been developed. These include, for example, peptides analogous to GRF and those described in US 4,411,890. These peptides are substantially smaller molecules than growth hormones, but are still sensitive to various proteases. Like most peptides, their biological potential is low when given orally.

It is an object of the present invention to provide compounds which are not peptide analogs and which promote growth hormone release and can be administered parenterally, nasally or orally.

Summary of the Invention

It has been found that some benzofused lactam derivatives stimulate the release of natural or endogenous growth hormone. These compounds are therefore useful in the treatment of conditions requiring stimulation of growth hormone production or secretion. They can be used, for example, in patients with natural growth hormone deficiency or in pets, where growth hormone stimulation increases productivity.

Accordingly, the present invention relates to benzofused lactam derivatives. The invention further relates to a process for the preparation of such compounds. The invention further relates to the use of such compounds to enhance growth hormone secretion in humans and animals.

The present invention also provides a growth hormone secretagogue composition comprising a benzofused lactam derivative. Other objects of the invention will become apparent from the following description.

Description of the Invention

In the novel benzofused lactam derivatives of the present invention, L is a group of formula (a), n is 0 or 1, p is 0-3, q is 0-4, w is 0 or 1,

X is -CO-, O,

-S (O) _m - -CH (OH) -, -NR ¹⁰ - or -CH = CH-, m is 0-2,

R ¹ , R ² , R ^1a , R ²³ , R ^1b , and R ^2b are each independently hydrogen, halogen, C 1-7 alkyl, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, - S (O) mR ^7a , cyano, nitro, R ^7b O (CH 2) _v -, R ^7b COO (CH 2) _v R ^7b OCO (CH 2) _v -, R ⁴ R ⁵ N (CH 2) V -, R ^7b CON (R ⁴ ) (CH 2) _v - or R ⁴ R ⁵ NCO (CH ₂ ) _V -, phenyl or substituted phenyl, wherein the substituent may be one to three halogens, C 1 -C 6 alkyl, alkoxy or hydroxy group of carbon,

R ^7a and R ^7b are independently hydrogen, C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, wherein the substituent is phenyl or substituted phenyl, and phenyl or substituted phenyl, wherein the substituents on the phenyl groups may be 1-3 halogens, C 1-6 alkyl, C 1-6 alkoxy or hydroxy, v is 0-3,

R ^3a and R ^3b are independently hydrogen, R ⁹ substituted C 1-6 alkyl group R ^9, substituted ^R9 groups phenyl or R-substituted phenoxy ⁹ group, with the proviso that R ^3a and R ^3b, at least one of R other than hydrogen,

R ⁹ is R ^4b R ^L2A NCON (R ^L2B) (CH 2) v R ^4b R ^L2A NCS _{N (R} ^2b) _{(CH 2) v} -,

R ^4b R ^L2A NN (R ^L2B) CSN (R ^L2C) (CH 2) v R ^4b R ^2a NN ^(R12b) CON (R ^12c) (CH 2) _v 2

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R ^4b R ^12a NN (R ^12b ) COO (CH 2) _v R ^4b R ^12a NCOO (CH 2) _v - or R ¹³ OCON (R ^12b ) (CH ₂ ) _v wherein v is 0-3,

R ^12a , R ' ^2b and R' ^2c are each independently R ⁵ , -OR ^5a, or -COR ^5a , or

R ^L2A and R ^12b, R ^12b and R ^{L2C, L3A,} R, and R ^12b, R ^I2a and R ^4b together form - (CH _{2) r} -B- (CH _{2) s} - form a group of the formula wherein

B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-3,

R ¹ and R ¹⁰ are as defined,

R ¹³ is C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, where the substituent may be hydroxy, -NR 10 R, carboxyl, phenyl or substituted phenyl, or phenyl or substituted phenyl, wherein the substituents on the phenyl may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy or hydroxy,

R ⁴ , R ^4b , R ⁵ and R ^5a are each independently hydrogen, phenyl, substituted phenyl, C 1-10 alkyl, substituted C 1-10 alkyl, C 3-10 alkenyl, substituted C 3-10 alkenyl, 3-10 alkynyl or substituted C3-10 alkynyl, wherein the phenyl, alkyl, alkenyl or alkynyl group may be substituted with one to five hydroxyl, C1-6 alkoxy, C3-7 cycloalkyl, fluoro, R ¹ substituted or independent groups ^R1 and Phenyl disubstituted with R ² groups and C 1 -C 3 phenylalkoxy in its alkoxy group, phenyl substituted with R ¹ or independent of R ¹ and R ² groups, C 1-20 alkanoyloxy group, C 1 -C 5 alkoxycarbonyl group, a carboxyl group, a formyl group or a group represented by the formula NR 1 R ¹¹ wherein _R 10 and R 10 are present ¹¹ is independently hydrogen, (C 1 -C 6) -alkyl, phenyl, (C 1 -C 6) -alkyl-alkyl, (C 1 -C 5) -alkoxycarbonyl or (C 1 -C 5) -alkanoyl and (C 1 -C 6) -alkanoyl (alkyl);

R ⁴ and R ⁵ together form - <CH ₂ ) _r -B- (CH ₂ ) _s -, wherein

B is -CHR ¹ -, -O, -S (O) _m -, or -NR 10 ° -, independently selected from 1-3,

R ¹ and R ^{i ()} are as defined above,

R ⁶ is hydrogen, (C 1 -C 10) alkyl, phenyl or (C 1 -C 10) -alkyl in the alkyl moiety,

A is a group of formula (b) wherein x and y are independently 0-3,

R ⁸ and R ^8a are independently hydrogen, C 1 -C 10 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl, indolyl, hydroxy, fluoro, -S (O) _m -R ^7a , C 1-6 -alkoxy, C 3-7 -cycloalkoxy, substituted with R ¹ or independently substituted with R ¹ and R ² and in its alkoxy is C 1-3 -phenyl-alkoxy, R ¹ or independently Phenyl substituted with R ¹ and R ² , C 1 -C 5 alkanoyloxy, C 1 -C 5 alkoxycarbonyl, carboxyl, formyl or -NR ¹⁰ R ', wherein

R ¹⁰ and R ¹¹ are phenite or

R ⁸ and R ^8a together form - (CH ₂ ) ₁ -, wherein t is 2 to 6, or

R ⁸ and R ^8a independently of each other form an alkylene bridge attached to R ⁴ and / or R ⁵ between the terminal nitrogen atom and the alkyl portion of A containing an alkylene bridge containing from 1 to 5 carbon atoms.

The present invention includes pharmacologically acceptable salts of the above compounds.

The groups defined in the above interpretation and in the remainder of the description have the following meanings:

The alkyl group may be a linear or branched alkyl group of the specified length. Examples include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The alkoxy group may be a linear or branched alkoxy group of the specified length. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy and isohexoxy.

The halogen atom may be fluorine, chlorine, bromine or iodine.

In the general formulas, the above groups may occur several times, and their interpretation is independent of the others at each appearance.

Preferred compounds of the formula I and their pharmacologically acceptable salts are those wherein n is 0 or 1, p is 0-3, q is 0-2, w is 0 or 1,

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X is O, -S (O) _m -, -NR ¹⁰ - or -CH = CH-, m is 0-2,

R ¹ , R ² , R ^1a , R ²³ , R ^1b , and R ^2b independently of one another are hydrogen, halo, C 1-7 alkyl, C 1-3 perfluoroalkyl, -S (O) m R ^7a , R ^7b O (CH2) _v -,

R ^7b COO (CH 2) v or R ^7b OCO (CH 2) _v -, phenyl or substituted phenyl, wherein the substituent may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy or hydroxy,

R ^7a and R ^7b are each independently hydrogen, C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, wherein the substituents are phenyl and phenyl, v is 0-2,

R ^3a and R ^3b are independently hydrogen, R ⁹ substituted C1-6 alkyl R ⁹ group, R is a substituted phenyl, or R is a substituted phenoxy ⁹ group, with the proviso that R ^3a and R ^3b, at least one of R ⁹ group, other than hydrogen,

R ⁹ is R ^4b R ^12a NCON (R ^12b ) (CH 2) v R ^4b R ^12a NCSN (R ^12b ) (CH 2) _v -, R ⁴ bR ^| CONN (R ^12b ) CON (R ^12b ) (CH 2) _v R ^4b R ^12a NN (R ^12b ) COO (CH 2) v R 1 R 4 R 4 NCOOfCH 3, or R ¹³ OCON (R ^12b ) (CH 2) _v , where v is 0-3,

R ^12a , R ^12b and R ^12c are each independently R ^5a , -OR ^5a, or -COR ^5a , or

R ^12a and R ^12b , R ^12b and R ^12c , R ^13a and R ^12b , R ^12a and R ^4b together form - (CH ₂ ) _r -B- (CH ₂ ) _s -, wherein

B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-3,

R ¹ is as defined above,

R ¹⁰ is hydrogen, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl (alkyl) or (C 15 -alkanoyl) -alkanoyl (C 1 -C 6) and (C 1 -C 6) -alkanoyl (alkyl);

R ¹³ is C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl wherein the substituent is hydroxy, -NR ¹⁰ R ^H , carboxyl, phenyl or substituted phenyl, and phenyl or substituted phenyl wherein the substituents on the phenyl may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy, wherein v is as defined above,

R ⁴ , R ^4b , R ⁵ and R ^5a are each independently hydrogen, phenyl, substituted phenyl, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the alkyl and phenyl substituents may be one of hydroxy, C 1 -C 6 alkoxy, C3-7 cycloalkyl group, a fluorine atom, a substituted or di-substituted independently R ¹ and R ² phenyl groups, independently of R ¹ and R ² groups disubstituted aryl part and C1-3 alkoxy-phenyl, R ¹ R ¹ group or a group of 1- C 20 alkanoyloxy, C 1 -C 5 alkoxycarbonyl, carboxyl, or

R ⁴ and R ⁵ together form - (CH ₂ ) _r -B- (CH ₂ ) _s -, wherein

B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, and r and s are independently 1-3,

R ¹ and R ¹⁰ are as defined above,

R ⁶ is hydrogen, (C 1 -C 10) -alkyl, or (C 1 -C 10) -alkyl-alkyl in its alkyl moiety,

A is a group of formula (b) wherein x and y are independently 0-2,

R ⁸ and R ^8a are each independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl groups, indolyl groups, hydroxy groups, fluorine, -S (O) _m -R ^7a groups. , C 1 -C 6 alkoxy, phenyl substituted with R ¹ or disubstituted with R ¹ and R ² independently, C 1 -C 5 alkanoyloxy, C 1 -C 5 alkoxycarbonyl, carboxyl, formyl or -NR ¹⁰ R ^H a group of the general formula wherein

R ¹⁰ and R ¹¹ are each independently hydrogen, C 1-6 alkyl or C 1-5 alkanoyl and C 1-6 alkanoylalkyl in alkyl; or

R ⁸ and R ^8a together form - (CH ₂ ) _t -, wherein t is 2 to 4, or

R ⁸ and R ^8a independently of one another are linked to R ⁴ and / or R ⁵ to form an alkylene bridge between the terminal nitrogen atom and the alkyl portion of A, wherein the alkylene bridge contains from 1 to 5 carbon atoms.

Particularly preferred are compounds of the formula I and their pharmacologically acceptable salts wherein n is 0 or 1,

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p is 0-2, q is 0-2, w is 0 or 1,

X is -S (O) _m - or -CH = CH-, m is 0 or 1,

R ¹ , R ² , R ^1a , R ²³ , R ^1b , and R ^2b independently of one another are hydrogen, halogen, C 1-7 alkyl, C 1-3 perfluoroalkyl, -S (O) m R ^7a , R ^7b O (CH2) _v -,

R ^7b COO (CH 2) v -, R ^7b OCO (CH 2) _v -, phenyl or substituted phenyl, wherein the substituent may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy or hydroxy,

R ^7a and R ^7b are each independently hydrogen, C 1-6 alkyl, C 1-6 substituted alkyl, wherein the substituent may be phenyl, v is 0-2,

R ^3a and R ^3b are independently hydrogen, R ⁹ substituted C 1-6 alkyl group R ^9, substituted ^R9 groups phenyl or R-substituted phenoxy ⁹ group, with the proviso that R ^3a and R ^3b, at least one of R other than hydrogen,

R ⁹ is R ^4b R ^12a NCON (R ^12b ) (CH ₂ ) _v -,

R ^4b R 2aNCSN (R ^12b ) (CH ₂ ) _v -,

R ^4b R ' ^2a NN (R ^12b ) CON (R ^12c ) (CH 2) v R ^4b R' ^ NN / R ^12b ) COO (CH 2) _v R ^4b R ^, 2aNcoO (CH 2) v - or R ¹³ OCON (R ^12b) ) (CH2) _v wherein v is 0-2,

R ' ^2a , R ^12b and R' ^2c independently represent R ^5a , -OR ^5a or -COR ^5a , or _R 12a _and Ria _R 12b _{and R} 12c _R 13a _{and R} 12b _R 12a _{and R} 4b together - (CH ₂ ) _r -B- (CH ₂ ) _s -, wherein

B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-2,

R ¹ is as defined above,

R 10 is hydrogen, (C 1 -C 6) -alkyl, or (C 1 -C 5) -alkanoyl and (C 1 -C 6) -alkanoylalkyl in its alkyl part,

R ¹³ is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl where the substituent may be phenyl or substituted phenyl, and phenyl or substituted phenyl where the substituents on the phenyl may be one to three halogens, C 1 -C 6 alkyl, 1-6 carbon atoms. alkoxy or hydroxy group of carbon,

R ⁴ , R ^4b cs R ^a are independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to five hydroxy groups, C 1 -C 6 alkoxy, fluoro, R ¹ substituted or unsubstituted. phenyl, C 1 -C 20 alkanoyloxy, C 1 -C 5 alkoxycarbonyl or carboxyl substituted by independent R ¹ and R ² groups,

R ⁶ is hydrogen, C 1-10 alkyl,

A is a group of formula (b) wherein x and y are independently 0-2,

R ⁸ and R ⁸³ are each independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl groups, indolyl groups, fluorine, -S (O) _m R ^7a groups, C 6 -alkoxy, phenyl substituted with R ¹ or disubstituted with R ¹ and R ² independently, C 1-5 alkanoyloxy, C 1-5 alkoxycarbonyl or carboxyl, or

R ⁸ and R ^8a together form - (CH ₂ ) -, wherein t is 2, or

R ⁸ and R ⁸³ are independently linked to R ⁴ and / or R ⁵ to form an alkylene bridge between the terminal nitrogen atom and the alkyl moiety of A, wherein the alkylene bridge contains from 1 to 5 carbon atoms.

Particular emphasis is given to the compounds of formula I and their pharmacologically acceptable salts wherein n is 0 or 1, p is 0-2, q is 1, w is 1,

X is -S (O) _m -, -CH = CH-, m is 0 or 1,

R ¹ , R ² , R ^1a , R ²³ , R ^1b , and R ^2b independently of one another are hydrogen, halogen, C 1-7 alkyl, C 1-3 perfluoroalkyl, -S (O) m R ^7a , R ^7b O (CH 2) v or R ^7b COO (CH ₂ ) _v -, phenyl or substituted phenyl, wherein the substituent may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy or hydroxy,

R ^7a and R ^7b are each independently hydrogen, C 1-6 alkyl or C 1-6 substituted alkyl, wherein the substituent may be phenyl, v is 0 or 1,

R ^3a and R ^3b are independently hydrogen, R ^{9 is} C 1-6 alkyl substituted with R ⁹ , with the proviso that at least one of R ^3a and R ^3b is other than hydrogen.

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R ⁹ is R ^4b R ^12a NCON (R ^12b ) (CH 2) v -, R 1 -> R ^{, 2a} NN (R ^12b ) CON (R ^{12 <} :) (CH 2) _v R 1 - R ¹ - N ¹ R ¹ - COO / CH), R ^4b R ^2a, n COO (CH2) v- or R ¹³ OCON (R ^12b) (CH 2) _v group of the formula wherein v is 0-2,

R ^12a , R ^12b and R ^12c are each independently R ^5a , or

R ^L2A and ^L2B R, R ^12b and R ^{£ l2, L3A,} R, and R ^12b, R ^12a and R ^4b together form - (CH _{2) r} -B- (CH _{2) s} - form a group of the formula wherein

B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-2,

R ¹ is as defined above,

R 10 is hydrogen, (C 1 -C 6) -alkyl or (C 1 -C 5) -alkanoyl and (C 1 -C 6) -alkanoyl (alkyl)

R ¹³ is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl where the substituent may be phenyl or substituted phenyl, and phenyl or substituted phenyl where the substituents on the phenyl may be one to three halogens, C 1 -C 6 alkyl, 1-6 carbon atoms. alkoxy or hydroxy group of carbon,

R ⁴ , R ^4b , R ⁵ and R ^5a are each independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three hydroxy groups, C 1 -C 3 alkoxy, fluoro, R * or phenyl, C 1-20 alkanoyloxy, C 1 -C 5 alkoxycarbonyl or carboxyl disubstituted with R ¹ and R ² independently of one another;

R ⁶ is hydrogen,

A is a group of formula (b) wherein x and y are independently 0 or 1,

R ⁸ and R ^8a are independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl, indolyl, hydroxy, fluoro, -S (O) _m -R ^7a. , - (C 1 -C 5) alkoxy, phenyl substituted with R ¹ or disubstituted with R ¹ and R ² independently of each other, C 1 -C 5 alkanoyloxy, C 1 -C 5 alkoxycarbonyl or carboxyl, or

R ⁸ and R ⁸ ® together form - (CH ₂ ) _t -, wherein t is 2, or

R ⁸ and R ^8a independently of one another are linked to R ⁴ and / or R ⁵ to form an alkylene bridge between the terminal nitrogen atom and the alkyl portion of A, wherein the alkylene bridge contains from 1 to 5 carbon atoms.

Examples of compounds having a beneficial growth hormone releasing effect include:

1. N- [1 - [[2 '- [(methoxycarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

2. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

3. N- [1 - [[2 '- [(ethylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

4. N- [1 - [[2 '- [(2-Propylaminocarbonyl) amino] [1,1'biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro -2-oxo-1,1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

5 · N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

6. N- [1 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

7. N- [1 - [[2 '- [(piperazinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

8. N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

9. N- [1- [2 '- [[(2-Hydroxypropylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4 , 5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

10. N- [1 - [[2 '- [(methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

11. N- [1 - [[2 '- [(dimethylaminocarbonyl) amino] [1,1'biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2 oxo-lH-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

12. N- [1 - [[2 '- [[(2 (R) -Hydroxypropylamino] carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2, 3,4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

13. N- [1 - [[2 '- [[(2 (S) -Hydroxypropylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2, 3,4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

14. N- [1 - [[2 '- [[[[(1-Hydroxyprop-2 (R) -yl] amino] carbonyl] amino] [1,1'-biphenyl] -4- yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

15. N- [1 - [[2 '- [4 - [(methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

16. N- [1 - [[2 '- [2 - [(methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

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17. N- [1 - [[2 '- [2 - [(aminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro -2-oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] amino-3-methylbutanamide,

18. N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo - 1H-1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide,

19. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] amino-3-methylbutanamide,

20. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1,1-benzazepin-3 (R) -yl] -3- [2 (S) -hydroxypropyl] amino] -methylbutanamide,

21. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-lH-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3 methyl-butanamide,

22. N- [1 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methyl-butanamide,

23. N- [1 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide,

24. N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] -amino-3-methyl-butanamide,

25. N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-2-oxo-1,1-benzazepin-3 (R) -yl] -3- [2 (S) -hydroxypropyl] amino-3-methylbutanamide,

26. N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide,

27. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-lH-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

28. N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo - 1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

29. N- [1 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

30. N- [1 - [[2 '- [(piperazinecarbonyl) amino] [1,1'-bi-phenyl] -4-yl] methyl] -2,3,4,5- tetrahydro-2-oxo-1 H -1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

31. N- [1 - [[2 '- [[(1-hydroxyethylamino) carbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

32. N- [1 - [[2 '- [(methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1 H -1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

33. N- [1 - [[2'-N - [(methoxycarbonyl-methyl-amino) -carbonyl] -amino] [1,1'-biphenyl] -4-yl] -methyl] -2,3; 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methyl 1-propanamide,

34. N- [1 - [[2 '- [(Hydroxyaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2 -oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

35. N- [1 - [[2 '- [(methoxycarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo -1Η-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

36. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5 tetrahydro-2-oxo-l-benzazepin-3- (R) -yl] -3 -amino-3-methyl-butanamide,

37. N- [1 - [[2 '- [(methylaminocarbonyl) aminone 1,1'-biphenyl] -4-yl] methyl] -7 trifluoro-2,3,4,5-tetrahydro -2-oxo-1H-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

38. N- [1 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7 trifluoro-2,3,4,5-tetrahydro -2-oxo-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

39. N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7 trifluoromethyl2 , 3,4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl]

3-amino-3-methylbutanamide,

40. N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2 3,4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide,

41. N- [1 - [[2 '- [(methylaminocarbonyl) oxy] [1,1'-biphenyl] 4-yl] methyl] -7-fluoro-2,3,4,5- tetrahydro-2-oxo-lH-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

42. N- [1 - [[2 '- [2 - [(methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -7 trifluoro-2 , 3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide,

43. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4, 5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methyl-butanamide,

44. N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4, 5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methyl-butanamide,

45. N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5- tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methyl-butanamide,

46. N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro -2-oxo-l-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methyl-butanamide,

47. N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro- 2,3,4,5-Tetrahydro-2-oxo-1 H -1-benzazepin-3 (R) -yl] -3- [2 (R) hydroxypropyl] amino-3-methylbutanamide,

48. N- [1 - [[2 '[(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5 -tetrahydro-2-oxo-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

HU 211 894 A9

49. N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5- tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

50. N- [1 - [[2 '- (piperazinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro -2-oxo-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

51. N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro- 2,3,4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

52. N- [1 - [[2 '- [(methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4, 5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide,

53. N- [5 - [[2 '- [(methoxycarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-4-oxo l, 5-benzothiazepin-3 (S) -yl] -3-amino-3-methyl-butanamide,

54. N- [5 - [[2 '- [(methoxycarbonylcarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-4 oxo-l, 5benzotiazepin-3 (S) -yl] -3-amino-3-methyl-butanamide,

55. N- [5 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-4- oxo-1,5-benzothiazepin-3 (S) -yl] -3-amino-3-methylbutanamide,

56. N- [5 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-Tetrahydro-4-oxo-1,5-benzothiazepin-3 (S) -yl] -3-amino-3-methyl-butanamide,

57. N- [5 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 4-oxo-1,5-benzothiazepin-3 (S) -yl] -3- [2 (R) -hydroxy-propyl] -amino3-methyl-butanamide,

58. N- [5 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-4- oxo-1,5-benzothiazepin-3 (S) -yl] -3- [2 (R) -hydroxypropyl] amino-3-methylbutanamide,

59. N- [5 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3; 4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3 (S) -yl] -3- [2 (R) -hydroxypropyl] amino-3-methyl-butanamide,

60. N- [5 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 4-oxo-l, 5-benzothiazepin-3 (S) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide.

The following nomenclature is illustrated by the following examples:

Compound 1: N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5 -tetrahydro-2-oxo-1,1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide: N- [1 - [[2 '- [(methylaminocarbonyl)] oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino- 3-methylbutanamide

Compound 3: N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5 -tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] -amino-3-methyl-butanamide

Compound 4: N- [5 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5- tetrahydro-2-oxo-1,5-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide.

The compounds of the present invention have at least one asymmetric center represented by an asterisk in formula (I). Depending on the nature of the various substituents, additional asymmetric centers may be present in the molecule. Each of these asymmetric centers results in two optical isomers, and these optical isomers, in particular the separated, pure or partially pure optical isomers, and their racemic mixtures are within the scope of the invention. With respect to the asymmetric center marked by an asterisk in formula (I), it has been found that compounds having a 3-amino substituent above the plane of the molecule, that is, compounds of formula (I), are more effective and accordingly more preferred than compounds in which the 3-amino substituent is located below the plane of the molecule. For the substituent (X) _n , when n is 0, the asymmetric center is considered to be the R isomer. If n is 1, the center is considered to be an R or S isomer according to the R / S rule, depending on the meaning of X.

The compounds of formula (I) are generally isolated in the form of a pharmaceutically acceptable acid addition salt. Such salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, while organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, succinic acid and malonic acid. In addition, compounds containing an acidic functional group such as a carboxyl group may be isolated in the form of an inorganic salt wherein the counter ion may be sodium, potassium, lithium, calcium or magnesium ions and ions derived from an organic base.

According to the invention, the compounds of formula (I) are prepared from amino-lactam intermediates, such as compounds of formula (Π). The intermediates of formula (II) may be prepared by various methods.

The benzofused lactam derivatives of formula (3), wherein the lactam forms a seven-membered ring, are preferably prepared from the substituted tetralone derivatives of formula (2). Substituted tetralone derivatives are commercially available or may be prepared from the appropriately substituted 4-phenylbutyric acid derivatives of formula (1). The cyclization of the compound of formula (I) is carried out in the usual manner, for example with polyphosphoric acid at elevated temperature. The reaction is shown in Scheme 1.

The conversion of the substituted tetralone compound (2) to the benzolactam derivative (3) is carried out in a conventional manner. For example, the substituted benzolactam derivatives of formula (3) may be formed with hydrogen azide (Schmidt or Curtius reaction).

Benzofused lactam derivatives (Formula 6) containing an eight membered ring can be prepared by D. H. Jones

J. Chem. Soc. C., 2176-2181 (1969), by a series of analogous transformations starting from a substituted 5-phenylpentanoic acid derivative of formula (4) (Scheme 2).

As shown in Scheme 3, the six-membered analogue 3-aminobenzolactam derivatives (Formula 11) can be prepared from the appropriately substituted 2-nitrobenzyl chloride or bromide derivative of Formula 7 AL Davis et al. : Arch. Biochem. Biophys. 102.48-51 (1963).

Conversion of substituted benzofused lactam derivatives to the desired 3-amino derivative can be accomplished by a number of known methods. As an example, the methods described by Watthey et al., 1985, J. Med. Chem. 28, 1511-1516 and the literature cited therein. Generally, a suitable 3-halogen derivative, such as a chlorine, bromine or iodine derivative, is first prepared and then the halogen atom is replaced by a nucleophilic reagent, preferably azide. For example, the 3-iodobenzolactam derivative of formula (12) can be prepared by reacting the corresponding benzolactam derivative with two equivalents of iodomethylsilane and iodine at low temperature. The reaction for the lactam derivative containing a seven membered ring is shown in Scheme 4, which is analogous to Scheme 3.

The iodobenzolactam derivative can be converted to the desired amino-lactam derivative of formula II by a two-step process (Scheme 4). In general, the iodobenzolactam derivative (12) is reacted with sodium azide in N, N-dimethylformamide at a temperature of 50-100 ° C to give the 3-azido derivative (13). Alternatively, tetramethylguanidinium azide may be used as a solvent in methylene chloride. Hydrogenation on a metal catalyst such as platinum on carbon or treatment with triphenylphosphine in wet toluene affords the amine (14). The analogous benzolactam derivatives containing the eight membered ring can also be prepared as shown in Scheme 4.

The racemate is resolved by conventional methods for the preparation of a chiral aminobenzolactam derivative. For example, resolution can be accomplished by forming diastereomeric salts of the racemic amine derivative with optically active acids such as D- and L-tartaric acid. Absolute stereochemistry can be determined by various methods, including, for example, X-ray analysis of the corresponding crystalline derivative.

Scheme 5 illustrates the preparation of the chiral intermediate (19). This involves converting 1-tetralone via oxime (15) to a seven-membered benzolactam (16) via Beckman rearrangement. This is treated with iodine and hexamethyldisilazane to give the 3-iodo derivative (17) which, after recrystallization with ammonia and D-tartaric acid, is converted to the diastereomer D-tartaric acid salt (18). The free amine of formula (19) is liberated from the D-tartaric acid salt by neutralization with potassium carbonate and isolation by extraction.

Intermediates of formula (II) wherein X is sulfur may be prepared by methods known in the art. In the example of an analog with a seven membered ring, the reaction is illustrated in Scheme 6, where 27 is prepared from the protected cysteine derivative 21 according to Slade et al., J. Med. Chem. 28, 1517-1521 (1985). In Scheme 6, CBz is a benzyloxycarbonyl group.

The sulfoxide and sulfone intermediates of formula (28) and (29) may be prepared by oxidizing the compound of formula (24) with various oxidizing agents such as sodium periodate or methachloroperbenzoic acid. The intermediate intermediates of formula (II) wherein X is sulfur and contain an eight membered ring can be prepared analogously from a homocysteine derivative.

Compounds of formula (II) wherein X is oxygen may be prepared by methods described in the literature. As an example, the process of Scheme 7 wherein a seven-membered ring analogous to Formula 26 is prepared from a substituted 3- (2-nitrophenoxy) propanoic acid derivative of Formula 30 J. Ott: Arch. Pharm. (Weinheim, Germany) 323 (9), 601-603 (1990).

Analogous compounds of formula (33) wherein X is oxygen and have a six membered ring can be prepared by the reaction of a substituted 2-aminophenol derivative of formula (32) with chloroacetyl chloride (Huang and Chan, Synthesis 10, 851 (1984)). according to. An amino group is then introduced into the 3-position of 31 or 33 as depicted in Scheme 4.

Compounds of formula (II) wherein X is carbonyl and contain a seven membered ring can be prepared from tryptophan derivatives according to Australian J. Chem. 33, 633-640 (1980). Compounds of formula (II) wherein X is -CH = CH- and have a seven membered ring can be prepared from the above-mentioned analogs having X as carbonyl. Reaction of 34 with a chemical reducing agent such as sodium borohydride in a polar solvent such as methanol or ethanol affords the secondary alcohol derivative 35 (X is -CH (OH) -).

Compounds of formula (35) may be dehydrated in a conventional manner. For example, compound (35) in an inert solvent such as benzene is converted to an analogue (36) which is unsaturated with a strong acid such as p-toluenesulfonic acid.

They can be converted to the novel compounds of formula (III) substituted at the amino group of the compounds of formula (II). Reductive alkylation of the compounds of formula (II) is carried out in the customary manner with aldehyde, for example by catalytic hydrogenation in the presence of hydrogen and platinum, palladium or nickel, or by chemical reducing agents such as sodium cyanohydrochloride in a solvent such as methanol or ethanol.

Scheme 10 illustrates the attachment of the amino acid side chain to the intermediate (III). The coupling is preferably realized

With a suitably protected amino acid derivative, such as a compound of formula IV, wherein the coupling agent is, for example, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) in an inert solvent such as methylene chloride. . Separation of the unwanted by-products and purification of the intermediates is carried out by chromatography on silica gel, for example, by flash chromatography [W. C. Still,

M. Kahn and A. Mitra, J. Org. Chem. 43, 2923 (1978)] or medium pressure liquid chromatography.

A10. in Scheme G, G is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBz). Protected amino acid derivatives of formula (IV) containing such a group are generally commercially available. Preferably, the side chain is the preferred compound of formula (41). showing the reaction scheme. Accordingly, N-chlorosulfonyl isocyanate (37) is reacted with isobutylene in diethyl ether. From the resulting azetidinone (38), the chlorosulfonyl group is removed with aqueous sodium sulfite and the BOC protected intermediate (40) is formed with di-tert-butyl dicarbonate. This can be converted to the protected amino acid derivative (41) in good yield by alkaline hydrolysis.

The preparation of intermediates of formula (VII) is illustrated in Scheme 12. Accordingly, the corresponding lactam derivative of formula (V) is reacted with an alkylating agent of formula (VI):

Y is a leaving group such as chlorine, bromine or iodine, O-methanesulfonyl or O-p-toluenesulfonyl,

G is tert-butoxycarbonyl or benzyloxycarbonyl.

Alkylation of the compound of formula (V) is preferably carried out in anhydrous dimethylformamide (DMF) in the presence of a base such as sodium hydride or potassium tert-butoxide for 0.5-24 hours at a temperature of 20-100 ° C. During alkylation, certain substituents on the alkylating agent of formula (VI) may be optionally protected. Suitable protecting groups include those listed in Protecuve Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons, New York (1981).

The alkylating agents of formula VI are commercially available or can be prepared by methods known in the art.

Compounds of formula (I) wherein R ^3a or R ^3b is attached via a nitrogen atom to the phenyl ring may be prepared from starting materials of formula (42) and R ^3a or R ^{3b are} nitro which are Scheme 13 is obtained by alkylation with a compound of formula VI.

Preferred alkylating agents are the compounds of formula (46), the preparation of which is illustrated in Scheme 14. Accordingly, 4-tolylboronic acid (43) is reacted with 2-bromo-nitrobenzene (44) in the presence of a transition metal catalyst, such as tetrakis (triphenylphosphine) palladium, in a solvent consisting of aqueous sodium hydroxide, water, 2-propanol and benzene at hours to give 45 in good yield. Preferably, the unwanted by-products are chromatographed on silica gel, eluting with standard organic solvents such as hexane, ethyl acetate, and methylene chloride. The compound of formula (45) is converted to the bromide derivative of formula (46) by heating with N-bromosuccinimide in carbon tetrachloride in the presence of a radical initiator such as benzoyl peroxide or 2,2'-azobis (isobutyronitrile) (AIBN).

As shown in Scheme 15, the nitro group of the compounds of Formula 42 is reduced by hydrogenation in the presence of a metal catalyst such as palladium on carbon in a protic solvent such as methanol or ethanol. It will be apparent to those skilled in the art that, for derivatives where the existing functional groups do not permit catalytic hydrogenation, the reduction may alternatively be effected, for example, with tin chloride in an acidic medium. It is further noted that the intermediate protecting group G uses a protecting group G which is compatible with the experimental conditions chosen for the reduction, such as the intermediate 42 containing G in place of t-butoxycarbonyl (BOC) under catalytic reduction conditions. . The intermediates of formula (47) can be converted to a new intermediate of formula (48) by reductive alkylation with aldehyde by the above procedures.

Compounds of formula (47) can be converted to the carbamate derivative (49) with the appropriate chloroformate reagent in pyridine or methylene chloride to form the carbamate derivative (49).

The amine intermediates of formula (47) can be converted to the corresponding urea derivatives by various methods. Terminally disubstituted compound is obtained by reacting compound (47) directly with disubstituted carbamoyl chloride (50) in an inert solvent such as methylene chloride in the presence of triethylamine or 4-dimethylaminopyridine. Additionally, a monosubstituted compound of formula (53) is obtained wherein R ^4b or R ^12a is hydrogen when reacted with compound (47) with isocyanate (52). The reactions are shown in Scheme 17. The terminally unsubstituted urea derivative ^{R12b of} formula (61) is hydrogen, may be prepared by reacting the amine derivative of formula (56) with trimethylsilyl isocyanate, wherein ^{, in} formula (60) ^{, R2b} is a trimethylsilyl group. .

Alternatively, the amine derivative (47) can be converted to the isocyanate derivative (54) using phosgene or an equivalent reagent such as bis (trichloromethyl) carbonate triphosgene as shown in Scheme 18. The isocyanate derivative (54) can be converted with the primary or secondary amine in an inert solvent such as methylene chloride to the corresponding urea derivative (51). In addition, the isocyanate derivative of formula (54) is substituted with a hydrazine or hydroxy or alkoxyamine of formula (55).

The A9 can be converted to a carbazide derivative or a hydroxy or alkoxyurea derivative of formula (56).

Compounds of formula (I) wherein R ^3a or R ^3b is substituted on the phenyl by an oxygen atom or a carbamate derivative can be prepared from the acetophenone derivative (57) according to Scheme 19. The acetophenone derivative (57) is oxidatively rearranged using a peroxycarboxylic acid such as m-chloroperbenzoic acid (Baeyer-Villager reaction) to give the ester derivative (58), which is a strong base such as sodium hydroxide. or in the presence of lithium hydroxide, to hydrolyze the phenol compound (59). The phenol derivative (59) can be directly converted to the carbamate (60) with isocyanate. In addition, the phenol derivative (59) can be activated with Ν, Ν'-carbonyldiimidazole in dimethylformamide to convert the substituted hydrazine derivative (61) to the carbazate derivative (61).

The final product of formula (I) wherein R ⁴ is hydrogen is obtained from the intermediate of formula (VII) by simultaneous or sequential deprotection of Scheme 20.

For example, the benzyloxycarbonyl group can be removed by a number of known methods. Catalytic hydrogenation may be used in the presence of platinum or palladium catalysts in a protic solvent such as methanol. If catalytic hydrogenation is not possible due to the presence of other potentially reactive functional groups, the benzyloxycarbonyl group may be removed by addition of a solution of hydrobromic acid in acetic acid. The tert-butoxycarbonyl (BOC) group can be removed with a strong acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as methylene chloride or methanol. The conditions required for the removal of the other protecting groups are described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons, New York (1981).

Compounds of formula (I) wherein R ⁴ and R ^{5 are} hydrogen may be reductively alkylated with an aldehyde as described above or alkylated with various epoxides. The products obtained may be purified by reverse phase high performance liquid chromatography (HPLC) or by recrystallization in the form of the hydrochloride or trifluoroacetate salt.

Note that the order of the reactions described above is not critical and may be varied by those skilled in the art to accelerate the reaction or to avoid unwanted side reactions.

The growth hormone releasing compounds of formula (I) are useful in vitro for controlling the regulation of growth hormone secretion from the pituitary gland. They can also be used to study other factors that influence growth hormone secretion, such as age, gender, nutritional characteristics, glucose, amino acid, fatty acid, and fasting or non-fasting condition. In addition, the above compounds may be used to investigate how other hormones modify growth hormone release activity. For example, somatostatin has already been found to inhibit growth hormone release. Other important hormones to be tested for their effect on growth hormone release include the gonadal hormones such as testosterone, estradiol and progesterone, adrenal hormones such as cortisol and other corticoids, epinephrine and norepinephrine, pancreas and gastrointestinal, insulin, glucagon, gastrin and secretin, vasoactive intestinal peptides such as bombesin, and thyroid hormones such as thyroxine and triiodothyronine. The compounds of formula (I) may also be used to test for possible negative or positive feedback of certain pituitary hormones, such as growth hormone and endorphm peptides, to modify growth hormone release. The above compounds are particularly useful for studying the subcellular mechanisms that influence growth hormone release.

In addition, the compounds of formula I can be administered to humans and animals to induce growth hormone release in vivo. The compounds may be administered, for example, to domestic animals such as pigs, cattle, and sheep to accelerate and enhance physical growth and enhance milk production. In addition, these compounds may be used in vivo as a diagnostic agent to assess the growth hormone production capacity of the pituitary gland. In particular, the compounds of formula (I) may also be administered to in vivo children. Serum samples taken before and after dosing can be assayed for growth hormone levels. By comparing the results obtained, the ability of the patient's pituitary gland to produce growth hormone can be determined.

Accordingly, the present invention provides pharmaceutical compositions comprising as active ingredient at least one compound of formula I in association with a pharmaceutical carrier or diluent. In addition to the compounds of formula (I), the pharmaceutical composition may optionally contain a growth promoter or other active ingredient, such as an antibiotic.

Suitable growth promoters are, for example, TRH, diethylstilesterol, theophylline, enkephalin, prostaglandin. These derivatives are the compounds disclosed in US 3,239,345, such as zeranol, the compounds disclosed in US 4,036,979, such as sulbenox, and the peptide derivatives disclosed in US 4,411,890.

The compounds of formula (I) may also be combined with other agents that influence growth hormone secretion, such as, for example, GHRP-6, GHRP-1 and GHRP-2, US 4,411,890, WO 89/07110 and WO 89/07111. ) as well as BHt 920, growth hormone releasing factors and ana11

A9 analogs and growth hormone and its analogs or somatomedins such as IGF-1 and IGF-2.

It is well known to those skilled in the art that growth hormone has various known and potential effects. Accordingly, the compounds of the present invention can be used to stimulate endogenous growth hormone release in the same way as growth hormone itself. Examples of such uses include stimulation of growth hormone release in the elderly, inhibition of the catabolic side effect of glucocorticoids, treatment of osteoporosis, stimulation of the immune system, treatment of retardation, acceleration of wound healing, acceleration of the healing and progression of , treatment of a physiological small space, such as growth hormone deficient children or a small space associated with a chronic disease, treatment of obesity and associated reduced growth, treatment of reduced growth associated with Prader-Willis syndrome and Turner syndrome, accelerated burn healing, delayed intrauterine growth, treatment of bone growth disorder, hypercortisolism, and Cushing's syndrome, variable growth hormone release induction of growth hormone replacement, growth hormone replacement in stress patients, eccentric osteochondrodystrophy, noonan's syndrome, schizophrenia, depression, treatment of Alzheimer's disease, delayed wound healing and psychosocial deficits, treatment of respiratory distress and disorders, severe cataract, reduction of cancer and AIDS-related deterioration and protein loss; treatment of increased insulin levels such as neidioblastosis; metabolic homeostasis and maintenance of renal haemostasis in elderly patients with impaired bone formation, bone formation and cartilage stimulation of growth, stimulation of the immune system in companion animals, and treatment of companion-aging disorders, acceleration of weight gain in domestic animals and stimulation of wool production in sheep.

The compounds of the invention may be administered orally, parenterally, for example, intramuscularly, intraperitoneally, intravenously, subcutaneously by injection or implant, nasally, vaginally, rectally, sublingually or topically, and may be formulated as appropriate to the mode of administration.

Examples of solid compositions suitable for oral administration include capsules, tablets, pills, powders, and granules. For preparing such solid compositions, the active ingredient is admixed with at least one inert pharmaceutical carrier such as sucrose, lactose or starch. Such formulations further comprise conventional pharmaceutical excipients. Examples include lubricants such as magnesium stearate and, for capsules, tablets and pills, buffering agents. The tablets and pills may be coated, if desired, with an enteric coating.

Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs, which contain the usual pharmaceutical diluents, such as water. Other components include wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

For parenteral administration, sterile aqueous and non-aqueous solutions, suspensions and emulsions may be used. Non-aqueous solvents or carriers include, for example, propylene glycol, polyethylene glycol, a vegetable oil such as olive oil or corn oil, gelatin, and an injectable organic ester such as ethyl oleate. Examples of excipients for use in such formulations include preservatives, wetting agents, emulsifying agents and dispersing agents. Sterilization of such compositions may be accomplished, for example, by filtration through a bacterial retention filter, the use of a sterilizing agent, irradiation or heating. Alternatively, sterile solid compositions may be formulated for injection with sterile water or other sterile medium immediately prior to use.

Suppositories may be used for rectal or vaginal administration which may contain, for example, cocoa butter or suppository wax as carriers, in addition to the active ingredient.

Formulations suitable for nasal or sublingual administration are prepared with the usual additives.

The dosage of the active ingredient in the composition of the invention may be varied within wide limits and will be adjusted according to the dosage form chosen. The dose will also depend on the therapeutic effect desired, the route of administration and the duration of treatment. The daily dose is generally 0.0001-100 mg / kg body weight, which effectively promotes the release of growth hormone in humans and animals.

The present invention will be further illustrated by the following examples, without limiting the scope thereof to the examples.

/. Example 1 '- [(Methoxycarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-3 ( R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The step is 1-Tetralone oxime

In a four-necked 50 L flask equipped with a stirrer, a thermometer and a reflux condenser, 3.72 kg (27.36 mol) of sodium acetate was added to 4.6 L of water over a steam bath with stirring. Then 1.9 kg

A9 (27.36 mol) of hydroxylamine hydrochloride was added. To the suspension was added 12 liters of ethanol at room temperature followed by 1.994 kg (13.68 moles) of 1-tetralone. The addition funnel was rinsed with an additional 1.7 L of ethanol. The resulting pale orange slurry was heated to 75 ° C for 40 minutes and maintained at 75-85 ° C for a further 75 minutes. The reaction mixture was then cooled by external ice cooling and, after reaching an internal temperature of 32 ° C, was pumped into a 200 liter vessel containing 60 liters of ice in 15 minutes. The reaction vessel was rinsed with additional 2 L of water to a 200 L vessel. After melting the ice, the mixture was filtered and the wet filtrate was washed with water (4 L). It was then dried under a water jet vacuum for 1 hour, then divided into two trays and further dried under vacuum at 40 ° C for 2 days. 2.094 kg (13.01 mol, 95%) of product are obtained.

1 H-NMR (250 MHz, CDCl ₃ ): δ = 1.90 (m, 2H), 2.80 (t, 6 Hz, 2H), 2.88 (t, 6 Hz, 2H), 7.15 -7.35 (m, 3H),

7.90 (d, 8 Hz, 1H), 8.9 (brs, 1H).

Step B.

2,3,4,5-Tetrahydro-lH-l-benzazepin-2-one

In a three-necked 22 L flask fitted with a stirrer, a thermometer, a nitrogen inlet and a reflux condenser was added 2.6 kg (18.61 mol) of phosphorus pentoxide to 10 L of methanesulfonic acid. The remainder of the phosphorus pentoxide was rinsed with an additional 1.6 L of methanesulfonic acid into the reaction vessel. The mixture was heated at 90 ° C for 2.5 hours, cooled to 50 ° C in an ice bath, and 2.00 kg (12.41 mole) of 1-tetralone oxime was added in portions over 15 minutes. The mixture was heated at 63 ° C for 10 minutes, then slowly warmed to 80 ° C and maintained at this temperature for 3 hours. It is then pumped onto 70 L of ice and mixed with 11.25 L of 50% w / w aqueous sodium hydroxide over 90 minutes at a rate such that the temperature remains below 28 ° C. The mixture was then filtered and the reaction vessel was rinsed with 4 L of filtrate. The wet pink material was washed with 8 liters of water and dried in a water jet vacuum for 45 minutes. It was then divided into two trays and further dried under vacuum at 40 ° C for 2 days. 1.9 kg (11.79 mol, 95%) of product are obtained.

1 H-NMR (250 MHz, CDCl ₃ ): δ = 2.24 (m, 2H), 2.38 (t, 6 Hz, 2H), 2.82 (t, 6 Hz, 2H), 7.03 (d, 8 Hz, 1H),

7.13 (m, 1H), 7.24 (m, 2H), 8.63 (brs, 1H).

Step C

3-Iodo-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one

1.8 kg (11.17 mol) of 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 22.33 liters of methylene chloride and 11.78 liters (55.83 mol) of hexamethyldisilazane The mixture was stirred at reflux for 10 minutes and then cooled to 30 ° C and treated with 8.503 kg (33.5 moles) of iodine in one portion. The reaction mixture was refluxed for 2.5 hours and then cooled to room temperature. A solution of 4.926 kg of sodium sulfite in 44 liters of water is cooled to 0 ° C and the above reaction mixture is added in portions under vigorous stirring at a temperature below 10 ° C. The reaction vessel was rinsed with methylene chloride (22.33 L) and the wash was poured onto the above mixture. The mixture is stirred vigorously and the phases are allowed to separate. The aqueous phase was removed and extracted with methylene chloride (22.33 L). The combined organic phases are washed with 11 L of water and concentrated in vacuo to a volume of about 5 L. The residue was mixed with 55 L of loluene and concentrated in vacuo to 10 L. The resulting slurry was filtered, the filtrate washed with additional toluene (5 L) and dried in vacuo at room temperature for 24 hours. 1.842 kg (6.42 mol, 57%) of product are obtained.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 2.6-2.8 (m, 3H),

2.93 (m, 1H), 4.64 (t, 8 Hz, 1H), 6.97 (d, 8 Hz, 1H),

7.10-7.35 (m, 3H), 7.55 (br s, 1H).

Step D.

3 (R) -amino-2,3,4,5-tetrahdiro-] H -] - benzazepin-2-one, D-tartaric acid salt

1.79 kg (6.24 mol) of 3-iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one are suspended in 6.2 L of methanol and the suspension is placed in an autoclave. 1.55 L of condensed ammonia are added, the autoclave is sealed and heated to 100 ° C for 1 hour with stirring. After 2 hours at this temperature, the reaction was allowed to cool to room temperature over 1 hour with an internal pressure of 1033-1067 kPa. The reaction mixture was poured into a polyethylene vessel and the autoclave was rinsed twice with 8 L of methanol. The washings were concentrated in vacuo at 30 ° C and then added to the reaction mixture. The reaction mixture was evaporated to near dryness in vacuo at 30 ° C, then the residue was dissolved in ethyl acetate (4 L) and evaporated to dryness in vacuo at 30 ° C.

712 g of sodium chloride are dissolved in 2 liters of water and 1.0 kg of sodium carbonate are dissolved in 6 liters of water. Two liters of sodium carbonate solution were added to the concentrated residue and the resulting suspension was transferred to an extraction vessel. An additional 2 liters of sodium carbonate solution was added to the residue and the solution was transferred to the extraction vessel. The remaining sodium carbonate solution was used in a similar manner. The sodium chloride solution was added to the sodium carbonate / aminolactam emulsion and the resulting mixture was stirred for 10 minutes. It is then extracted four times with 6 liters of methylene chloride. The combined methylene chloride phases are evaporated to dryness, the residue is diluted with 2 L of ethanol and the suspension is evaporated to dryness in vacuo to give 1.171 kg of crude product.

The crude product is suspended in 8 L of ethanol and mixed with 900 kg of D-tartaric acid in one portion. Water (7 L) was added, the mixture was heated to 77 ° C, diluted with an additional 45 L of ethanol and further heated. It is then cooled to 43 ° C and treated with rennet slurry (prepared as described above from 10.50 g of crude product and 9.1 g of D-tartaric acid). The solution was left at room temperature for 48 hours13

HU 211 894 A9

The slurry was filtered, the wet material was washed with ethanol (1.8 L), dried in a nitrogen atmosphere and under a water jet vacuum for 20 hours and then dried in a drying tray under vacuum for 24 hours. 354 g (1.085 mol, 17.4%) of product are obtained.

1 H-NMR (250 MHz, CDCl ₃ ): δ = 2.13 (m, 1H), 2.51 (m, 2H), 2.73 (m, 2H), 3.68 (t, 6 Hz) 1H), 3.98 (s,

2H), 7.05 (d, 8 Hz, 1H), 7.16 (t, 8 Hz, 1H), 7.30 (m,

2H), 7.6 (br s, 5H), 10.26 (br s, 1H).

This step

3 (R) -amino-2,3,4,5-tetrahydro-lH -] - benzazepin-2-one

To a solution of 229.23 g (0.700 mol) of 3 (R) -amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one-D-tartaric acid salt in 4 liters of water, 194 g (1, 40 moles of potassium carbonate are added. A further 100 g and 135 g of potassium carbonate are then added to adjust the pH to 10.5. The mixture was extracted with methylene chloride (4 x 4 L) and the combined organic phases were dried over magnesium sulfate. The aqueous phase was treated with 1.4 kg of sodium chloride and extracted four times with 4 liters of methylene chloride. The combined extracts were dried over magnesium sulfate. The combined extracts (2 x 16 L) were filtered and evaporated to dryness in vacuo. 115.5 g of product are obtained, containing 1.6% by weight of impurities. This was found to be 7-iodo-3 (R) -amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one.

A solution of 107.02 g (0.607 mol) of the above intermediate in 1.712 L of ethanol is hydrogenated at room temperature and 276 kPa (4.00 g) in 10% palladium on carbon for 4 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo to give 101.08 g (0.574 mol, 94.4%) of product.

Step F

4,4-Dimethyl-azetidin-2-one

In a three-liter round-bottomed flask equipped with a magnetic stirrer, a thermometer, a plunger condenser and a nitrogen inlet, 1 liter of ether was charged. The flask was cooled to -65 C and 500-600 mL of isobutylene was condensed. The protruding condenser was replaced with a dropping funnel and chlorosulfonyl isocyanate (200 mL, 325 g, 2.30 mol) was added dropwise over 1.5 h. thereafter

After 1.5 hours at -65 ° C, the dry ice / acetone cooling bath was changed to methanol / ice bath and the internal temperature was allowed to slowly rise to -5 ° C. During this time, the reaction begins, the internal temperature rises to 15 ° C, and gas evolution is observed. The internal temperature was maintained at 15 'C for several minutes, then lowered again to -5' C, and the mixture was stirred at this temperature for 1 hour. The methanol / ice bath was removed and the reaction mixture was warmed to room temperature and stirred overnight.

The reaction mixture was transferred to a 12-neck round bottom flask equipped with a mechanical stirrer and diluted with 2 liters of ether. After stirring vigorously with 2 L of a saturated aqueous sodium sulfite solution, after 1 hour, a further 1 L of a saturated aqueous sodium sulfite solution is added and finally adjusted to about pH 7 with sodium bicarbonate. The mixture was stirred for an additional 30 minutes and then the phases were allowed to separate. The ethereal phase is removed and the aqueous phase is extracted twice with 1 liter of ether. The combined ethereal extracts were washed once with 500 mL of saturated aqueous sodium carbonate solution and once with 500 mL of saturated aqueous sodium chloride solution. The ethereal layer was removed, dried over magnesium sulfate, filtered and concentrated in vacuo. 33 g of a pale yellow oil are obtained. The aqueous phase was made basic with solid sodium bicarbonate and extracted three times with 1 liter of ether. The combined ethereal phases are washed and dried as described above, then combined with the original 33 g of a pale yellow oil and concentrated in vacuo. 67.7 g of product are obtained. The aqueous phase was further extracted with methylene chloride (4 x 1 L) and washed and dried as described above. An additional 74.1 g of product is obtained. The aqueous phase was re-extracted with 4 L of methylene chloride to give an additional 21.9 g of product. The combined product (163.7 g, 1.65 mol, 72%) was used in Step G without further purification.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.45 (s, 6H), 2.75 (d, 3 Hz, 2H), 5.9 (brs, 1H).

Step G

N- (t-Butoxycarbonyl) -4,4-dimethyl-azetidin-2-one In a 5 L three-necked round bottom flask with magnetic stirrer, thermometer, nitrogen inlet and addition funnel, 88.2 g (0.89 mol) of 4,4-dimethyl azetidin-2-one (step F), 800 mL of methylene chloride, 150 mL (1.08 mole) of triethylamine and 10.9 g (0.089 mole) of 4-dimethylaminopyridine. A solution of 235 g (1.077 mol) of di-tert-butyl dicarbonate in 300 ml of methylene chloride is added dropwise with stirring at room temperature for 15 minutes. After stirring overnight at room temperature, the reaction mixture was diluted with 1 L of methylene chloride and washed with 500 mL of saturated aqueous ammonium chloride solution, 500 mL of water and 500 mL of saturated aqueous sodium chloride solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. 180.3 g of crude product are obtained in the form of an orange solid which can be used in Step H without further purification.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.50 (s, 9H), 1.54 (s, 6H), 2.77 (s, 2H).

Step H

3-t-Butoxycarbonylamino-3-methylbutanoic acid In a three-liter round-bottomed flask fitted with a magnetic stirrer, thermometer, nitrogen inlet and addition funnel, 180.3 g (0.89 mole) of N- (t-butoxycarbonyl) -4 A solution of 4-dimethyl-azetidin-2-one in 1 liter of tetrahydrofuran is charged. The solution was cooled to 0-5 ° C and 890 mL of 1.0 M aqueous lithium hydroxide solution was added dropwise over 30 minutes. The reaction mixture is stirred for 2 hours at 0-5 ° C and then diluted with 1 liter of ether and 1 liter of water. The phases are allowed to separate, and

The aqueous phase was extracted with additional 1 liter of ether. The aqueous phase was acidified with 1 L of saturated aqueous sodium hydrogen sulfate solution and extracted with ether (1 L, then 500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried over magnesium sulfate and evaporated in vacuo. 173 g of a yellow oil are obtained which solidifies on standing. This material was taken up in warm hexane, filtered and dried under high vacuum. so

168.5 g (0.775 mol, 87%) of product are obtained in the form of a white solid.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.39 (s, 6H), 1.44 (s,

9H), 2.72 (s, 2H).

FAB-MS calculated for C ₁₀ H ₁₉ NO ₄ 217, found 218 (M + M, 54%).

Step I

3-t-Butoxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -butanamide

Of a solution of 8.70 g (49.4 mmol) of 3 (R) -amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one (Step E) in 100 mL of methylene chloride. 73 g (49.4 mmol)

3-t-Butoxycarbonylamino-3-methylbutanoic acid (Step H) and triethylamine (13.8 mL, 10.0 g, 99 mmol, 2 equiv.) Were added. The reaction flask was immersed in a water bath at room temperature and then treated in one portion with 26 g (59 mmol,

Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.2 equivalents) was added and stirred for 2 hours at room temperature. It was then diluted with 300 ml of ethyl acetate and washed three times with 5% aqueous citric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was removed, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative high pressure liquid chromatography on silica gel eluting with ethyl acetate / hexane (4: 1). 17.42 g (46.4 mmol, 94%) of product are obtained in the form of a white solid.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.37 (s, 6H), 1.44 (s,

9H), 1.95 (m, 1H), 2.46 (d, 15 Hz, 1H), 2.59 (d, 15

Hz, 1H), 2.6-3.0 (m, 3H), 4.53 (m, 1H), 5.30 (br s,

1H), 6.72 (d, 7Hz, 1H), 6.98 (d, 8Hz, 1H), 7.1-7.3 (m, 3H), 7.82 (brs, 1H).

FAB-MS for C ₂₀ H ₂₉ N ₃ O ₄ 375, found 376 (M + M, 70%).

Step J

4-Methyl-2'-nitro-1,1'-biphenyl g (0.25 mol) 4-tolylboronic acid and 34 g (0.168 mol) 2-bromo-1-nitrobenzene in 170 ml 5N sodium hydroxide solution in 57 ml water To a mixture of isopropanol (215 ml) and benzene (1080 ml) was added tetrakis (triphenylphosphine) palladium (11.9 g) under vigorous stirring and under nitrogen. The stirred biphasic reaction mixture was refluxed for 3 hours, cooled, filtered through celite and the filtrate washed with fresh benzene. The organic layer was separated, washed three times with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue (46.1 g) was purified by preparative HPLC on silica gel eluting with 20: 1 hexane / ethyl acetate. 28.05 g of product are obtained.

EI-MS calculated for C ₁₃ H ₁₁ NO ₂ 213, found 213 (M ⁺ ).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 2.38 (s, 3H), 7.20 (m, 4H), 7.34 (m, 2H), 7.59 (t, 1H), 7.8 (d, 1H).

Step K

4-Bromomethyl-2 '-nitro-1,1' -biphenyl

6.0 g (28.2 mmol) of 4-methyl-2'-nitro-1,1'-biphenyl (Step J), 4.99 g (28.2 mmol) of N-bromosuccinimide and 653 mg of AIBN in 75 mL solution of carbon tetrachloride was refluxed until a negative potassium iodide test (1.5 hours). The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo to give 8.41 g of crude product. According to α-NMR, the product contains about 75% by weight of a monobromo derivative and 10% by weight of a dibromo derivative with 15% by weight of unreacted starting material.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, 1H).

EI-MS C ₁₄ H ₁₀ BrN 272, found 272, 274 (M ⁺ ).

Step L

4-Hydroxymethyl-2 '-nitro-1,1'-biphenyl

To a solution of 4-bromomethyl-2'-nitro-1,1'-biphenyl (7.27 g, 24.8 mmol) in acetic acid (50 mL) was added potassium acetate (4.88 g, 49.1 mmol). The reaction mixture was refluxed for 2 hours, then cooled, filtered and the precipitate washed twice with acetic acid. The filtrate was concentrated in vacuo and the residue was triturated with ethyl ether. The ether phase was washed successively with water, three times with saturated aqueous sodium bicarbonate solution and with water. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methanol (50 mL) and treated with 6N potassium hydroxide solution in methanol (5 mL), whereupon starting material was no longer detectable by thin layer chromatography. The reaction mixture was acidified with acetic acid and concentrated in vacuo. The residue was dissolved in ether and the solution was washed with an aqueous solution of sodium bicarbonate and water to remove acetic acid. It was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by preparative high pressure liquid chromatography on silica gel eluting with hexane / ethyl acetate 3: 1. 620 mg of 2'-nitro-1,1'-biphenyl-4-carboxaldehyde are obtained, followed by 3.06 g (13.4 mmol, 54%) of 4-hydroxymethyl-2'-nitro-1,1'-biphenyl.

Step M

4- (Tetrahydro-pyranyloxy) methyl-2'-nitro-1,1'-biphenyl 3.06 g (13.4 mmol) of 4-hydroxymethyl-2'-nitro-1,1'-biphenyl and To a solution of 3,4-dihydropyran (1.8 mL, 20.1 mmol) in methylene chloride (50 mL) was added pyridinium p-toluenesulfonate (336 mg, 1.34 mmol) under nitrogen. After stirring for 3 hours at room temperature, thin layer chromatography was used as starting material.

EN 211 894 A9 is no longer detectable. The reaction mixture was diluted with ethyl ether (300 mL), and the ether layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was purified by preparative high pressure liquid chromatography on silica gel (hexane: ethyl acetate = 10: 1). 4.47 g of product are obtained.

Step N

4- (Tetrahydro-pyranyloxy) -methyl-2 '-amino-1,1' -biphenyl

A solution of 4.12 g (13.2 mmol) of 4- (tetrahydropyranyloxy) methyl 2'-nitro-1,1'-biphenyl in 100 ml of methanol was hydrogenated at 5 psi with 5% palladium on carbon catalyst. Hydrogen uptake is complete within 2 hours. The reaction mixture was filtered over diatomaceous earth, the filtrate washed with methanol and the filtrate evaporated in vacuo. 3.57 g of product are obtained.

Step O

4-Hydroxymethyl-2 '- (methoxycarbonyl) amino-1,1' biphenyl

To a solution of 500 mg (1.76 mmol) of tetrahydropyranyloxy-methyl-2-amino-1,1'-biphenyl in 6 mL of pyridine was added 0.41 mL (5.3 mmol) of methyl chloroformate. The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The residue was taken up in ethyl ether and washed three times with water. The ether layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. This gives 547 mg of crude 4- (tetrahydropyranyloxy) methyl-2 '- (methoxycarbonyl) amino-1,1' -biphenyl.

To a solution of 250 mg of crude 4- (tetrahydropyranyloxy) methyl-2 '- (methoxycarbonyl) amino-1,1-biphenyl in 4 ml of methanol is added 1 ml of 10% p-toluenesulfonic acid in methanol. . After stirring for 1 hour at room temperature, the reaction mixture was basified with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with methylene chloride / methanol 100: 3 to give 137 mg of product.

FAB-MS (Li ⁺⁾ _C] H ₁₅ NO ₅ calculated from ₃ to 257, found 264 (M + Li).

1 H-NMR (200 MHz, CDCl ₃ ): δ = 3.51 (s, 3H), 4.75 (s,

2H), 6.62 (br s, 1H), 7.14 (dd, 2H), 7.34 (dd, 1H),

7.4 (dd, 4H).

Step P

4-Bromomethyl-2 '- (methoxycarbonyl) amino-1,1'-biphenyl

To a solution of 239 mg (0.93 mmol) of 4-hydroxymethyl-2 '- (methoxycarbonyl) amino-1,1'-biphenyl in 4 mL of methylene chloride was added 3.0 mL (22.7 mmol) of bromo-trimethyl- silane was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with additional methylene chloride and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with methylene chloride / methanol (100: 3). 190 mg of product are obtained.

Step Q.

N- [1 - [[2 '- [(Methoxycarbonyl) amino} [1,1'-biphenyl) 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 hl-benzazepin-3 (R) -yl] -3t-butoxycarbonyl-amino-3-methylbutanamide

222 mg (0.594 mmol) of 3-t-butoxycarbonylamino-3-methyl-N- (2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl) -butanamide (I Step 6) To a solution of 6 mL of dry dimethylformamide was added 30 mg of a 60% w / w oily sodium hydride dispersion (18 mg of sodium hydride, 0.75 mmol, 1.3 equivalents). After stirring for 30 minutes at room temperature, solid 4-bromomethyl-2 '- (methoxycarbonyl) amino-1,1'-biphenyl (190 mg, 0.594 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and then with 50 ml of water. The organic layer was washed four times with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with methylene chloride / methanol (100: 3). 231 mg (0.376 mmol, 63%) of product are obtained.

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.23 (s, 3H), 1.33 (s,

3H), 1.39 (s, 9H), 1.85 (m, 1H), 2.40 (dd, 2H), 2.49 (m, 1H), 2.54 (m, 2H), 3, 68 (s, 3H), 4.53 (m, 1H),

4.94 (d, 1H), 5.17 (d, 1H), 6.53 (br s, 1H), 6.66 (d,

1H), 7.2 (m, 12H), 8.09 (d, 1H).

Step R

N- [l - [[2 '- [(methoxycarbonyl) -anüno] [l, r-bi.fenil] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo- -1-Benzazepine-3 (R) -yl-3-amino-3-methylbutanamide trifluoroacetate To a solution of Step Q (86 mg, 0.14 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (1.0 mL). After stirring for one hour at room temperature, the volatiles were removed in vacuo and the residue was purified by medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (60:40). The product-containing fractions were combined and the solvent removed in vacuo. The residue was lyophilized from water to give 69 mg (0.13 mmol, 96%) of the title compound as a white solid.

FAB-MS: C ₃₀ H ₃₄ N ₄ O ₄ 514, found 515 (M + M).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.39 (s, 3H), 2.12 (m, 1H), 2.31 (m, 1H) , 2.52 (dd, 2H),

2.6 (m, 2H), 3.54 (br s, 3H), 4.40 (dd, 1H), 5.02 (d,

1H), 5.28 (d, 1H), 7.30 (m, 12H), 7.54 (br s, 1H).

Example 2

N- [1 - [[2 '-1 (Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide acetate

The step

N- [1 - [[2'-Nitro) [1,1'-biphenyl] -4-yl] -methyl] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -amino3-methyl-butanamide

The title compound was obtained from 4-bromomethyl-2'-nitrol, 1'-biphenyl (Example 1, Step K) and 3-tert-butoxycarbonyl.

A9 is prepared from Bonylamino-3-methyl-N- (2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl) -butanamide (Example 1, Step I). as described in Example 1, Step Q. 1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 6H), 1.41 (s,

9H), 1.83 (m, 1H), 2.35-2.70 (m, 5H), 4.50 (m,

1H), 4.84 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 5.27 (s, 1H), 6.64 (d, 7 Hz, 1H), 7, 1-7.6 (m, 11H), 7.80 (d, 8 Hz, 1H).

FAB-MS C ₃₃ H ₃₈ N ₄ O ₆ 586, found 587 (M + M).

Step B.

N- [1 - [[2'-Amino) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-3 (R) - yl] -amino3-methyl-butanamide

A solution of 7.79 g (13.23 mmol) of the compound of Step A and 0.9 g of 5% palladium on carbon in 200 ml of methanol is hydrogenated at 276 kPa. After the uptake of hydrogen, the catalyst was filtered off with celite and the filtrate was concentrated in vacuo. 6.6 g (11.9 mmol, 90%) of product are obtained. FAB-MS: Calcd. For C ₃₃ H ₄ N ₄ O ₄ 556, found 557 (M + M).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.32 (s, 6H), 1.39 (s,

9H), 1.87 (m, 1H), 2.51 (dd, 1H), 2.59 (m, 1H),

4.51 (m, 1H), 4.89 (d, 1H), 5.15 (d, 1H), 5.32 (br s,

1H), 6.71 (d, 1H), 6.81 (s, 1H), 7.21 (m, 10H).

Step C

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-benzazepin-3 (R) -yl] -3-t-butoxycarbonyl-3-amino-3-methylbutanamide

To a solution of the compound of Step B (88.4 mg, 0.158 mmol) in methylene chloride (4 mL) was added methyl isocyanate (0.5 mL, 8.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours at which time no starting material was detected by thin layer chromatography. The reaction mixture was concentrated in vacuo and the residue was eluted on silica gel with ethyl acetate / n-hexane (3: 1). 66 mg (0.11 mmol, 68%) of product are obtained.

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.21 (s, 3H), 1.23 (s,

3H), 1.39 (s, 9H), 1.89 (m, 1H), 2.49 (dd, H), 2.60 (m, 2H), 2.69 (s, 3H), 4, 50 (m, 1H), 4.95 (d, 1H),

5.06 (d, 1H), 5.26 (br s, 1H), 6.24 (br s, 1H), 6.70 (d, 1H), 7.22 (m, 11H), 7.71 (d, 1H).

Step D.

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl) -4-yl] methyl] -2,3,4,5-tetrahydro-2- To a solution of oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (2 mg, 0.11 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour at which time no starting material was detected by TLC. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (60:40). The product-containing fractions were combined, concentrated in vacuo and the residue lyophilized from water. This gave 26 mg (0.051 mmol, 46%) of the title compound as a white solid.

FAB-MS: Calcd. For C ₃₀ H ₃₅ N ₅ O ₃ 536 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.37 (s, 3H), 2.13 (m, 1H), 2.39 (m, 1H) , 2.54 (dd, 1H),

2.63 (s, 3H), 3.29 (dd, 1H), 4.59 (d, 1H), 5.11 (d,

1H), 7.22 (m, 10H), 7.60 (d, 1H).

Example 3

N- [1 - [[2 '- [(Ethylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The step

N- [1 - [[2 '- [(Ethylaminocarbonyl) amino} [1,1'-biphenyl) -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide The title compound is N- [1 - [[(2'-amino) [1,1'-biphenyl] -4-yl] -methyl] -2,3,4,5-tetrahydro-2-oxo-1,1-benzazepin-3 (R) -yl] -3-tert-butoxycarbonylamino-3-methylbutanamide (Example 2B) Step 1) and prepared from ethyl isocyanate as described in Example 2, Step C.

Step B.

N- [1 - [[2 '- [(Ethylaminocarbonyl) amino] -1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide acetate

The title compound was prepared from the compound of Step A as described in Example 2, Step D. FAB-MS: C ₃₁ H ₃₇ N ₅ O ₃ 527, found 550 (M + Na).

1 H-NMR (2400 MHz, CD ₃ OD): δ = 1.04 (t, 3H), 1.34 (s,

3H), 1.38 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.52 (dd,

2H), 2.62 (m, 2H), 3.09 (q, 2H), 4.41 (dd, 1H), 5.01 (d,

1H), 5.24 (d, 1H), 7.24 (m, 1H), 7.60 (d, 1H).

Example 4

N- [1 - [[2 '- [(2-Piperylaminocarbonyl) amino] [1,1'biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-7β-1 benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The step

N- [1 - [[2 '- [(2-Propylaminocarbonyl) amino] [1,1'biphenyl] -4-yl] -methyl-J-2,3,4,5-tetrahydro-2 -oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide The title compound is N- [1 - [[(2'-amino] [1,1'-biphenyl]] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-tert-butoxycarbonylamino-3-methyl from t-butanamide (Example 2, Step B) and isopropyl isocyanate as described in Example 2, Step C. 1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.06 (d, 3H), 07 (d, 3H), 1.32 (s, 3H), 1.39 (s, 9H), 1.88 (m, 1H),

2.48 (dd, 1H), 2.50 (m, 1H), 2.62 (m, 2H), 3.80 (m,

1H), 4.52 (m, 1H), 3.98 (d, 1H), 5.10 (d, 1H), 5.28

HU 211 894 A9

/.

t (br s, 1H), 6.08 (br s, 1H), 6.68 (br s, 1H), 7.22 (m,

UH), 7.70 (d, 1H).

Step B.

N- [1 - [[2 '- [(2-Pmylaminocarbonyl) amino] [N, biphenyl) -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-benzazepin-3 (R) -yl) -3-amino-3-methylbutanamide acetate

The title compound was prepared from the compound of Step A as described in Example 2, Step D. FAB-MS ₃₂ H ₃₉ calculated for N ₅ O ₃ 541; found 541 (M ⁺ ).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.05 (dd, 6H),

1.34 (s, 3H), 1.37 (s, 3H), 2.5 (m, 1H), 2.34 (m,

1H), 2.5 (m, 1H), 2.64 (m, 2H), 3.73 (m, 1H), 4.41 (dd, 1H), 5.02 (d, 1H), δ, 24 (d, 1H), 7.3 (m, 12H),

7.63 (d, 1H).

Example 5

N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H -1-Benzazepin-3 (R) -yl) -3-amino-3-methylbutanamide trifluoroacetate

The step

N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] 4-U] methyl) -2,3,4,5-tetrahydro-2-oxo-1H -l-benzazepin-3 (R) -yl) -3-tert-butoxycarbonylamino-3-methylbutanamide

445 mg (0.80 mmol) of N- [1 - [[(2'-amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- of a solution of oxo-1 H -1-benzazepine-3 (R) -yl] -3-tert-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) in 3 mL of methylene chloride under nitrogen Trimethylsilyl isocyanate (4 ml, 29.5 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, concentrated in vacuo and purified on silica gel eluting with ethyl acetate / hexane (4: 1) to give 211 mg (0.35). mole, 44%) FAB-MS: Calcd for C 11 H 13 N 3 O 5 599, found 622 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.31 (s, 3H), 1.38 (s,

3H), 1.39 (s, 9H), 1.90 (m, 1H), 2.48 (dd, 2H), 2.60 (m, 2H), 4.48 (m, 1H), 4, 95 (d, 1H), 5.08 (d, 1H),

5.28 (br s, 1H), 6.66 (br s, 1H), 6.78 (d, 1H), 7.22 (m, 11H), 7.72 (d, 1H).

Step B '- [(Aminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl) -2,3,4,5-tetrahydro-2-oxo-1H-J-benzazepine-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound was prepared from the compound of Step A as described in Example 2, Step D. FAB-MS: C ₂₉ H ₃₃ N ₅ O ₃ 499, found 500 (M + M).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.37 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H) , 2.50 (dd, 1H),

2.65 (m, 2H), 4.42 (dd, 1H), 4.42 (dd, 1H), 5.02 (d,

1H), 5.25 (d, 1H), 7.27 (m, 10H), 7.60 (d, 1H).

Example 6

N- [1 - [[2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl) methyl] -2,3,4,5-tetrahydro-2-oxo 1H-Benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The step

N- [1- (1- (2'-Isocyanato)) 1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-3 (R) -yl] -3-amino-3-methylbutanamide

2.0 g (3.6 mmol) of N- [1 - [[(2'-amino) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2 -oxo-1β-1-benzazepin-3 (R) yl] -3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and 2.0 mL (14 mmol) of triethylamine A solution of 40 ml of methylene chloride was cooled to -10 ° C under nitrogen and mixed in one portion with triphosgene (2.12 g, 7.15 mmol). An exotherm begins when the mixture is stirred at room temperature for 1.5 hours at which time starting material is no longer detectable by thin layer chromatography on silica gel with hexane / ethyl acetate 1: 1. The reaction mixture was diluted with hexane (40 mL), filtered, and the filtrate was purified on silica gel (150 g, 1: 1 hexane / ethyl acetate). 1.65 g (2.84 mmol, 79%) of product are obtained. 1 H-NMR (400 MHz, CDCl ₃ ): δ-1.34 (s, 6H), 1.39 (s,

9H), 1.84 (m, 1H), 2.40 (m, 1H), 2.49 (dd, 1H),

2.52 (m, 1H), 4.51 (m, 1H), 4.88 (d, 1H), 5.25 (d,

1H), 5.34 (brs, 1H), 6.71 (d, 1H), 7.20 (m, 12H).

Step B.

N- [1 - ([2 '- [(Morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl) -2,3,4,5-tetrahydro-2-oxo 1H-1 Benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

To a solution of the title compound (100 mg, 0.17 mmol) in methylene chloride (2 mL) was added morpholine (0.017 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 1 hour at which time no starting material was detected by TLC. The reaction mixture was diluted with 1 mL of trifluoroacetic acid, stirred at room temperature for 0.5 h, and then concentrated in vacuo. The residue was purified by preparative medium pressure reverse phase liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (65:35). The product-containing fractions were combined, concentrated in vacuo and the residue lyophilized from water. 88 mg (0.15 mmol, 88%) of the title compound are obtained in the form of a white solid.

FAB-MS: C ₃₃ H ₃₉ N ₅ O ₄ 569;

found 592 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.35 (s, 3H), 1.39 (s,

3H), 2.12 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H),

2.60 (m, 2H), 3.25 (m, 4H), 3.4 (m, 4H), 4.40 (dd,

1H), 4.95 (d, 1H), 5.30 (d, 1H), 7.3 (m, 12H).

Example 7

N - (1 - [[2 '- [(Piperazinecarbonylamino) [1,1'-biphenyl) -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanate 18)

HU 211,894 A9 to) [1,1'-Biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxol-1-benzazepin-3 (R) -yl] -3 t-Butoxycarbonylamino-3-methylbutanamide and piperazine were prepared as described in Example 6.

FAB-MS: calculated for C 11 H 11 N 8 Cl 2, 5.68; found 593 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.27 (s, 3H), 1.30 (s,

3H), 2.07 (m, 1H), 2.30 (m, 1H), 2.4 (dd, 2H), 2.59 (m, 2H), 3.20 (dd, Hz), 3, 30 (dd, 4H), 4.40 (dd,

1H), 4.90 (d, 1H), 5.33 (d, 1H), 7.30 (m, 12H).

Example 8

N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino} [1'-biphenyl] -4-yl} methyl] -2,3,4,5- tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide trifluoroacetate

The step

N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-tert-butoxycarbonylamino-3-methylbutanamide

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxyamino-3-methylbutanamide and ethanolamine were prepared as described in Example 6, Step A.

FAB-MS: C ₃₆ H ₄₅ N ₅ O ₆ 643;

found 666 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.29 (s, 3H), 1.31 (s,

3H), 1.38 (s, 9H), 1.90 (m, 1H), 2.5 (dd, 2H), 2.58 (m, 2H), 2.7 (m, 1H), 3, 21 (t, 2H), 3.54 (m, 2H),

4.49 (m, 1H), 4.88 (d, 1H), 5.10 (d, 1H), 6.81 (d,

1H), 7.21 (m, 11H), 7.74 (d, 1H).

Step B.

N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound was prepared from the compound of Step A as described in Example 6, Step B. FAB-MS: C ₃ | calculated H ₃₇ N ₅ O ₄ to 543; found 545.

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.37 (s,

3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.52 (dd, 2H),

2.64 (m, 2H), 3.20 (t, 2H), 3.51 (t, 2H), 4.41 (dd,

1H), 5.02 (d, 1H), 5.20 (d, 1H), 7.24 (m, 1H), 7.62 (d, 1H).

Example 9

N- [1- [2 '- [[(2-Hydroxypropylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5- tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methyl-butanamide and l-amino-2-propanol were prepared as described in Example 6.

FAB-MS: C 11 ₀ H | _{Calcd for} N ₅ O ₄ 557;

found 580 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.00 (d, 3H), 1.34 (s,

3H), 1.37 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.52 (dd,

2H), 2.68 (m, 2H), 3.01 (dd, 1H), 4.41 (dd, 1H), 5.02 (d,

1H), 5.21 (d, 1H), 7.25 (m, 1H), 7.62 (d, 1H).

Example 10

N- [1 - [[2 '- [[(3-Hydroxypropylamino / carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5- tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and 3-amino-2-propanol were prepared as described in Example 6.

FAB-MS: C ₃₂ H ₃₉ N ₅ O ₄ 557;

found 580 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.38 (s,

3H), 1.60 (m, 2H), 2.18 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H), 2.65 (m, 3H), 3, 39 (m, 2H), 3.52 (m, 2H),

4.42 (dd, 1H), 5.04 (d, 1H), 5.21 (d, 1H), 7.28 (m,

11H), 7.59 (d, 1H).

Example 11

N - [1 - [[2 '- [[(2,3-Dihydroxypropylamino) carbonyl] amino] [1,1' '- biphenyl] -4-yl] methyl] -2,3, 4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1-benzazepine -3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and 3-amino-1,2-propanediol were prepared as described in Example 6.

FAB-MS: C ₃₂ H ₃₉ N ₅ O ₄ 557;

found 580 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.37 (s,

3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.51 (dd, 1H),

2.66 (m, 2H), 3.09 (m, 1H), 3.2 (m, 2H), 3.42 (m,

2H), 3.59 (m, 1H), 4.41 (dd, 1H), 5.05 (d, 1H), 5.17 (d, 1H), 7.25 (m, 10H), 7 59 (d, 1H).

Example 12

N- [1 - [[2 '- [(Methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide acetate

The step

4-Methylphenyl-trimethyl stannane

A solution of p-tolylmagnesium bromide (1.04 M, 41.4 L, 41.4 mol) in diethyl ether was added dropwise over 4 hours at -5 ° C to 546 g (2.79 mol) of trimethyl of tin chloride in 4 liters of tetrahydrofuran and cooled to -10 ° C under a nitrogen atmosphere. The suspension was allowed to warm slowly to room temperature over 12 hours, then diluted with 1 L of saturated ammonium chloride solution and then with water (about 1 L) needed to dissolve the precipitate. The solution is once 4 liters and three

The A9 was extracted with 2 liters of ether / hexane 1: 1. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 95: 5 hexane: ethyl acetate. This gave a white yellow oil containing 4,4'-dimethylbiphenyl crystals, which was filtered off to give 711.3 g (100%) of product.

1 H-NMR (300 MHz, CDCl ₃ ): δ = 0.30 (s, 9H), 2.34 (s,

3H), 7.19 (d, 7.7 Hz, 2H), 7.40 (d, 7.7 Hz, 2H).

Step B.

4-Methyl-2'-acetyl-1'-biphenyl

To a solution of 13.25 g (66 mmol) of 2'-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannate in 190 mL of dimethylformamide under vigorous stirring was added 8.64 g ( Bis (triphenylphosphone) palladium (n) chloride (12 mmol) was added and the mixture heated at 150 ° C for 6 hours. The reaction mixture was cooled, poured into 1000 ml of water and the suspension was extracted with ethyl ether. The combined extracts were washed four times with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative high pressure liquid chromatography on silica gel eluting with 10: 1 hexane: ethyl acetate. 9.8 g (47 mmol, 71%) of product are obtained in the form of an oil.

EI-MS: calculated for C ₁₅ H ₁₄ , 210;

found 210 (M ⁺ ).

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.98 (s, 3H), 2.37 (s,

3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).

Step C

4-Methyl-2 '-hydroxy-1,1' -biphenyl

To a solution of 4-methyl-2'-acetyl-1,1'-biphenyl (step B) (4.2 g, 20.0 mmol) in methylene chloride (8.98 g, 85% m-chloroperbenzoic acid) was added under nitrogen. The resulting slurry was cooled to 0 ° C and 1.54 mL of trifluoroacetic acid was added dropwise over 10 minutes. After stirring at room temperature for 16 hours, the reaction mixture was diluted with methylene chloride (50 mL) and washed successively with 50 mL of 10% sodium sulfite solution, 50 mL of saturated aqueous potassium carbonate solution and three times with 50 mL of water. The organic phase was removed, dried over magnesium sulfate and concentrated in vacuo. The resulting oil (4.1 g) was dissolved in methanol (20 ml), treated with 5N aqueous sodium hydroxide (2.0 ml) and stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 5-6 with acetic acid, the methanol was removed in vacuo, the residue taken up in ether, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product (3.0 g) was purified by preparative pressure liquid chromatography on silica gel eluting with 10: 1 hexane: ethyl acetate. 1.85 g (10.0 mmol, 50%) of product are obtained in the form of an oil. 1 H-NMR (200 MHz, CDCl ₃ ). δ = 2.40 (s, 3H), 5.22 (br s, 1H), 6.96 (m, 2H), 7.2-7.4 (m, 6H).

EI-MS: C ₁ H _{3 Calculated for} O 184; found 184 (M + 100%).

Step D.

4-Methyl-2 '-acetoxy-1,1' -biphenyl

To a solution of 4-methyl-2'-hydroxy-1,1'-biphenyl (1.0 g, 5.4 mmol) in pyridine (2.0 mL) was added acetic anhydride (2 mL). The reaction mixture was stirred at room temperature for 5 hours and then the solvent was removed in vacuo. 1.11 g (4.9 mmol, 90%) of product are obtained in the form of an oil.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 2.07 (s, 3H), 2.36 (s,

3H), 7.07 (dd, 3.8 Hz; 1H), 7.15 (d, 8 Hz, 2H),

7.2-7.4 (m, 5H).

Step E is '-Bromomethyl-2-acetoxy-1,1' -biphenyl

The title compound was prepared from 4-methyl-2'-acetoxy-1,1'-biphenyl as described in Example 1, Step K.

1 H-NMR (200 MHz. CDCl ₃ ): δ = 2.05 (s, 3H), 4.50 (s,

2H), 7.08 (m, 1H), 7.20-7.45 (m, 7H).

Step F

N- [1 - [[(2'-Acetoxy) [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-3 (R) - yl] -3-tert-butoxycarbonylamino-3-methylbutanamide

The title compound was prepared from 4-bromomethyl-2'-acetoxy-1,1'-biphenyl and 3-tert-butoxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo -1-1-Benzazepin-3 (R) yl] -butanamide (Example 1, Step I) was prepared as described in Example 1, Step Q.

1 H-NMR (200 MHz, CDCl ₃ ); δ = 1.38 (s, 6H), 1.45 (s,

9H), 1.85 (m, 1H), 2.02 (s, 3H), 2.35-2.65 (m, 5H),

4.52 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.30 (d, 15 Hz,

1 H), 6.71 (d, 7 Hz, 1H), 7.1-7.4 (m, 12H).

Step G

N- [1 - [[(2'-Hydroxy) [1,1'-biphenyl] -4-yl] methyl] 2.3.4.5-tetrahydro-2-oxo-1H-1-benzazepine-3 (R) - ilj3-tert-butoxycarbonyl-amino-3-methylbutanamide

To a solution of Step F (469 mg, 0.87 mmol) in methanol (25 mL) was added 5N aqueous sodium hydroxide (5 mL) at room temperature. After stirring for one hour at room temperature, the reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 450 mg of crude product which was used in the next step without further purification.

Step H

N- [1 - [[2 '- [(Methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide

To a solution of the crude product of Step G (100 mg, about 0.2 mmol) in methylene chloride (5 mL) was added methyl isocyanate (1.0 mL, 17 mmol) and 1,8-diazabicyclo [5.4.0] undec. -7 was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. 146 mg of crude product are obtained.

1 H-NMR (400 MHz, CDCl ₃ ); δ = 1.32 (s, 3H), 1.33 (s,

HU 211 894 A9

3H), 1.39 (s, 9H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H), 2.57 (m, 2H), 2, 59 (s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26 (d, 1H), 7.10 (d, 1H), 7.36 (m, 11H) ).

/ step

N- [1 - [[2 '- [(Methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- To a solution of oxo-1 H-1 benzazepine-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate in 1.0 ml of a solution of the product obtained in Step H in 3.5 ml of methylene chloride is added 1.0 ml of trifluoroacetic acid. After stirring for 15 minutes at room temperature, the mixture was concentrated in vacuo and the residue was purified by reverse phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (60:40). The product-containing fractions were combined, concentrated in vacuo and the residue lyophilized from water. This gave 34 mg (0.066 mmol) of the title compound as a white solid. FAB-MS: calculated for C ₃₀ H ₃₄ N ₄ O ₄ 514; found 537 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 3H), 1.38 (s,

3H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H),

2.57 (m, 2H), 2.59 (s, 3H), 4.38 (dd, 1H), 4.8 (d,

1H), 5.26 (d, 1H), 7.10 (d, 1H), 7.36 (m, 11H).

Example 13

N-11'-2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide acetate

The step

N- [1 - {[(2'-Isothiocyanato) [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-3 (R) -yl] 3-t-butoxycarbonylamino-3-methylbutanamide and

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide

300 mg (0.60 mmol) of N- [1 - [[(2'-amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo 1Η-1-Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and 1.8 g (25 mmol) of methyl isothiocyanate in 15 mL of benzene The resulting solution was refluxed under nitrogen for 24 hours, then concentrated in vacuo and purified by preparative thin layer chromatography on silica gel with ethyl acetate / hexane (3: 1) to give 69 mg of the faster-moving product, identified as N [1 - [(2'-Isothiocyanato) [1,1-biphenyl] -4-yl'-methyl] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3 -t-butoxycarbonylamino-3-methylbutanamide.

FAB-MS: C ₃₄ H ₃₉ N ₄ O ₄ 598;

found 621 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.35 (s, 3H), 1.36 (s,

3H), 1.40 (s, 9H), 1.84 (m, 1H), 2.48 (dd, 2H), 2.52 (m, 3H), 4.50 (m, 1H), 4, 86 (d, 1H), 5.29 (d, 1H),

6.68 (d, 1H), 7.14 (m, 1H), 7.30 (m, UH).

122 mg of N- [1 - [[2 ', (melylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro as a slower moving product. -2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide is obtained. FAB-MS: C ₃₅ H ₄₃ N ₅ O ₄ 629; found 652 (M + Na). 1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.32 (s, 3H), 1.33 (s,

3H), 1.40 (s, 9H), 1.85 (m, 1H), 2.48 (dd, 2H), 2.55 (m, 3H), 2.95 (s, 3H), 4, 50 (m, 1H), 4.88 (s, 1H),

5.20 (s, 1H), 6.68 (d, 1H), 7.22 (m, 12H).

Step B.

N- [1 - [[2 '- [(Methylaminothiocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

122 mg (0.19 mmol) of N- [1 - [[2 '- [(methylaminothiocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2.3, To a solution of 4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide in 3 mL of methylene chloride was added 1.0 mL of trifluoro acetic acid is added. After 1 hour, thin layer chromatography revealed no starting material. The solvent was removed in vacuo and the residue was purified by reversed phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (60:40). The product-containing fractions were combined, concentrated in vacuo and the residue lyophilized from water. This gave 84 mg (0.16 mmol, 84%) of the title compound as a white solid. FAB-MS: C ₃₀ H ₃₅ N ₄ O ₂ 529;

found 531.

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.32 (s, 3H), 1.38 (s,

3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.53 (dd, 2H),

2.70 (m, 2H), 2.72 (s, 3H), 4.4 (dd, 1H), 4.89 (d,

1H), 5.81 (d, 1H), 7.3 (m, 12H).

Example 14

N- [l - [[2'- l (aminocarbonyl-ylthio) amino] [l, r-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo -1H-1 Benzazepin-3 (R) -yl] amino-3-methylbutanamide trifluoroacetate

100 mg (0.17 mmol) of N- [1 - [[(2'-isothiocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo A solution of -1 Η-1-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide (Example 13, Step A) in 5 mL of methanol with gaseous aqueous ammonia for 5 minutes treated. The starting isothiocyanate was no longer detectable by thin layer chromatography. The reaction mixture was evaporated in vacuo, the residue was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL). After leaving for one hour at room temperature, evaporate in vacuo and purify the residue by reverse phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (60:40). The product-containing fractions were combined, the solvent removed in vacuo and the residue lyophilized from water. This gave 53 mg of the title compound as a white solid.

FAB-MS: C ₂₉ H ₃₃ N ₅ O ₂ 515;

found 516 (M + H).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.38 (s,

HU 211 894 A9

3H), 2.12 (m, 1H), 2.30 (m, 1H), 2.54 (dd, 2H),

2.60 (m, 2H), 4.42 (dd, 1H), 4.92 (d, 1H 5.26 (d,

1H), 7.30 (m, 12H).

Example 15

N- [1 - [[2- (Dimethylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H- 1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide acetate

The step

4- (Tetrahydro-pyrazyloxy) -methyl-2 '-isocyanato-Ι, Γ-biphenyl

To a solution of 4- (tetrahydropyranoloxy) methyl 2'-amino-1,1'-biphenyl (200 mg, 0.70 mmol) in Example 1, Step N and 0.40 mL of triethylamine in 10 mL of methylene chloride was added triphosgene (420 mg, 0.24 mmol) was added under an atmosphere. The reaction mixture was stirred for 30 minutes at room temperature, whereupon no residual amine was detected by TLC on silica gel with hexane / ethyl acetate 2: 1. The reaction mixture was concentrated in vacuo to give a crude product which was used in the next step without further purification.

Step B.

4-Hydroxymethyl-2 '- (dimethylaminocarbonyl) amino-1,1'-biphenyl

To a solution of the crude product of Step A in 4 mL of methanol is added 4 mL of a 40% aqueous solution of dimethylamine. After stirring at room temperature for 15 minutes, the mixture was concentrated in vacuo and the residue was dissolved in methanol (4 mL) and treated with 10% p-toluenesulfonic acid in methanol (1 mL). After being left at room temperature for 15 minutes, it is mixed with saturated aqueous sodium bicarbonate solution. The mixture was diluted with water and extracted with methylene chloride. The organic phase was dried and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with 2: 1 hexane / ethyl acetate to give 133 mg of product.

Step C

4-Bromomethyl-2 '- (N-dimethylamino) biphenyl -amino1,1'

To a solution of the product of Step B in 4 mL of methylene chloride was added trimethylsilyl bromide (0.16 mL, 1.21 mmol). After stirring for 18 hours at room temperature, the mixture was diluted with methylene chloride, washed twice with a saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. 133 mg of crude product are obtained. 1 H-NMR (400 MHz, CDCl ₃ ): δ = 2.78 (s, 6H), 4.5 (s,

2H), 6.4 (br s, 1H), 7.08 (t, 1H), 7.16 (dd, 1H), 7.34 (m, 4H), 7.49 (d, 1H), δ , 10 (d, 1H).

Step D.

N- [1 - [[2 '- ((Dimethylaminocarbonyl) amino] [1,1'biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo -lH-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide acetate

147 mg (0.39 mmol) of 3-t-butoxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1 H -1-benzazepin-3 (R) -yl] - To a solution of butanamide (Example 1, Step I) in 5 mL of dry dimethylformamide was added 20 mg of a 60% w / w solution of sodium hydride in oil (12 mg, 0.5 mmol, 1.3 equivalents of NaH). After stirring at room temperature for 30 minutes, 4-bromomethyl-2 '- (dimethylaminocarbonyl) amino-1,1' -biphenyl (133 mg) was added. After stirring for 2 hours at room temperature, it was diluted with ethyl acetate. After washing four times with water, the organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride (4 mL) and treated with trifluoroacetic acid (1 mL). After stirring for 1.5 hours at room temperature, the solvent was removed in vacuo and the residue was purified by reverse phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (65:35). The product-containing fractions were collected, the solvent removed in vacuo and the residue lyophilized from water. 116 mg of the compound of the form are obtained in the form of a white solid.

FAB-MS: calculated for C ₃ H ₃₇ N ₅ O ₃ 527;

found 529.

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.40 (s,

3H), 2.15 (m, 1H), 2.34 (m, 1H), 2.54 (dd, 2H),

2.59 (m, 2H), 2.78 (s, 6H), 4.44 (dd, 1H), 4.88 (d,

1H), 5.38 (d, 1H), 7.28 (m, 11H), 7.49 (d, 1H).

Example 16

N- [II [2 '- [[(1,3-Dihydromixi-pmp-2-yl) -aminocarbonyl] -amino] [1,1'-biphenyl] -4-yl] methyl] -2, 3,4,5-Tetrahydm-2-ol-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The step

N- [l - [[2 '- [aminocarbonyl (l, 3-dihydroxy-prop-2-yl)) amino] [l, l'-biphenyl} -4-yl} methyl} -2 , 3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide

125 mg (0.23 mmol) of N- [1 - [(2'-amino) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo -1H-1-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and 0.10 mL (0.72 mmol) of triethylamine. A solution of triphosgene (133 mg, 0.45 mmol) was added to a solution of methylene chloride (1 mL) in methylene chloride at -10 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. It was then cooled again to -10 ° C and another 0.30 mL (0.23 mmol) of triethylamine was added. Thereafter, 280 mg (2.20 mmol) of serinol hydrochloride in one portion were added to the reaction mixture and stirred at room temperature until no residual isocyanate was eluted by TLC eluting with 1: 1 hexane: ethyl acetate. The reaction mixture was concentrated in vacuo to give crude product.

Step B.

N- [1 - [[2 '- [[(1,3-Dihydroxyprop-2-yl) aminocarbonyl) amino] [], 1'-biphenyl] -4-yl] methyl} -2 , 3,4,5-tetrahidno-2-oxo-lH-l-benzazepin-3 (R) -yl-3-amino-3-methylbutanamide, trifluoroacetate

The crude product of Step A is 5 ml of methylene chloride22

To a solution of A9 in B9 was added 2 mL of trifluoroacetic acid. After stirring for one hour at room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by reverse phase medium pressure liquid chromatography (C8, methanol / 0.1% aqueous trifluoroacetic acid 55:45). The product-containing fractions were combined, the solvent removed in vacuo and the residue lyophilized from water. This gave 66 mg (0.096 mmol, 42% based on the two steps) of the title compound as a white solid.

FAB-MS: C ₃₂ H ₃₉ N ₅ O ₅ 573;

found 596 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 3H), 1.37 (s,

3H), 2.14 (m, 1H), 2.30 (m, 1H), 2.48 (dd, 2H),

2.69 (m, 2H), 3.52 (m, 4H), 3.70 (m, 1H), 4.40 (dd,

1H), 5.05 (d, 1H), 5.20 (d, 1H), 7.25 (m, 1H), 7.62 (d, 1H).

Example 17

N - [1 - [[2 '- [[(2 (R, R-hydroxypropylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4 , 5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1-1 Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and (R) - (-) - 1-amino-2-propanol were prepared as described in Example 6.

FAB-MS: C ₃₂ H ₃₉ N ₅ O ₄ 557; found 580 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.09 (d, 3H), 1.34 (s,

3H), 1.37 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H), 2.65 (m, 2H), 2, 95 (dd, 1H), 3.16 (dd,

1H), 3.75 (m, 1H), 4.82 (dd, 1H), 5.02 (d, 1H), 5.20 (d, 1H), 7.27 (m, 11H), 7, 61 (d, 1H).

Example 18

N - [1 - [[2 '- [[(2 (S) -Hydroxypropylamino) carbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3, 4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and (S) - (+) - 1-amino-2-propanol were prepared as described in Example 6.

FAB-MS: C ₃₂ H ₃₉ N ₅ O ₄ 557; found 581 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.09 (d, 3H), 1.34 (s,

3H), 1.37 (s, 3H), 2.15 (m, 1H), 2.45 (m, 1H), 2.55 (dd, 2H), 2.68 (m, 2H), 3, 02 (dd, 1H), 3.16 (dd,

1H), 3.75 (m, 1H), 4.41 (dd, 1H), 5.06 (d, 1H), 5.22 (d, 1H), 7.27 (m, 11H), 7, 62 (d, 1H).

Example 19

N - {] - [[2'-flfl (1H-hydroxyprop-2 (R) -yl] amino] carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2 , 3,4,5-Tetrahydro-2-oxo-1H-J-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate The title compound is N- [1 - [[( 2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxol-1-benzazepin-3 (R) -yl] -3- Prepared from t-butoxycarbonylamino-3-methyl-butanamide and (R) -2-amino-2-propanol as described in Example 6.

FAB-MS: C ₃₂ H ₃₉ N ₅ O ₄ 557; found 580 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.07 (d, 3H), 1.34 (s,

3H), 1.37 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.51 (dd, 2H), 3.41 (m, 2H), 3, 75 (m, 1H), 4.41 (dd, 1H),

5.03 (d, 1H), 5.21 (d, 1H), 7.25 (m, 11H), 7.64 (d,

IH).

Example 20

N- [1 - [[2 '- [(Hydrazinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo 1H-1 Benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and anhydrous hydrazine were prepared as described in Example 6.

FAB-MS: C ₂₉ H ₃₅ N ₆ O ₃ 514;

found 537 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.35 (s, 3H), 1.38 (s,

3H), 2.29 (m, 1H), 2.35 (m, 1H), 2.57 (dd, 1H),

2.62 (m, 2H), 4.46 (dd, 1H), 5.30 (d, 1H), 7.29 (m,

10H), 7.73 (d, 1H).

Example 21

N- [1 - [[2 '- [(2,2-Dimethylhydrazinocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl J-2,3,4 , 5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and 1,1-dimethylhydrazine were prepared as described in Example 6.

FAB-MS: calculated for C _3I H ₃₉ N ₆ O ₃ 542;

found 565 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 3H), 1.38 (s,

3H), 2.14 (m, 1H), 2.30 (s, 6H), 2.36 (m, 1H), 2.52 (dd, 1H), 2.64 (m, 2H), 4, 28 (dd, 1H), 5.00 (dd,

1H), 5.30 (dd, 1H), 7.26 (m, 10H), 7.90 (d, 1H).

Example 22

N- [1 - [[2 '- [[(Carboxymethylamino) carbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4 , 5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The step

N- [1 - [[2 '- [[(t-Butoxymethylamino) carbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl J-2,3 , 4,5-tetrahydro-2-oxo-1 - - benzazepin-3 (R) -yl-3-t-butoxycarbonylamino-3-methylbutanamide

The title compound is N- [1 - [[(2'-amino) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine -3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and glycine tert-butyl23

A9 ester hydrochloride was prepared as described in Example 16, Step A.

Step B.

N- [1 - [[2 '- [[(Carboxymethylamino) carbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl} methyl] -2,3,4 , 5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate and

N- {1 - [[2 [(Methoxycarbonylmethylamino) carbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5 -tetrahidm-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

To a solution of the crude product of Step A in 4 mL of methylene chloride was added 2 mL of trifluoroacetic acid. After stirring for one hour at room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (55:45). The early fractions containing product were combined, the solvent removed in vacuo and the residue lyophilized from water. 60 mg of the title compound are obtained in the form of a white solid.

FAB-MS: calculated for C, _3] H 5 N ₅ O _{3 5} to 557;

found 558 (M + M).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.38 (s,

3H), 2.15 (m, 1H), 2.34 (m, 1H), 2.52 (dd, 2H),

2.68 (m, 2H), 3.84 (s, 2H), 4.42 (s, 1H), 5.05 (d,

1H), 5.20 (d, 1H), 7.25 (m, 11H), 7.64 (d, 1H).

Subsequent fractions were combined, the solvent removed in vacuo and the residue lyophilized from water. Thus 18 mg of N- [1 - [[2 '- [[(methoxycarbonylmethylamino) carbonylamino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4 5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate is obtained.

FAB-MS: C ₃₂ H ₃₇ N ₅ O ₅ 571;

found 594 (M + Na).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 3H), 1.39 (s,

3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H),

2.66 (m, 2H), 2.71 (s, 3H), 2.87 (s, 2H), 4.42 (dd,

1H), 5.05 (d, 1H), 5.22 (d, 1H), 7.28 (m, 1H), 7.61 (d, 1H).

Example 23

N- [1 - [[2 '- [[(Methoxycarbonylmethylamino) carbonyl) amino] - [1,1'-biphenyl] -4-yl] methyl] -2,3,4 , 5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[2 '- [(tert-butoxycarbonylmethylamino) carbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3, 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-tert-butoxycarbonylamino-3-methylbutanamide was prepared as described in Example 22, Step B.

FAB-MS: C ₃₂ H ₃₇ N ₅ O ₅ 571;

found 594 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.39 (s,

3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H),

2.66 (m, 2H), 2.71 (s, 3H), 2.87 (s, 2H), 4.42 (dd,

1H), 5.05 (d, 1H), 5.22 (d, 1H), 7.28 (m, 1H), 7.61 (d, 1H).

Example 24

N- [l - [[2 '- [[(benzyloxycarbonyl-amino) amino-phenoxy] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro -2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and benzylamine were prepared as described in Example 6.

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.34 (s, 3H), 1.37 (s,

3H), 2.13 (m, 1H), 2.33 (m, 1H), 2.45-2.70 (m,

4H), 4.28 (s, 2H), 4.42 (dd, 1H), 5.00 (d, 1H), 5.25 (d, 1H), 7.1-7.4 (m, 16H). ), 7.62 (d, 1H).

FAB-MS: C ₃₆ H ₃₉ N ₅ O ₃ 589; found: 590 (M + H).

Example 25

N- [1 - [[2 '- [(Phenylaminocarbonyl) amino} [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The title compound is N- [1 - [[(2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide and aniline were prepared as described in Example 6. FAB-MS: C ₃₅ H ₃₇ N ₅ O ₃ 578;

found 598 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.32 (s, 3H), 1.35 (s,

3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.52 (m, 2H), 2.65 (m, 1H), 4.40 (dd, 1H), δ, 03 (d, 1H), 5.21 (d, 1H),

6.99 (m, 1H), 7.15-7.45 (m, 9H), 7.74 (d, 1H).

Example 26

N - [] - [[2 '- [(Hydroxylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo 1H-1 Benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The title compound is N- [1 - [((2'-isocyanato) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxolH-1- Benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methyl-butanamide and O-trimethylsilyl-hydroxylamine were prepared as described in Example 6. FAB-MS: C ₂₉ H ₃₃ N 515 calculated for N ₅ O ₄ , found 518 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.26 (s, 1H), 1.28 (s,

3H), 2.11 (m, 1H), 2.32 (m, 1H), 2.52 (dd, 2H),

2.60 (m, 2H), 4.40 (dd, 1H), 5.0 (d, 1H), 5.24 (d,

1H), 7.55 (m, 11H), 8.0 (d, 1H).

Example 27

N- [1 - [[2 '- [4 - [(Methylaminocarbonyl-famino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2 oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The step

4-Methyl-2 '- (4-nitrophenoxy) -1,1' -biphenyl

To a solution of 184 mg (1.0 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) in 3 ml of dimethylformamide was added 55 mg of 60% sodium hydride (33%).

A9 mg, 1.4 mmol NaH) was added. After stirring for 30 minutes at room temperature, 1-fluoro-4-nitrobenzene (169 mg, 1.19 mmol) was added. After heating for two hours at 100 ° C, the reaction mixture was cooled, poured into water (50 mL) and extracted with ethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 10: 1 hexane: ethyl acetate. 271 mg (0.89 mmol, 88%) of product are obtained. FAB-MS: calculated for C 24 H 30 N 4 O 3, 305;

found 306 (M + M).

1 H-NMR (200 MHz, CDCl ₃ ): δ = 2.28 (s, 3H), 6.82 (d,

2H), 7.19 (d, 3H), 7.2-7.5 (m, 5H), 8.05 (d, 2H).

Step B.

4-Bromomethyl-2 '- (4-nitrophenoxy) -1,1'-biphenyl

The title compound was prepared from 4-methyl-2 '- (4-nitrophenoxy) -1,1'-biphenyl as described in Example 1, Step K.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 4.43 (s, 2H), 6.83 (d,

Hz, 2H), 7.09 (d, 8H, 1H), 7.3-7.5 (m, 7H), 8.04 (d, 8 Hz, 2H).

Step C

N- [1 - [[2 '- (4-Nitrophenoxy) [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro-2-oxo-1H-J-benzazepine 3 (R) -yl] amino) -3-t-butoxycarbonylamino-3-methylbutanamide

The title compound was obtained from 4-bromomethyl-2 '- (4-nitrophenoxy) -1,1'-biphenyl and 3-tert-butoxycarbonylamino-3-methyl-N- [2,3,4,5 is prepared from the tetrahydro-2-oxo-1-1-benzazepin-3 (R) -yl] -butanamide (Example 1, Step I) as described in Example 1, Step Q.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.32 (s, 6H), 1.38 (s,

9H), 1.78 (m, 1H), 2.3-2.7 (m, 5H), 4.47 (m, 1H),

4.75 (d, 15 Hz, 1H), 5.13 (d, 15 Hz, 1H), 6.63 (d, 7

Hz, 1H), 6.75 (d, 8 Hz, 2H), 7.05-7.50 (m, 11H),

7.97 (s, 1H), 7.98 (d, 8 Hz, 2H).

Step D.

N- [1 - [[2 '- (4-Aminophenoxy) [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H -benzazepin3 (R) -yl] amino] -3-t-butoxycarbonylamino-3-methylbutanamide

A solution of the compound of Step C (282 mg, 0.415 mmol) in methanol (30 mL) was hydrogenated at 276 kPa in the presence of 5% palladium on carbon. After hydrogen uptake was complete, the mixture was filtered through celite and the filtrate was concentrated in vacuo. 264 mg of product are obtained.

This step

N- [1 - [[2 '- [4 - [(Methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl] amino] -3-t-butoxycarbonylamino-3-methylbutanamide

To a solution of the compound of Step D (264 mg, 0.40 mmol) in methylene chloride (5 mL) was added methyl isocyanate (0.90 mL, 15 mmol) under nitrogen. After stirring for 18 hours at room temperature, the volatiles were removed in vacuo and the residue on silica gel with ethyl acetate / hexane.

Purify by chromatography eluting with 3: 1. so

287 mg (0.40 mmol, 100%) of product are obtained.

1 H-NMR (400 MHz, CD ₃ OD): δ-1.24 (s, 3H), 1.31 (s,

6H), 1.39 (s, 9H), 2.00 (m, 1H), 2.30 (m, 1H), 2.42 (m, 3H), 2.50 (dd, 1H), 2, 73 (s, 3H), 4.32 (dd, 1H),

4.82 (d, 1H), 5.24 (d, 1H), 6.70 (m, 2H), 6.95 (d,

1H), 7.2 (m, 13H).

Step F

N - [] - [[2 '- [4 - [(Methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl-4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -amino] -3-amino-3-methylbutanamide trifluoroacetate

To a solution of the compound of Step E (287 mg, 0.40 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (1.5 mL). After stirring for 1 hour at room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (50:50). The product-containing fractions were combined, the solvent removed in vacuo and the residue lyophilized from water. This gave 165 mg (0.23 mmol, 57%) of the title compound as a white solid. FAB-MS: C ₃₆ H ₃₉ N ₅ O ₄ 605;

found 628 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.33 (s, 3H), 1.36 (s,

3H), 2.06 (m, 1H), 2.26 (m, 1H), 2.48 (m, 4H), 2.74 (s, 3H), 4.36 (dd, 1H), 4, Δ (d, 1H), 5.17 (d, 1H).

Example 28

N- [l - [[2 '- [2-f (methylamino-carbonyl) amino] phenoxy] [I, r-biphenyl] -4-yl] methyl] -2,3,4,5 -tetrahidro2-oxo- -] - benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, trifluoroacetate

The step

4-Methyl-2 '- (2-nitrophenoxy) -1,1' -biphenyl

The title compound was prepared from 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) and 1-fluoro-2-nitrobenzene as described in Example 27, Step A.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 2.30 (s, 3H), 6.74 (dd,

2.8 Hz, 1H), 6.9-7.5 (m, 10H), 7.84 (dd, 2.8 Hz, 1H).

Step B.

4-Bromomethyl-2 '- (2-nitrophenoxy) -1,1' -biphenyl

The title compound was prepared from 4-methyl-2 '- (2-nitrophenoxy) -1,1'-biphenyl as described in Example 1, Step K.

1 H-NMR (400 MHz, CD ₃ OD): δ = 4.52 (s, 2H), 7.4 (m,

11H), 7.86 (d, 1H).

Step C

N- [1 - [[2 '- (2-Nitrophenoxy) [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro-2-oxo-1 H-] benzazepine 3 (R) -yl] amino) -3-t-butoxycarbonylamino-3-methylbutanamide

The title compound was 4-bromomethyl-2 '- (2-nitro25)

A9 from phenoxy) -1,1'-biphenyl and 3-tert-butoxycarbonylamino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine -3 (R) -yl] -butanamide (Example 1, Step I) was prepared as described in Example 1, Step Q.

1 H-NMR (200 MHz, CDCl ₃ ): δ = 1.32 (s, 6H), 1.38 (s,

9H), 1.78 (m, 1H), 2.3-2.7 (m, 5H), 4.47 (m, 1H),

4.75 (d, 15 Hz, 1H), 5.13 (d, 15 Hz, 1H), 6.63 (d,

7Hz, 1H), 6.75 (d, 8Hz, 2H), 7.05-7.50 (m, 11H),

7.97 (s, 1H), 7.98 (d, 8 Hz, 2H).

Step D.

N- [1 - [[2 '- (2-Aminophenoxy) [1,1'-biphenyl} -4-yl] methyl] -2,3,4,5-tetrahydio-2-oxo-1 H- l-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide

The title compound was prepared from the compound of Step C as described in Example 27, Step D.

This step

N- [1 - [[2 '- [2 - [(Methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-t-butoxycarbonylamino-3-methylbutanamide

The title compound was prepared from the compound of Step D as described in Example 27, Step E.

Step F

N - [1 - [[2 '- [2 - [(Methylaminocarbonyl) amino] phenoxy] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate

The title compound was prepared from the compound of Step E as described in Example 27, Step F. FAB-MS: C ₃₆ H ₃₉ N ₅ O ₄ 605; found 628 (M + Na).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.38 (s, 3H), 1.42 (s,

3H), 2.08 (m, 1H), 2.38 (m, 3H), 2.54 (dd, 2H), 2.8 (s, 3H), 4.39 (dd, 1H), 4, 85 (d, 1H), 5.3 (d, 1H),

6.51 (d, 1H), 5.8 (dt, 1H), 6.84 (dt, 1H), 7.00 (dd,

1H), 7.34 (m, 12H), 8.94 (dd, 1H).

Example 29

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] -amino-3-methylbutanamide trifluoroacetate

The step

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -benzoyloxypropyl] amino-3-methylbutanamide trifluoroacetate

250 mg (0.399 mmol) of N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 1.35 g of a solution of 5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (Example 2) in 12 ml of methanol were added. powdered 4A molecular sieve and then 713 mg (4.34 mmol) of (R) -2-benzyloxypropanal (prepared from ethyl D-lactate according to Hanessian and Kloss, Tetrahedron Lett. 26, 1261-1264 (1985)). The slurry was adjusted to pH 5.5 in glacial acetic acid, stirred at room temperature for 3 hours, then treated with 2.5 ml of 1.0M sodium cyanoborohydride in tetrahydrofuran and added dropwise at room temperature for 18 hours. After filtration, the filtrate was mixed with 2 ml of trifluoroacetic acid (caution, evolution of hydrogen cyanide), stirred for 10 minutes, the volatiles removed in vacuo and the residue on silica gel. len in methylene chloride / methanol / concentrated ammonia 90: 5: 1 as eluant to give an oil. 225 mg (0.339 mmol, 85%) of product are obtained.

FAB-MS: C ₄₀ H ₄₇ N ₅ O ₄ 661;

found: 668 (M + Li).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.19 (d, 3H), 1.19 (s,

3H), 1.21 (s, 3H), 2.005 (m, 1H), 2.3 (m, 1H), 2.4 (m, 2H), 2.20 (s, 3H), 2.3 ( m, 2H), 3.64 (m, 1H),

4.40 (dd, 1H), 4.58 (s, 1H), 4.62 (d, 1H), 5.05 (d,

1H), 5.14 (d, 1H), 7.23 (m, 16H), 7.66 (d, 1H).

Step B.

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] -methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] -amino3-methylbutanamide trifluoroacetate

To a solution of the title compound (225 mg, 0.339 mmol) in methanol (5 mL) was added trifluoroacetic acid (0.2 mL) and hydrogenation (500 mg, 30% palladium on carbon) at room temperature for 24 hours. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and the residue was purified by reverse phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (65:35). The product-containing fractions were combined, the solvent removed in vacuo and the residue lyophilized from water. This gave 160 mg (0.23 mmol, 69%) of the title compound as a white solid.

FAB-MS: C ₃₃ H ₄₁ N ₅ O ₄ 571;

found: 572 (M + H).

1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.20 (d, 1H), 1.36 (s,

3H), 1.37 (s, 3H), 2.15 (m, 1H), 2.34 (m, 1H), 2.34 (m, 1H), 2.62 (dd, 2H), 2, 63 (s, 3H), 2.68 (m, 2H),

2.80 (dd, 1H), 3.09 (dd, 1H), 3.90 (m, 1H), 4.40 (dd, 1H), 5.08 (d, 1H), 5.16 (d) , 1H), 7.22 (m, 11H),

7.62 (d, 1H).

Example 30

N- [1 - [[2 '- [(Moifolinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] -amino3-methyl-butanamide trifluoroacetate

The title compound is N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1- (1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (Example 6) and (R) -2-benzyloxypropanal were prepared as described in Example 29. way.

FAB-MS: Calcd. For C ₃₆ H ₄₅ N ₅ O ₅ 627;

found: 650 (M + Na).

HU 211,894 A9 1 H-NMR (400 MHz, CDCl ₃ ): δ = 1.20 (d, 3H), 1.36 (s,

3H), 1.39 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.62 (dd, 2H), 2.66 (m, 2H), 2, 7 (dd, 1H), 3.09 (dd, 1H),

3.25 (m, 4H), 3.63 (m, 4H), 3.83 (m, 1H), 4.39 (m,

1H), 5.05 (d, 1H), 5.20 (d, 1H), 7.29 (m, 12H).

Example 31

N- [1- [2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -d-yl] -methyl] -5SdS-tetrahydro-4-oxo-1 H- benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] -amino-3-methylbutanamide trifluoroacetate The title compound is N- [1 - [[2 ' - [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] 2,3,4,5-tetrahydro-2-oxo-1 Η-1 Benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (Example 8) and (R) -2-benzyloxypropanal were prepared as described in Example 29.

FAB-MS: calculated for C ₃₄ H ₄₃ N ₅ O ₅ 601; found: 602 (M + M).

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.20 (d, 3H), 1.36 (s, 20 3H), 1.38 (s, 3H), 2.18 (m, 1H ), 2.35 (m, 1H), 2.62 (dd, 2H), 2.68 (m, 2H), 2.78 (dd, 1H), 3.09 (dd,

1H), 3.2 (t, 2H), 3.52 (t, 2H), 3.93 (m, 1H), 4.40 (dd, 1H), 5.12 (d, 1H), 5, 18 (d, 1H), 7.28 (m, 11H),

7.65 (d, 1H). 25

Example 32

N- [1 - [[2 '- [(Methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] -30-amino-3-methylbutanamide trifluoroacetate 368 mg (0.716 mmol) of N- [ l - [[2 '- [(methylaminocarbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo- A solution of -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (Example 2) in dry methanol (12 mL) under nitrogen and with stirring was treated with 1.35 g of a powdered 4A molecular weight filter. followed by 0.4 g D-glyceraldehyde acetonide [L. W. Hertel,

C. S. Grossman and J. S. Kroin, Synth. Comm. 21, 151-154 (1991)) is added in 1 ml of 40 dry methanol. The mixture was carefully adjusted to pH 5.5 with glacial acetic acid and triethylamine and stirred at room temperature for 2 hours, during which 3.0 ml of a 1.0 M solution of sodium cyanoborohydride in tetrahydrofuran was added dropwise. After stirring for 18 hours at room temperature, the mixture was filtered and the filtrate was diluted with 9 mL of trifluoroacetic acid and 9 mL of water. After one hour, evaporate in vacuo and purify the residue by reverse phase medium pressure liquid chromatography (C8) eluting with methanol / 0.1% aqueous trifluoroacetic acid (60:40). The product-containing fractions were combined, the solvent removed in vacuo and the residue lyophilized from water. This gave 167 mg of the title compound as a white solid.

FAB-MS: C ₃₃ H ₄₁ N ₅ O ₅ 587; found: 589.

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.37 (s, 3H), 1.39 (s,

3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.55-2.75 (m,

4H), 2.64 (s, 3H), 2.95 (dd, 1H), 3.18 (dd, 1H), 3.54 (m, 2H), 3.83 (m, 1H), 4, 42 (dd, 1H), 5.08 (d, 1H),

5.16 (d, 1H), 7.1-7.4 (m, 11H), 7.61 (d, 1H).

Example 33

N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H -l-benzazepin-3 (R) -pyrrole-3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide, trifluoroacetate

The title compound is N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-Oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (Example 5) and D-glyceraldehyde acetonide were prepared as described in Example 32. FAB-MS: calculated for C ₃₂ H ₄₁ N ₅ O ₄ 559; found 561.

1 H-NMR (400 MHz, CD ₃ OD): δ = 1.36 (s, 1H), 1.38 (s,

3H), 2.15 (m, 1H), 2.34 (m, 1H), 2.62 (dd, 2H),

2.68 (m, 2H), 2.95 (dd, 1H), 3.18 (dd, 1H), 3.52 (m,

2H), 3.82 (m, 1H), 4.40 (dd, 1H), 5.05 (d, 1H), 5.06 (d, 1H), 7.25 (m, 1H), 7 , 60 (d, 1H).

Example 34

N- [1 - [[2 '- [[(2-Hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5 -tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] -amino-3-methyl-butanamide trifluoroacetate The title compound was N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo -1H-1-Benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide trifluoroacetate (Example 8) and D-glyceraldehyde acetonide were prepared as described in Example 32.

Example 35

1-60. The following compounds of formula (Ib) are prepared from the appropriately substituted starting materials and reagents as described in Example 1 and standard organic synthetic methods.

R ' R ⁹ THE R ⁴ R ⁵ H O II -NH-C-NHCH ₃ ch ₃ ch ₃ \ / -ch ₂ -c- OH OH 1 1 -CH ₂ -CH-CH-CH ₂ OH H II She II -NH-C-NH, CH3 CH ₃ \ / -ch ₂ -c- -ch ₂ ch ₂ oh H

HU 211 894 A9

R ¹ R ⁹ THE R ⁴ R ⁵ H O II -nh-c-nhch ₃ CH3 CH ₃ \ / -ch ₂ -c- OH 1 -CH ₂ C (CH ₃ ) ₂ H H o II -NH-C-NHCH ₃ CH 3 CH ₃ \ / CH ₂ -C- OH 1 -CH ₂ CH ₂ CHCH ₃ H H 0 II -nh-c-nhch ₃ CH3 CH ₃ \ / ch ₂ -c- H H o II -NH-C-NHCH ₃ CH3 CH ₃ \ / -ch ₂ -c- -CH ₂ CH ₂ CH ₃ H H o II -NH-C-NHCH ₃ CH3 CH ₃ \ / -ch ₂ -c- OH -ch ₂ -ch-ch. H 6-F o II -NH-C-NHCH ₃ CH3 _CH3 \ / CH ₂ -C- H H 7-F o II -NH-C-NHCH ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 7-CF3 while II -nh-c-nhch ₃ CH3 _CH3 \ / CH ₂ -C- H H 7-OCH ₃ o II -NH-C-NHCH ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 7-OH 0 II -NH-C-NHCH ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 7-SCH ₃ while II -nh-c-nhch ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 7-D (O) CH ₃ o II -NH-C-NHCH ₃ CH3 _CH3 \ / CH ₂ -C- H H 8-OCH ₃ o II -NH-C-NHCH ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 8-F while II -nh-c-nhch ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 8-C1 while II -nh-c-nhch ₃ CH3 CH ₃ \ / -ch ₂ -c- H H 8-1 0 II -nh-c-nhch ₃ CH ₃ CH ₃ \ / ch ₃ -CH ₂ -C- H H H 0 II -nh-c-nhch ₃ CH3 _CH3 \ / C- H H H She II -NH-C-NH, H CH, C- H H H 0 II -NH-C-NH, CH,, H — c— H H

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R ¹ R ⁹ THE R ⁴ R ⁵ H 0 II -NH-C-NHCH ₃ H. .CH, OH '·. z —c— H H H o II -NH-C-NHCH ₃ CHj ^ CHjOH -c- H H H o II -NH-C-NHCH ₃ H _{/ C} H ₃ —c- CH3 H H while II -nh-c-nhch ₃ CHj CHoOH * f -ch ₂ -c- H H H She II -NH-C-NHCH3 HOCHj CH ₃ \ / —CH ₂ -C - H H H 0 II -NH-C-NHCH ₃ HOCHj CH ₃ -CHj-C— OH CHjŐHCH. H H 0 II -NH-C-NHCH ₃ HOCH, CH ₃ -ch ₂ -c- OH CH ÍHCH, OH H H 0 II -nh-c-nhch ₃ C- H H H 0 II -nh-c-nhch ₃ 9 ^H S z ^CH »-Vnh —c- H H H 0 II -nh-c-nhch ₃ H \, ^ch 'Á? N —C - - - H 0 II -NH-C-NHCH ₃ xy - - H 0 II -NH-C-NHCH ₃ - - H 0 II -nh-c-nhch ₃ © -

Example 36

1-34. The following compounds of formula (Ic) may be prepared from the appropriately substituted starting materials and reagents using standard organic synthetic methods as described in Example 1b.

R ¹ R ⁹ THE R ⁴ H O II -NH-C-NH ₂ ch ₃ ch ₃ \ / —ch ₂ -c— H H 0 II -nh-c-nh ₂ ch ₃ ch ₃ \ / —c— H H O II -NH-C-NH ₂ ch ₃ ch ₃ \ / -ch ₂ -c— OH ch / 5hch.

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R ¹ R ⁹ THE R ⁴ H O II -NH-C-NHCH ₃ ch ₃ ch ₃ \ / -ch ₂ -c- OH CHjŐHCH. H 0 II -NH-C-NHCH ₂ CH ₂ OH ch ₃ ch ₃ \ / -ch ₂ -c— oh 1 -ch ₂ ch ₂ chch ₃ H 0 II -nh-c-nhch ₃ ch ₃ ch ₃ \ / -ch ₂ -c- OH CH / OhChet. H 0 II -nh-c-nhch ₃ ch ₃ ch ₃ \ / -ch ₂ -c— OH CHjÓHCH. 7-F 0 II -NH-C-NHCH ₃ CHj CH ₃ \ / -ch ₂ -c- OH ch £ HCH. 7 CFj 0 II -NH-C-NHCH ₃ ch ₃ ch ₃ '/ -ch ₂ -c- OH ch ₃ ohh. 7-OCH ₃ 0 II -nh-c-nhch ₃ ch ₃ ch ₃ \ / - ch ₂ -c- OH CH ₂ OHCH. 7 SCHj 0 II -NH-C-NHCH ₃ ch ₃ ch ₃ \ / -ch ₂ -c- OH CH.ÓHCH. 7-F 0 II -nh-c-nhch ₃ H _z CH ₃ —c- H 7-F 0 II -nh-c-nhch ₃ H 'CHjOH -CHj-'c- H 7-F 0 II -nh-c-nhch ₃ CH = CH ₂ OH, -CH ₂ -C- H 7-F 0 II -nh-c-nhch ₃ HOCHj CH ^3/3 _-CH2 -C H 7-F 0 II -nh-c-nhch ₃ hoch ₂ , ch ₃ "CH ₂ -'c- OH 1 -ch ₂ chch ₃ 7-CF ₃ 0 II -nh-c-nhch ₃ hoch ₂ ch ₃ \ r ³ -ch ₂ -c- OH 1 -CH ₂ CHCH ₂ OH 6-F 0 II -NH-C-NHCH ₃ hoch ₂ , ch ₃ -ch ₂ -c— OH 1 -CH ₂ CH ₂ CHCH ₃

Example 37

1-34. The following compounds of formula (ld) can be prepared from the appropriately substituted starting materials and reagents as described in Example 1 and standard organic synthetic methods.

X n P R ⁹ THE R ⁴ - 0 3 O II -NH-C-NHCH ₃ CHj ^ ch ₃ -ch ₂ -'c- H - 0 3 0 II -NH-C-NH, CHj y3Hj - ch ₂ -'c- OH -CHjCHCHj

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X n P R ⁹ THE R ⁴ - 0 1 0 II -NH-C-NHCH ₃ CH, ^ CHj —CHj-C— H - 0 1 She II -NH-C-NHCH, CH, ^ CHj —ch ₂ -c— OH -CH ₂ CHCH 3 - 0 0 0 II -NH-C-NHCH ₃ CHj CH, r -CHj-C- H - 0 0 0 II -nh-c-nhch ₃ Y3H CH, CH ₂ C- OH CH, CHCH 3 c = o 1 1 o II -NH-C-NHCH ₃ CH, ^ CH, -ch ₂ -c- OH -CH ₂ CHCH 3 CHOH 1 1 o II -NH-C-NHCH ₃ CHj ^ CHj —ch ₂ -c— OH -CH ₂ CHCH 3 S 1 0 o II -NH-C-NHCH ₃ CH 1, CH, -ch ₂ -c- H S 1 0 o II -NH-C-NHCH ₂ CH ₂ OH CHj ^ CH, C- H S 1 0 while II -nh-c-nhch ₃ CH, ^ CH, -ch ₂ -'c- OH -CHjCHCHj SALT 1 0 0 II -NH-C-NHCH ₃ CHj ^ CH, - ch ₂ -c- H SALT 1 0 while II -nh-c-nhch ₃ ch _{? z} ch, —c— H SALT 1 0 o II -NH-C-NHCH ₃ CHj, CHj -ch ₂ -c- OH ? -CHjCHCHj SALT 1 0 while II -nh-c-nhch ₃ CHj ^ CHj —ch ₂ -c— OH I -CH ₂ CHCH ₂ OH s 1 2 0 II -nh-c-nhch ₃ ch, ch, r - ch ₂ -c- H s 1 2 while II -nh-c-nhch ₃ CHj ^ CHj -c- H s 1 2 while II -nh-c-nhch ₃ ch, ^ ch, - ch ₂ -c— OH -CH ₂ CHCH 3 s 1 2 0 II -nh-c-nhch ₃ ch, ^ ch, -ch ₂ -c- OH X -CH ₂ CHCH ₂ OH s 1 2 She II -NH-C-NH ·, CHj y? H, -ch ₂ -c- H s 1 2 0 II -NH-C-NHCH ₃ CH _{3 z} CHj —c- H

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X n P R ⁹ THE R ⁴ s 1 2 0 II -nh-c-nhch ₃ CHj ^ CHj -ch ₂ -c— OH r -ch ₂ chch ₃ s 1 2 while II -nh-c-nhch ₃ CHj ^ CHj -ch ₂ -c— OH -CH ₂ CHCH ₂ OH She 1 1 while II -nh-c-nhch ₃ CHj ^ CHj -ch ₂ -c- H 0 1 1 o II -NH-C-NHCH ₃ CHj _z CH ₃ —c— H She 1 1 while II -nh-c-nhch ₃ CHj ^ CHj - ch ₂ -c- OH X -CHjCHCHj She 1 1 o II -NH-C-NHCH ₃ CHj _Z CH, -ch ₂ -c ~ OH -ch ₂ chch ₃

Example 38

1-34. The following compounds of formula (le) may be prepared from the appropriately substituted starting materials and reagents as described in Example 1 and standard organic synthetic methods:

R ¹ X m R ⁹ R ⁴ H 1 0 while II -nh-c-nhch ₃ OH X -CHjCHCHj H 1 0 o II -NH-C-NHCH ₃ OH -ch ₂ £ hch ₃ H 1 0 o II -NH-C-NHCH ₃ oh -ch ₂ chch ₂ oh H 0 0 while II -nh-c-nhch ₃ H H 0 0 while II -nh-c-nhch ₃ OH 1 -CH ₂ CH ₂ CHCH ₃ H 1 1 while II -nh-c-nhch ₃ OH -ch ₂ Chch ₃ H 1 1 0 II -nh-c-nhch ₃ QH -CH ₂ CHCH ₂ OH H 1 1 while II -nh-c-nhch ₃ OH -CHj & HCHj H 1 1 while II -nh-c-nhch ₃ OH 1 -CH ₂ CH ₂ CHCH ₃ H 1 0 0 II -NH-C-NHCH ₃ och ₃ i ³ • CH ₂ CHCH ₃ 8-F 1 0 o II -NH-C-NHCH ₃ OH -CH ₂ CHCH ₃

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R ¹ X m R ⁹ R ⁴ 8-CF ₃ 1 0 o II -NH-C-NHCH ₃ OH -CHjCHCH, 8-OCH ₃ 1 0 0 II -NH-C-NHCH ₃ OH -CHjCHCH, 8-SCH, 1 0 0 II -NH-C-NHCH ₃ OH -CHjCHCH, 9-F 1 0 0 II -NH-C-NHCH ₃ OH -CHjCHCH, 8-F 1 0 o II -NH-C-NHCH ₃ OH -CHjifCH,) 8-F 1 0 o II -NH-C-NHCH ₃ OH OH -CHjCH-CH-CH H 1 0 o II -NH-C-NHCH ₂ CH ₂ OH H H 1 0 0 II -NH-C-NHCH ₂ CH ₂ OH OH -CHjCHCH, H 1 1 o II -NH-C-NHCH ₂ CH ₂ OH OH 1 -CHjCHCH, H 1 0 0 II -NH-C-NHCH ₂ CH ₂ OH OH c -CHjCHCHjOH H 1 0 o II -NH-C-NHCH ₂ CH ₂ OH OH 1 -CHjCHjCH-CH H 0 0 o II -NH-C-NHCH ₂ CH ₂ OH OH 1 -CHjCHjCH-CH H 1 0 o II -NH-C-NHCH ₂ CH ₂ OH OH OH -CHjCH-CH-CH, 8-F 1 0 o II -NH-C-NHCH ₂ CH ₂ OH OH -CHjCHCH, 8-CF ₃ 1 0 o II -NH-C-NHCH ₂ CH ₂ OH OH T -CHjCHCH, 8-OCH ₃ 1 0 o II -NH-C-NHCH ₂ CH ₂ OH OH ? -CHjCHCH, 8-F 1 0 0 II -NH-C-NHCH ₂ CH ₂ OH OH -CHjCHCH,

Claims (8)

A pharmacologically acceptable salt of formula (I), wherein: L is a group of formula (a), n is 0 or 1, p is 0-3, q is 0-4, w is 0 or 1, X is -CO- or -CH (OH) -, m is 0-2, R ¹ , R ² , R ^1a , R ²³ , R ^1b , and R ^2b are each independently hydrogen, halogen, C 1-7 alkyl, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, - S (O) m R ^7a , cyano, nitro, R ^7b O (CH 2) _v -, R ^7b COO (CH 2) v -, R ^7b OCO (CH 2) _v -, R ⁴ R ⁵ N (CH 2) V -, R ^7b CON (R ⁴ ) (CH 2) _v - or R ⁴ R ⁵ NCO (CH ₂ ) _V -, phenyl or substituted phenyl, wherein the substituent may be one to three halogens, C 1-6 alkyl, C 1 -C 6 alkoxy or hydroxy, _R 7a and R ^7b are independently hydrogen, C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, wherein the substituent may be phenyl or substituted phenyl, and phenyl or substituted phenyl, wherein the substituents on the phenyl may be 1-3 halo, -C 6 -alkyl, C 1 -C 6 -alkoxy or hydroxy, v is 0-3, R ^3a and R ^3b are independently hydrogen, R ⁹ substituted C 1-6 alkyl group R ^9, substituted ^R9 groups phenyl or R-substituted phenoxy ⁹ group, with the proviso that R ^3a and R ^3b, at least one of R other than hydrogen, R ⁹ is R ^4b R ^12a NCON (R ^L2B) (CH2) ^ vR4bRi NCsN (R ^2b) (CH _{2) v} _ R ^4b R 1 2a _{NN (R} 12b _{) CSN (R} 12c _{) (CH 2) v} _ R ^4b R '2a _{NN (R} 12b _{) C0N (R 12c ) (CH 2) v} _ R ^4b R ^12a NN (R ^12b ) COO (CH 2) _v R (R ¹² ') NC (CH 2) (CH 2) 1 - or R ¹³ OCON (R ^12b ) (CH 2) _v wherein v is 0-3, R ^{I2a, L2B} R and R ^12c are independently R ⁵ group, -OR ⁵ or -COR ⁵ radical, or R ^12a and R ^12b, R ^12b and R ^{12c, R 3a} and R ^L2B, R ^12a and R ⁴⁰ together are - _(CH2), - B- (CH _{2) s} - form a group of the formula wherein B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-3, R ¹ and R ¹⁰ are as defined, R ¹³ is C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, wherein the substituent may be hydroxy, -NR 1 R ¹¹ , carboxyl, phenyl or substituted phenyl, and phenyl or substituted phenyl, wherein the substituents on the phenyl may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy or hydroxy, R ⁴ , R ^4b , R ⁵ and R ^5a are each independently hydrogen, phenyl, substituted phenyl, C 1-10 alkyl, substituted C 1-10 alkyl, C 3-10 alkenyl, substituted C 3-10 alkenyl, 3-10 alkynyl or substituted C3-10 alkynyl, wherein the phenyl, alkyl, alkenyl or alkynyl group may be substituted with one to five hydroxyl, C1-6 alkoxy, C3-7 cycloalkyl, fluoro, R ¹ substituted or independent groups ^R1 and Phenyl disubstituted with R ² groups and C 1 -C 3 phenylalkoxy in its alkoxy group, phenyl substituted with R ¹ or independent of R ¹ and R ² groups, C 1-20 alkanoyloxy group, C 1 -C 5 alkoxycarbonyl group, a carboxyl group, a formyl group or a group of the formula NR ¹⁰ R ^h wherein R ¹⁰ and R ¹¹ is independently hydrogen, (C 1 -C 6) -alkyl, (phenyl), (C 1 -C 6) -alkyl-alkyl, (C 1 -C 5) -alkoxycarbonyl or (C 1 -C 5) -alkanoyl and (C 1 -C 6) -alkanoylalkyl; or R ⁴ and R ⁵ together form - (CH ₂ ) _r -B- (CH ₂ ) _s -, wherein B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, and r and s are independently 1-3, R ¹ and R ¹⁰ are as defined above, R ⁶ is hydrogen, (C 1 -C 10) alkyl, phenyl or (C 1 -C 10) -alkyl in the alkyl moiety, A is a group of formula (b) wherein x and y are independently 0-3, R ⁸ and R ^8a are independently hydrogen, C 1-10 alkyl, trifluoromethyl, phenyl, substituted C 1-4 alkyl, wherein the substituent may be one to three imidazolyl, indolyl, hydroxy, fluoro, -S (O) _m R ^{7 a} radical of formula C 1 -C 6 alkoxy, 3-7C-cycloalkoxy, substituted or independent occurrences of R ¹ and R ² groups, substituted or egy34 disubstituted in the aryl and C1-3 alkoxy-phenyl, R ¹ with R ¹ group A9 is phenyl substituted with R ¹ and R ² independently of one another, C 1-5 alkanoyloxy, C 1-5 alkoxycarbonyl, carboxyl, formyl or -NR ¹⁰ R ⁿ wherein R ¹⁰ and R ¹¹ are as defined above, or R ⁸ and R ^8a together form - (CH ₂ ) -, wherein t is 2 to 6, or R ⁸ and R ^8a independently of each other form an alkylene bridge, attached to R ⁴ and / or R ⁵ , between the terminal nitrogen atom and the alkyl portion of A containing an alkylene bridge of 1 to 5 carbon atoms. A compound according to claim 1, and pharmaceutically acceptable salts thereof, wherein n is 0, p is 0-3, q is 0-2, w is 0 or 1, m is 0-2, R ¹ , R ² , R ^1a , R ²³ , R ^1b , and R ^2b are each independently hydrogen, halogen, C 1-7 alkyl, C 1-3 perfluoroalkyl, -S (O) m R ^7a , R ^7b O (CH 2) _v R ^7b COO (CH 2) v or R ^7b OCO (CH 2) _v -, phenyl or substituted phenyl, wherein the substituent may be one to three halogens, C 1-6 alkyl, alkoxy or hydroxy group of carbon, R ^7a and R ^7b are each independently hydrogen, C 1-3 perfluoroalkyl, C 1-6 alkyl, C 1-6 substituted alkyl, wherein the substituents may be phenyl and phenyl, v is 0-2, R ^3a and R ^3b are independently hydrogen, R ⁹ substituted C 1-6 alkyl group R ^9, substituted ^R9 groups phenyl or R-substituted phenoxy ⁹ group, with the proviso that R ^3a and R ^3b, at least one of R other than hydrogen, R ⁹ is R ^4b R ^12a NCON (R ^12b ) (CH ₂ ) _v -, R ⁴ bR '2a _NC SN (R' ^) (ϋΗ ₂ ) ν-, R ^4b R 2aNN (R ^12b ) CON (R ¹ ^ XCH ³ V R ^4b R ^12a NN (R ^12b ) COO (CH 2) _v R ^4b R ^12a NCOO (CH 2) v or R ¹³ OCON (R ^12b ) (CH 2) _a group of the formula v wherein v is 0-3, R ' ^2a , R ^12b and R ^12c are each independently R ^5a , -OR ^5a, or -COR ^5a , or R ^L2A _and L2B _{R12b R} 12C _{and R t R} 13a _{and R} 12a, _R L2B _{and R} 4b together form - (CH _{2) r} -B- (CH _{2) s} - form a group of the formula wherein B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-3, R ¹ is as defined above, R ¹⁰ is hydrogen, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl (alkyl) or (C 1 -C 6) -alkanoyl (C 1 -C 6) and (C 1 -C 6) -alkanoyl (alkyl); R ¹³ is C 1 -C 3 perfluoroalkyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, where the substituent may be hydroxy, -NR ¹⁰ R, carboxyl, phenyl or substituted phenyl, or phenyl or substituted phenyl. wherein the substituents on the phenyl moieties may be one to three halogens, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy wherein v is as defined above, R ⁴ , R ^4b , R ⁵ and R ^5a are each independently hydrogen, phenyl, substituted phenyl, C 1-10 alkyl, substituted C 1-10 alkyl, wherein the alkyl and phenyl substituents may be one to five hydroxy, C 1-6 alkoxy, C3-7 cycloalkyl, fluoro, R * independently substituted or ^R1 and ^R2 groups and the aryl di-substituted 1-3C-alkoxy, phenyl, substituted or independent occurrences of R ¹ and R ² groups disubstituted by R ¹ group phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxyl, or R ⁴ and R ⁵ together form - (CH ₂ ) _r -B- (CH ₂ ) _s - wherein B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, and r and s are independently 1-3, R ¹ and R ¹⁰ are as defined above, R ⁶ is hydrogen, (C 1 -C 10) -alkyl, or (C 1 -C 10) -alkyl-alkyl in its alkyl moiety, A is a group of formula (b) wherein x and y are independently O-2, R ⁸ and R ⁸³ are each independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl, indolyl, hydroxy, fluoro, -S (O) _m -R ^7a. , - (C 1 -C 5) alkoxy, phenyl substituted with R ¹ or independently substituted with R ¹ and R ² , C 1 -C 5 alkanoyloxy, C 1 -C 5 alkoxycarbonyl, carboxyl, A9 is formyl or -NR ¹⁰ R ⁿ wherein R ¹⁰ and R ¹¹ are each independently hydrogen, C 1-6 alkyl or C 1-5 alkanoyl and C 1-6 alkanoylalkyl in alkyl; or R ⁸ and R ⁸ ® together form -fCH ₂ ) _t -, where t is 2-4, or R ⁸ and R ⁸ ® are independently linked to R ⁴ and / or R ⁵ to form an alkylene bridge between the terminal nitrogen atom and the alkyl portion of A, wherein the alkylene bridge contains from 1 to 5 carbon atoms. A compound according to claim 2, and pharmaceutically acceptable salts thereof, wherein n is 0, p is 0-2, q is 0-2, w is 0 or 1, m is 0 or 1, R ¹ , R ² , R ¹ ®, R ² ®, R ^1b , and R ^2b independently of one another are hydrogen, halogen, C 1 -C 7 alkyl, C 1 -C 3 perfluoroalkyl, -S (O) m R ⁷ R ^{7b is} O (CH 2) _v -, R ^{7b is} COO (CH 2) v -, R ^{7b is} OCO (CH 2) _v -, phenyl or substituted phenyl wherein the substituent may be one to three halogens, 1-6. C 1 -C 6 alkyl, C 1 -C 6 alkoxy or hydroxy, R ^7a and R ^7b are each independently hydrogen, C 1-6 alkyl, C 1-6 substituted alkyl, wherein the substituent may be phenyl, v is 0-2, r 3 R ^3b are independently hydrogen, R ^{9 is} R ⁹ substituted C1-6 alkyl group, phenyl group substituted with R ⁹ or phenoxy substituted with R ⁹ group, with the proviso that at least one hydrogen atom of R ³ and R ^3b ®, R ⁹ is R ^4b R ^12a NCON (R ^12b ) (CH 2) v R ^4b R ¹² aNCSN (R ^12b ) (CH 2) _v -, R ^4b R 12 'N (R ^12b ) CON (R ¹ ^ (CH ¹ , R ^4b R ¹² ®NN (R ^12b ) COO (CH ₂ ) _v R ^4b R ¹² 3NCOO (CH ₂ ) _v - or R ¹³ OCON (R ^12b ) a group of formula (CH ₂ ) _v wherein v is 0-2, ® R ^12, R ^{L2B I2C} and R are independently R ⁵ group or -OR ⁵ ® ® group of formula or R ¹² ® and R ^12b , R ^12b and R ^12c , R ¹³ ® and R ^12b , R ¹² ® and R ^4b together form - (CH 2) _r -B- (CH ₂ ) _s -, wherein B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-2, R ¹ is as defined above, R ¹⁰ is hydrogen, (C 1 -C 6) -alkyl, or (C 1 -C 5) -alkanoyl and (C 1 -C 6) -alkanoylalkyl in its alkyl part, R ¹³ is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl where the substituent may be phenyl or substituted phenyl, and phenyl or substituted phenyl where the substituents on the phenyl may be one to three halogens, C 1 -C 6 alkyl, 1-6 carbon atoms. alkoxy or hydroxy group of carbon atoms, R ⁴ , R ^4b , R ⁵ and R ⁵ ® are independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, where the substituent may be one to five hydroxy groups, C 1 -C 6 alkoxy, fluoro, with R ¹ phenyl, C 1 -C 20 alkanoyloxy, C 1 -C 5 alkoxycarbonyl or carboxyl, substituted or unsubstituted by R ¹ and R ² ; R ⁶ is hydrogen, C 1-10 alkyl, A is a group of formula (b) wherein x and y are independently 0-2, R ⁸ and R ⁸ ® are independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl groups, indolyl group, hydroxy group, fluorine, -S (O) _m -R ⁷ a radical of formula Ιό -C alkoxy radical, R is a substituted or disubstituted independently of R ¹ and R ² groups, a phenyl group, C1-5 alkanoyloxy group, C1-5 alkoxycarbonyl group, or carboxy, or r8, g _and r & i * group _this yields _a group of the formula t _ (CH ₂ ) -, where t is 2, or R ⁸ and R ⁸ are independently linked to R ⁴ and / or R ⁵ to form an alkylene bridge between the terminal nitrogen atom and the alkyl portion of A, wherein the alkylene bridge contains from 1 to 5 carbon atoms. A compound according to claim 3 and pharmaceutically acceptable salts thereof, wherein n is 0, p is 0-2, q is 1, w is 1, m is 0 or 1, R ¹ , R ² , R ¹ ®, R ² ®, R ^1b , and R ^2b independently of one another are hydrogen, halogen, C 1 -C 7 alkyl, C 1 -C 3 perfluoroalkyl 36 GB 211 894 A 9, -S (O) _m R ^7a, R ^7b O (CH2) v- or R ^7b COO (CH 2) _v - group, phenyl or substituted phenyl wherein the substituents are one to three halogen, C 1-6 -alkyl, C 1-6 -alkoxy or hydroxy, R ^7a and R ^7b are each independently hydrogen, C 1-6 alkyl or C 1-6 substituted alkyl, wherein the substituent may be phenyl, v is 0 or 1, R ^3a and R ^3b are independently hydrogen, R ^{9 is} C 1-6 alkyl substituted with R ⁹ , with the proviso that at least one of R ^3a and R ^3b is other than hydrogen, R ⁹ is R ^4b R ^12a NCON (R ^12b ) (CH ₂ ) _v -, R ^4b R> ^ NNfR ^12b ) CON (R ^12c ) (CH 2) _v R ^ R 2a 2aNN (R ^12b ) COO (CH 2) _v R ^4b R 11> NCOO (CH 2) v - or R ¹³ OCON (R ^12b ) (CH 2) a group of formula _v, wherein v is 0-2, R ^12a, R ^L2B, and R ^12c are independently R ^5a group, or Rl2a _{and R} 12b _R 12b _R 12c & _R 3a _{and R} 12b _(R 12a & _R 4b together - (CH _{2) r} -B- (CH _{2) s} - form a group of the formula wherein B is -CHR ¹ -, -O, -S (O) _m - or -NR ¹⁰ -, wherein m is 0, 1 or 2, r and s are independently 0-2, R ¹ is as defined above, R ¹⁰ is hydrogen, (C 1 -C 6) alkyl or (C 1 -C 5) alkanoyl and (C 1 -C 6) alkanoylalkyl, R ¹³ is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl where the substituent may be phenyl or substituted phenyl, and phenyl or substituted phenyl where the substituents on the phenyl may be one to three halogens, C 1 -C 6 alkyl, 1-6 carbon atoms. alkoxy or hydroxy group of carbon, R ⁴ , R ^4b , R ⁵ and R ^5a are each independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three hydroxy groups, C 1 -C 3 alkoxy, fluoro, R ¹ or phenyl disubstituted with R ¹ and R ² independently of one another, C 1-20 alkanoyloxy, C 1-5 alkoxycarbonyl, or a carboxyl group, R ⁶ is hydrogen, A is a group of formula (b) wherein x and y are independently 0 or 1, R ⁸ and R ^8a are independently hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, wherein the substituent may be one to three imidazolyl, indolyl, hydroxy, fluoro, -S (O) _m -R ^7a. , - (C 1 -C 5) alkoxy, phenyl substituted with R ¹ or disubstituted with R ¹ and R ² independently of each other, C 1 -C 5 alkanoyloxy, C 1 -C 5 alkoxycarbonyl or carboxyl, or R ⁸ and R ^8a together form - (CH ₂ ) _t -, wherein t is 2, or R ⁸ and R ^8a independently of one another are linked to R ⁴ and / or R ⁵ to form an alkylene bridge between the terminal nitrogen atom and the alkyl portion of A, wherein the alkylene bridge contains from 1 to 5 carbon atoms. 5. A stereospecific compound of formula (Ia) which is a narrow group of compounds according to claim 1, wherein R ¹ , R ² , X, n, p, q, L, w, R ^1a , R ²³ , R ^3a , R ⁴ , R ⁵ , R ⁶ and A are as defined in claim 1. 6. A compound according to claim 1 which is selected from the group consisting of N- [1 - [[2 '- [(methoxycarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2, 3,4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(methylamino) -carbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1,1'-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(ethylaminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2, 3,4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide, N- [1 - [[2 '- [(2-Propylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro- 2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo -1Η-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 Η-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [l - [[2 '- [(piperazino-carbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo- -l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide, N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxol-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1- [2 '- [[(2-hydroxypropylamino)] carbonyl] amino] [l, -biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -3 amino-3-methylbutanamide, N- [1 - [[2 '- [(methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -2,3, 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(dimethylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide, N- [l - [[2 '- [[(2 (R) -hydroxy-propylamino] carbonyl] amino] [l, l'-biphenyl] -4-yl] methyl] -2,3, 4,5-tetrahydro-237 A9 oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [l - [[2 '- [[(2 (S) -hydroxy-propylamino) carbonyl] amino] [l, l'-biphenyl] -4-yl] methyl] -2,3, 4,5-tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [I - [[2 '- [[[[(l-Hydroxy-prop-2 (R) -yl] amino] carbonyl] amino] [l, l'-biphenyl] -4-yl] -methyl] -2,3,4,5-tetrahydro-2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [l - [[2 '- [4 - [(methylaminocarbonyl) amino] phenoxy] [l, l'-biphenyl] -4-yl] methyl] -2,3,4, 5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide, N- [l - [[2 '- [2 - [(methylaminocarbonyl) amino] phenoxy] [l, l'-biphenyl] -4-yl] methyl] -2,3,4, 5-Tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [2 - [(aminocarbonyl) amino] [1,1'-biphenyl] -4yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-l-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methyl-butanamide, N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 Α-1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide, N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methylbutanamide, N- [l - [[2 '- [(methylaminocarbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-lH-l-benzazepin-3 (R) -yl] -3- [2 (S) -hydroxy-propyl] amino-3-methylbutanamide, N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1 H -1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide, N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1H -l-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methylbutanamide, N- [l - [[2 '- [(morpholinocarbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo- -l-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methyl-butanamide, N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1' - biphenyl] -4-yl] methyl] -2 3,4,5-tetrahydro-2-oxol-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] amino-3-methylbutanamide, N- [l - [[2 '- [[(2-hydroxy-ethylamino) carbonyl] amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4, 5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -3- [2 (S) -hydroxy-propyl] amino-3-methyl-butanamide, N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4, 5-tetrahydro-2-oxo-1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide, N- [l - [[2 '- [(methylaminocarbonyl) amino] [l, r-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo lH-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [1 - [[2 '- [(aminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 Α-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [l - [[2 '- [(morpholinocarbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo- hl-benzazepine 3 (R) -yl] -2-amino-2-methylpropanamide, N- [1 - [[2 '- [(piperazinocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1 Η-1 Benzazepine 3 (R) -yl] -2-amino-2-methylpropanamide, N- [l - [[2 '- [[(l-hydroxy-ethylamino) carbonyl] amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4, 5-tetrahydro-2-oxo-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [l - [[2 '- [(methylaminocarbonyl) oxy] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo- lH-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [l - [[2 '- [[(methoxycarbonyl-methylamino) carbonyl] amino] [l, l'-biphenyl] -4-yl] methyl] -2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [1 - [[2 '- [(Hydroxyaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2- oxo-1 H -1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N - [1 - [[2 '- [(methoxycarbonyl) amino] [1,1] '-biphenyl] -4-yl] methyl] -2,3,4,5-tetrahydro-2-oxo-1,1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5- tetrahydro-2-oxo-1,1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [(methylaminocarbonyl) amino] ] [1,1'-Biphenyl] -4-yl] methyl] -7 trifluoro-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3 (R) -yl] -3-amino -3-methylbutanamide, N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -7 trifluoromethyl-2,3 , 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [[(2-hydroxy) ethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7 trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine 3 (R) -yl] -3-amino-3-methyl-butanamide, N - [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4, 5-tetrahydro-2-oxo-1HL-benzazepin-3 (R) -yl] -3-amino-3-methyl-butanamide, N- [1 - [[2 '- [(methylaminocarbonyl) oxy] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro- 2-oxo-1 H -1-benzazepin-3 (R) -yl] -3-amino-3-methylbutanamide, N- [1 - [[2 '- [2 - [(methylaminocarbonyl)] -amino] -phenoxy] [1,1'-biphenyl] -4-yl] methyl] -7 trifluoro-2,3,4,5-tetrahydro-2-oxo-1,1'-1-benzazepine-3 (R ) -yl] -3-amino-3-methylbutanamide, N- [l - [[2 '- [(methylaminocarbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5- tetrahydro-2-oxo-lH-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methyl-butanamide, N- [1 - [[2 '- [(methylaminocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5- tetrahydro-2-oxo-1,1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide, N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro-2-oxo -1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxypropyl] amino-3-methylbutanamide, HU 211 894 A9 N- [l - [[2 '- [(morpholinocarbonyl) amino] [l, l'-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro-2 oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (S), 3-dihydroxypropyl] amino-3-methylbutanamide, N- [1 - [[2 '- [[(2-hydroxyethylamino) carbonyl] amino] [1,1'-biphenyl] -4-yl] methyl] -7-fluoro -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -3- [2 (R) -hydroxy-propyl] amino-3-methyl-butanamide, N- [1 - [[2 '[(methylaminocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro- 2-oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [1 - [[2 '- [(morpholinocarbonyl) amino] [1,1'-biphenyl] 4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro-2 -oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [1 - [[2 '- (piperazinocarbonyl) amino] [1,1' -biphenyl] 4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methyl EMI, N- [l - [[2 '- [[(2-hydroxy-ethylamino) carbonyl] amino] [l, r-biphenyl] -4-yl] methyl] -7-fluoro-2,3 4,5-Tetrahydro-2-oxo-1H-1-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, N- [l - [[2 '- [(methylaminocarbonyl) oxy] [l, r-biphenyl] -4-yl] methyl] -7-fluoro-2,3,4,5-tetrahydro-2 oxo-lH-l-benzazepin-3 (R) -yl] -2-amino-2-methylpropanamide, 7. A method of increasing the level of endogenous growth hormone in a human or animal, comprising administering to the human or animal an effective amount of a compound according to claim 1. A composition for increasing endogenous production or release of growth hormone in a human or animal, comprising an effective amount of a compound according to claim 1 in an inert carrier.