ΉTLE OF THE INVENTION

BENZO-FUSED LACTAMS PROMOTE RELEASE OF GROWTH

HORMONE

BACKGROUND OF THE INVENTION

Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body:

1. Increased rate of protein synthesis in all cells of the body;

2. Decreased rate of carbohydrate utilization in cells of the body;

3. Increased mobilization of free fatty acids and use of fatty acids for energy.

A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.

Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressiή, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone- releasing hormone or all of these.

In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently,

recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.

Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or peptides of U.S. Patents 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. The instant compounds are non-peptidyl agents for promoting the release of growth hormone which may be administered parenterally, nasally or by the oral route.

SUMMARY OF THE INVENTION

The instant invention covers certain benzo-fused lactam compounds which have the ability to stimulate the release of natural or endogenous growth hormone. The compounds thus have the ability to be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food production where the stimulation of growth hormone will result in a larger, more productive animal. Thus, it is an object of the instant invention to describe the benzo-fused lactam compounds. It is a further object of this invention to describe procedures for the preparation of such compounds. A still further object is to describe the use of such compounds to increase the secretion of growth hormone in humans and animals. A still further object of this invention is to describe compositions containing the benzo- fused lactam compounds for the use of treating humans and animals so as to increase the level of growth hormone secretions. Further objects will become apparent from a reading of the following description.

DESCRIPTION OF THE INVENTION

The novel benzo-fused lactams of the instant invention are best described in the following structural Formula I:

where L is

nisOor 1; p is 0 to 3; q is 0 to 4; wis Oor 1;

OH R ¹⁰

X is C=0, O, S(0) _m , -CH-, -N-, -CH=CH-; m is 0 to 2; KisO,SorN-R6b _;

Rl, R2, Rla, R2a, Rib and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(0) _m R ^7a , cyano, nitro, R7bO(CH2) _v - R7bCOO(CH2) _v - R7bOCO(CH2)v- R5bRl2bN(CH2)v-, R ^5b R ^12b NCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; v is 0 to 3 and m is 0 to 2;

R7a and R b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl where the substitutents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substitutents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy;

R3a and R^b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9 or phenoxy substituted with R9;

R9 is

R7bθ(CH2)v- R ^7b COO(CH2)v-, R ^7b OCO(CH2) _v -,

R7bC0(CH2)v- R ^7b O(CH2)vCO-, R5bRl2b _N (CH2)v-.

_R 5b _R 12b _NC θ(CH2)v- R ^5b R ^12b NCS(CH2)v-

R5bRl2c _NN ( _R 12b)cθ(CH2)v-

R5 Rl2cNN Rl2b)cs(CH2)v-,

R5b _R 12bNCON(Rl2a)(CH2)v-

R5bRl2bNCSN(Rl2a)(CH2)v-

R5bRl2cNN(Rl2b)CSN(Rl2a)(CH2)v-

R5bRl2cNN(Rl2b)CON(Rl2a)(CH2)v-

R5bRl2cNN(Rl2b)COO(CH2)v- R ⁵ Rl2bNCOO(CH2)v- or Rl30CON(Rl2a)(CH2)v- where v is 0 to 3.

Rl2a, Rl2b and Rl2c are independently R5a, OR5a or COR5a. Rl2a and Rl2b, or Rl2b and Rl2c, or Rl2a and Rl2c, or Rl2b and R5b, ₀ r Rl2c and R5b, ₀ r Rl3 and Rl2a can be taken together to form -(CH2)r- B-(CH2)s- where B is CHRl, O, S(0) _m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 3 and Rl and R 10 are as defined.

Rl3 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substitutents are hydroxy, -NRlORll, carboxy, phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy.

RlO and Rll are independently hydrogen, C1-C6 alkyl, phenyl, phenyl C1-C6 alkyl, C1-C5 alkoxycarbonyl or C1-C5 alkanoyl-Cl-C6 alkyl;

R4, R4a _? R5, R5aand R5b are independently hydrogen, phenyl, substituted phenyl, Cl-ClO alkyl, substituted Cl-ClO alkyl, C3-C10 alkenyl, substituted C3-C10 alkenyl, C3-C10 alkynyl or substituted C3- ClO alkynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, Rl, R2 independently disubstituted phenyl, Rl, R ² independently disubstituted phenyl C1-C3 alkoxy, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRlθRll where Rl, R ² , RlO and Rl 1 are as defined above; or R4 and R5 can be taken together to form -(CH2)r-B-(CH2)s- where B is CHRl, O, S(0) _m or N-RlO, r and s are independently 1 to 3, m is 0, 1 or 2 and Rl and RlO are as defined above;

are independently 1 to 3, m is 0, 1 or 2 and Rl and R are as defined above;

A is

where x and y are independently 0-3;

R^a and R° ^* b are independently hydrogen, Cl-ClO alkyl, trifluoromethyl, Rl, R ² independently disubstituted phenyl, substituted Cl-ClO alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0)mR ^7a , Cl-Cfc alkoxy, C3-C7 cycloalkyl, Rl, R ² independently disubstituted phenyl, R 1 , R ² independently disubstituted phenyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRIORI 1 where Rl , R ² , R ^7a , RlO, Rl 1 and m are as defined above; or R^a and R^b can be taken together to form -(CH2)t- where t is 2 to 6; and R° ^* a and R°"b can independently be joined to one or both of R4 and R^ to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from one to five carbon atoms; and pharmaceutically acceptable salts thereof.

In the above structural formula and throughout the instant specification, the following terms have the indicated meanings:

The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy,

ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.

Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other.

Preferred compounds of the instant invention are realized when in the above structural formula: n is O or 1; p is 0 to 3; q is 0 to 2; w is O or 1;

RlO

X is O, S(0) _m , -N-, -CH=CH-; m is 0 to 2; K is O, S or N-R6b _;

Rl, R2, Rla, R2a, Rib and R.2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) _m R ^7a , R7bθ(CH2)v-. R7bCOO(CH2)v- R7bθCO(CH2)v- phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-Q3 alkyl, C1-C6 alkoxy, or hydroxy;

R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl where the substitutents are phenyl; phenyl and v is 0 to 3;

R3a and R^b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9 or phenoxy substituted with R^;

R9 IS

R7bθ(CH2) _v - R7bC00(CH2)v- R ^7b OCO(CH2)v- R7bcθ(CH2)v- R ^5b Rl ^2b N(CH2)v- R5bRl2bNCO(CH2)v- R ^5b R ^12b NCS(CH2)v- R5bRl2cNN(Rl2b)C0(CH2)v- R5bRl2bNCON(Rl2a)(CH2)v- R5bRl2bNCSN(Rl2a)(CH2)v- R5bRl2cNN(Rl2b)CSN(Rl2a)(CH2)v- R5bRl2cNN(Rl2b)CON(Rl2a)(CH2)v- R5bRl2cNN(Rl2b)COO(CH2)v- R ^5b Rl ^2b NCOO(CH2)v- or Rl30CON(Rl2a)(CH2)v- and v is 0 to 3.

Rl2a, Rl2b and Rl2c are independently R5a, OR5a or COR5a. Rl2a and Rl2b, ₀ r Rl2b and Rl2c, ₀ r Rl2a and Rl2c, or Rl2b and R5b, or Rl2c and R5b, ₀ r Rl3 and Rl2a can be taken together to form - CH2)r- B-(CH2)s- where B is CHRl, o, S(0) _m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 3 and Rl and RlO are as defined.

Rl3 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substitutents are hydroxy, -NRlORl 1, carboxy, phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy.

RlO and Rl 1 are independently hydrogen, C1-C6 alkyl, phenyl Cl-Qj alkyl, or C1-C5 alkanoyl-Cl-C6 alkyl;

R4, R4a, R5, R5aand R5b are independently hydrogen, phenyl, substituted phenyl, Cl-ClO alkyl, substituted Cl-ClO alkyl where the substituents on the alkyl or phenyl are from 1 to 5 of hydroxy, Cl-C6 alkoxy, C3-C7 cycloalkyl, fluoro, Rl, R ² independently disubstituted phenyl, Rl, R ² independently disubstituted phenyl C1-C3 alkoxy, Cl- C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy or formyl; R4 and R5 can be taken together to form -(CH2)r-B-(CH2)s- where B is CHRl, O, S(0)m or N-RlO, r and s are independently 1 to 3, m is 0, 1 or 2 and Rl and RlO are as defined above;

R6 and R6D are independently hydrogen, Cl-ClO alkyl or phenyl Cl- C10 alkyl; or R6a and R ^6b can be taken together to form -(CH2)r-B- (CH2)s- where B is O, S(0)m or N-RlO, Γ and s are independently 1 to 2, m is 0 and R and R O are as defined above;

A is

where x and y are independently 0-2;

R8a and R^b _a re independently hydrogen, Cl-ClO alkyl, substituted Cl- Cio alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0) _m R ^7a , C1-C6 alkoxy, C3-C7 cycloalkyl, Rl, R ² independently disubstituted phenyl, Rl, R ² independently disubstituted phenyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRIORI 1 where Rl, R ² , R ^7a , Rl°, Rl 1 and m are as defined above; or R^a and R^ ^b can be taken together to form -(CH2)t- where t is 2 to 4; and R^a and R^b can independently be joined to R5 to form alkylene bridges between the terminal nitrogen and the

alkyl portion of the A group wherein the bridge contains from one to five carbon atoms; and pharmaceutically acceptable salts thereof.

Additional preferred compounds are realized in the above structural formula when: n is O or 1; p is 0 to 2; q is 0 to 2; w is 0 or 1 ;

X is S(0) _m or -CH=CH-; m is 0 or 1 ; K is O or N-R6t>

Rl, R2, Rla, R2a, Rib and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) _m R ⁷ a, R7bθ(CH2)v- R7bC00(CH2)v- R7 ^b OCO(CH2)v- phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-Q5 alkyl, C1-C6 alkoxy, or hydroxy;

R7a and R7t> are independently hydrogen, C1-C6 alkyl or substituted C1-C alkyl where the substitutents are phenyl and v is 0 to 2;

R3a and R3t> are independently hydrogen, R9, C1-C6 alkyl substituted with R9 or phenoxy substituted with R9;

R9 is

_R 4a

R7 ^b O(CH2)v- R ⁷ COO(CH2)v- R ⁷ OCO(CH2)v ^~ R ^7b CO(CH2) _v - R ^5b Rl ² N(CH2)v- R5bRl2bNCO(CH2) _v - R ^5b R ^12c NN(Rl ^b )CO(CH2)v- R5bRl2bNCON(Rl ^2a )(CH2)v- R5bRl2cNN(Rl2b)CSN(Rl2a)(CH2)v- R5bRl2cNN(Rl ^2b )CON(Rl ² a)(CH2)v- R5bRl2cNN(Rl2b)COO(CH2)v- R ⁵ Rl ^2b NCOO(CH2)v- or Rl3θCON(Rl2a)(CH2) _v - where v is 0 to 2.

Rl2a, Rl2b and Rl ² c are independently R5a or OR5a. Rl2a and Rl ^2b , or Rl ^2b and Rl ² c, or Rl ² a and Rl ² c, or Rl ^2b and R5b, or Rl ² c and R5b, or Rl3 and Rl2a can be taken together to form -(CH2)r~B- (CH2) _S - where B is CHRl , o, S(0)m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 2 and Rl and RlO are as defined.

Rl3 is Cι-C6 alkyl, substituted C1-C6 alkyl, where the substitutents are phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy or hydroxy.

RlO and Rl 1 are independently hydrogen, Cl-C6 alkyl, phenyl C1-C6 alkyl, or C1-C5 alkanoyl-Cl-C6 alkyl;

R4, R4a, R5, R5aand R5b are independently hydrogen, Cl -ClO alkyl or substituted C1-C10 alkyl where the substituents are from 1 to 5 of hydroxy, C1-C6 alkoxy, fluoro, Rl, R ² independently disubstituted phenyl, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy; where Rl and R ² are as defined above;

R6a and R ^6b are independently hydrogen or Cl-ClO; or R6a and R6b can be taken together to form -(CH2)r-B-(CH2)s- where B is O or S(0)m _. r and s are 2, m is 0 and R and RlO are as defined above;

A is

where x and y are independently 0-1;

R8a and R^ ^b are independently hydrogen, Cl-ClO alkyl, substituted Cl- ClO alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0) _m R ^7a , Cl-C6 alkoxy, C3-C7 cycloalkyl, Rl , R ² independently disubstituted phenyl, Rl, R ² independently disubstituted phenyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRIORI 1 where Rl, R ² , R ^7a , Rl°, Rl 1 and m are as defined above; or R^a and R^b can be taken together to form -(CH2)t- where t is 2; and R^a and R^ ^b can independently be joined to R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from one to five carbon atoms; and pharmaceutically acceptable salts thereof.

Still further preferred compounds of the instant invention are realized in the above structural formula when; n is O or 1; p is 0 to 2; q is l; w is 1;

X is S(0) _m or -CH=CH-; m is O or 1; K is O or N-R6 ^b ;

Rl, R2, Rla, R2a, Rib and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) _m R ⁷ a, R7bO(CH2)v- R7bCOO(CH2)v-. phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, Cl- j alkyl, C1-C6 alkoxy, or hydroxy;

R7a and R7t> are independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl where the substituents are phenyl and v is 0 or 1;

R3a and R^ ⁰ are independently hydrogen, R or C1-C6 alkyl substituted with R9;

R9 IS

R7 ^b O(CH2)v- R ^7b COO(CH2)v- R ^7b OCO(CH2)v- R ^7b CO(CH2)v- R ^5b R ^i2b N(CH2)v- R5bRl2bNCO(CH2)v- R ^5b R ^12c NN(Rl ^2b )CO(CH2)v- R5b _R 12bNCON(Rl ² a)(CH2)v- R5bRl2cNN(Rl2b)CON(Rl2a)(CH2)v- R5bRl2cNN(Rl2b)COO(CH2)v- R ^5b Rl ^2b NCOO(CH2)v- or Rl3θCON(Rl2a)(CH2)v- where v is 0 to 2.

Rl2a, Rl2b and Rl2c are independently R5a. Rl2a and Rl2b, or Rl2b and Rl2c, or Rl2a and Rl2c, or Rl2b and R5b, or Rl2c and R5b, or Rl3 and Rl2a can be taken together to form -(CH2)r-B-(C.H2)s- where B is CHRl, o, S(0)m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 2 and Rl and RlO are as defined.

R 13 is C l -C6 alkyl, substituted C l -C6 alkyl, where the substitutents are phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy or hydroxy.

RlO and Rl 1 are independently hydrogen, Cl-C6 alkyl or C1-C5 alkanoyl-Cl-C6 alkyl;

R4, R4a, R5, R5aand R5b are independently hydrogen, Cl-ClO alkyl or substituted Cl-ClO alkyl where the substituents are from 1 to 3 of hydroxy, C1-C3 alkoxy, fluoro, Rl, R ² independently disubstituted phenyl, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy; where Rl and R2 are as defined above;

R6a and R^b are hydrogen;

A is

where x and y are independently 0 or 1 ;

R^a and R^b are independently hydrogen, C1-C10 alkyl, substituted Ci- Cχo alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0) _m R ⁷ a, Cl -C6 alkoxy, C3-C7 cycloalkyl, Rl , R independently disubstituted phenyl, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy, where Rl, R ² , R ^7a , and m are as defined; or R8a and R^b can be taken together to form -(CH2)t- where t is 2; and R8a and R^b can independently be joined to R5 to form alkylene bridges

between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from one to five carbon atoms; and pharmaceutically acceptable salts thereof.

Representative preferred growth hormone releasing compounds of the present invention include the following:

1. 7V-(2-Amino-2-methylpropyl)-Λ^'-[2,3 ,4,5-tetrahydro-2-oxo- l-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-lH- benzazepin-3 (R)-yl]urea;

2. -(2-Amino-2-methylpropyl)-^V'-[2,3,4,5-tetrahydro-7- methoxy-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l ,1 '-biphenyl] -4- yl]methyl]-lH-benzazepin-3(R)-yl]urea;

3. -(2-Amino-2-methylpropyl)-yV'-[2,3,4,5-tetrahydro-7- methylthio-2-oxo- 1 -[[2'-( lH-tetrazol-5-yl) [1,1 '-biphenyl]-4- yl]methyl]-lH-benzazepin-3(R)-yl]urea;

4. -(2-Amino-2-methylpropyl)- '-[2,3,4,5-tetrahydro-7- trifluoromethyl-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,r- bipheny 1] -4-yl]methyl] - 1 H-benzazepin-3 (R)-yl]urea;

5. ^-(2-Amino-2-methylρropyl)- '-[2,3,4,5-tetrahydro-7- fluoro-2-oxo-l -[[2'-(lH-tetrazol-5-yl)[l ,l'-biphenyl]-4- yljmethy 1] - 1 H-benzazepin-3 (R)-yl]urea;

6. 7v ⁷ -[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl] - amino] -2,3 ,4,5-tetrahy dro-2-oxo- 1 H-benzazepin- 1 -yl] - methyl] [1,1 '-biphenyl] -2-yl]-W-methylurea;

7. -[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-7-methoxy-2-oxo-lH-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] -2-yl] -TV'-methylurea;

8. -[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-7-methylthio-2-oxo-lH-benz- azepin- 1 -yl]methyl] [1,1 '-biphenyl] -2-yl] -N '-methy lurea;

9. Λ^-[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahydro-7-fluoro-2-oxo- 1 H-benzazepin- 1 - yl]methyl] [1,1 '-biphenyl] -2-yl] -TV '-methy lurea;

10. Λ^-[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahydro-7-trifluoromethy 1-2-oxo- 1H- benzazepin- 1 -y l]methyl] [1,1 '-biphenyl] -2-yl] -TV'-methy lurea;

11. -[[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]- carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-l- yl]methyl][l,r-biphenyl]-2-yl]methyl]- '-methylurea;

12. 7V-[[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]- carbonyl]amino]-2,3,4,5-tetrahydro-7-methoxy-2-oxo-lH- benzazepin- 1 -y l]methyl] [1,1 '-biphenyl] -2-yl]methyl] -N'- methylurea;

13. V-[[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]- carbonyl]amino]-2,3,4,5-tetrahydro-7-fluoro-2-oxo-lH- benzazepin- 1 -y l]methyl] [1,1 '-biphenyl] -2-yl]methyl] -N'- methylurea;

14. _J /V-[[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]- carbonyl]amino]-2,3,4,5-tetrahydro-7-trifluoromethyl-2-oxo- lH-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl]-2-yl]methyl]-7V ^r '- methylurea;

15. yV-[[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]- carbonyl]amino]-2,3,4,5-tetrahydro-7-methylthio-2-oxo-lH- benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] -2-yl]methyl] -N'- methylurea;

16. 4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahy dro-2-oxo-lH- 1 -benzazepin- 1 -yl]- methyl]-7V-ethyl[ 1 , 1 '-biphenyl] -2-carboxamide;

17. 4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-7-methylthio-2-oxo- 1H- 1 - benzazepin- 1 -yl]methyl] -JV-ethyl[ 1 , 1 '-biphenyl]-2- carboxamide;

18. 4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-7-methoxy-2-oxo- 1 H- 1 -benz¬ azepin- 1 -yl]methyl] -Λ -ethyl[ 1 , 1 '-biphenyl]-2-carboxamide;

19. 4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahy dro-7-fluoro-2-oxo- 1H- 1 -benzazepin- 1 -yl]methyl] -7V-ethyl[ 1 , 1 '-biphenyl] -2-carboxamide;

20. 4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahy dro-7-trifluoromethyl-2-oxo- 1H- 1 ■ benzazepin- 1 -yl]methyl] -7V-ethyl[ 1 , 1 '-biphenyl]-2- carboxamide;

21. [2,3,4,5-Tetrahydro-l -[[2'-[[(methylamino)carbonyl]- amino] [1,1 ' -biphenyl] -4-yl]methyl] -2-oxo- 1H- 1 - benzazepin-3(R)-yl]carbamic acid, (2-amino-2- methylpropyl) ester;

22. [2,3,4,5-Tetrahydro-7-methylthio-l-[[2'-[[(methylamino)- carbonyl] amino] [1,1' -biphenyl] -4-yl]methy 1] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl]carbamic acid, (2-amino-2-methyl- propyl) ester;

23. [2,3,4,5-Tetrahydro-7-fluoro-l -[[2'-[[(methylamino)- carbonyl] amino] [1,1 ' -biphenyl] -4-yl]methyl] -2-oxo- 1H- 1 - benzazepin-3(R)-yl]carbamic acid, (2-amino-2-methyl- propyl) ester;

24. [2,3,4,5-Tetrahydro-7-methoxy-l-[[2'-[[(methylamino)- carbonyl] amino] [1,1 ' -biphenyl] -4-yl]methyl] -2-oxo- 1 H-l - benzazepin-3(R)-yl]carbamic acid, (2-amino-2-methyl- propyl) ester;

25. [2,3,4,5-Tetrahydro-7-trifluoromethyl-l -[[2'-[[(methyl- amino)carbonyl] amino] [1 ,1 ' -biphenyl] -4-yl]methyl] -2-oxo- lH-l-benzazepin-3(R)-yl]carbamic acid, (2-amino-2- methylpropyl) ester;

26. [l-[[2'-[(Ethylamino)carbonyl][l ,1 '-biphenyl] -4-yl]methyl- 2,3 ,4,5-tetrahy dro-2-oxo- 1 H- 1 -benzazepin-3 (R)-yl] carbamic acid, (2-amino-2-methylpropyl) ester;

27. [1 -[[2'-[(Ethylamino)carbonyl] [1,1 '-biphenyl] -4-yl]methyl- 2,3,4,5-tetrahydro-7-fluoro-2-oxo-lH-l-benzazepin-3(R)- yl] carbamic acid, (2-amino-2-methylpropyl) ester;

28. [1 -[[2'-[(Ethylamino)carbonyl] [1,1 '-biphenyl] -4-yl]methyl- 2,3,4,5-tetrahydro-7-trifluoromethyl-2-oxo-lH-l-benz- azepin-3(R)-yl] carbamic acid, (2-amino-2-methylpropyl) ester;

29. [1 -[[2'-[(Ethylamino)carbonyl][l ,1 '-biphenyl] -4-yl]methy 1- 2,3,4,5-tetrahydro-7-methoxy-2-oxo-lH-l-benzazepin-3(R)- yl] carbamic acid, (2-amino-2-methylpropyl) ester;

30. [l-[[2'-[(Ethylamino)carbonyl][l,l'-biphenyl]-4-yl]methyl-

2,3,4,5-tetrahydro-7-methylthio-2-oxo-lH-l-benzazepin- 3(R)-yl]carbamic acid, (2-amino-2-methylpropyl) ester;

31. Λ^[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl] -N'- [2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,l'- biphenyl] -4-yl]methyl] - 1 H-benzazepin-3(R)-yl]urea;

32. -[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]- '- [2,3,4,5-tetrahydro-7-methoxy-2-oxo-l-[[2'-(lH-tetrazol-5- yl) [ 1 , 1 '-biphenyl] -4-yl]methyl] - 1 H-benzazepin-3 (R)-y l]urea;

33. ^ -[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]- '- [2,3,4,5-tetrahydro-7-methylthio-2-oxo-l-[[2'-(lH-tetrazol- 5-yl)[ 1 , 1 '-biphenyl]-4-yl]methyl] - 1 H-benzazepin-3(R)-yl] - urea;

34. Λ^[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl] -W- [2,3,4,5-tetrahydro-7-trifluoromethyl-2-oxo-l-[[2'-(lH- tetrazol-5-yl)[l ,1 '-biρhenyl]-4-yl]methyl]-lH-benzazepin- 3(R)-yl]urea;

35. Λ^2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]-ΛT- [2,3,4,5-tetrahydro-7-fluoro-2-oxo-l-[[2'-(lH-tetrazol-5- y 1) [ 1 , 1 ' -biphenyl] -4-yl]methy 1] - 1 H-benzazepin-3 (R)-y 1] urea;

36. ,IV-[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo- lH-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl]-2-yl]- '-methyl- urea;

37. 7V-[4 ^* -[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methoxy-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] - 2-yl] -W-methy lurea;

38. 7V-[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5-tetrahy dro-7- methylthio-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1'- biphenyl] -2-yl] -TV'-methylurea;

39. -[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahy dro-7-fluoro- 2-oxo- lH-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] -2-yl] -N'- methylurea;

40. -[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5 -tetrahydro-7- trifluoromethyl-2-oxo-l H-benzazepin- l-yl]methyl][l ,1 '- biphenyl] -2-yl] -W-methy lurea;

41. -[[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-

1 H-benzazepin- 1 -yljmethyl] [1,1 '-biphenyl] -2-yl]methyl] -N'- methylurea;

42. -[[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methoxy-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] - 2-yl]methyl] -TV'-methy lurea;

43. -[[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7-fluoro- 2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1 ,l'-biphenyl]-2-yl]- methyl]- '-methylurea;

44. -[[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- trifluoromethyl-2-oxo- 1 H-benzazepin- 1 -y l]methyl] [1,1'- biphenyl] -2-yl]methyl] -W-methy lurea;

45. 7V-[[4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methylthio-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 - biphenyl] -2-yl]methyl] -JV'-methy lurea;

46. 4 ^* -[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5 -tetrahydro-2-oxo- 1 H- 1 -benzazepin- 1 -yl]methyl] -/* -ethyl[ 1 , 1 '-biphenyl] -2- carboxamide;

47. 4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methylthio-2-oxo- 1H- 1 -benzazepin- 1 -yl]methyl]-7V- ethyl[l,l'-biphenyl]-2-carboxamide;

48. 4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5 -tetrahydro-7- methoxy-2-oxo-lH-l -benzazepin-1 -yl]methyl]- -ethyl[ 1,1'- biphenyl] -2-carboxamide;

49. 4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5 -tetrahydro-7-fluoro- 2-oxo- 1 H- 1 -benzazepin- 1 -yl]methyl] -7V-ethyl[ 1 , 1 '- biphenyl] -2-carboxamide;

50. 4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5 -tetrahydro-7- trifluoromethy 1-2-oxo- 1 H- 1 -benzazepin- 1 -yl]methyl] -N- ethyl[l,l'-biphenyl]-2-carboxamide;

51. [2,3,4,5-Tetrahydro-l-[[2'-[[(methylamino)carbonyl]- amino][l, -biphenyl]-4-yl]methyl]-2-oxo-lH-l- benzazepin-3(R)-yl]carbamic acid, [2-[2(R)- hydroxypropyl]amino-2-methylpropyl] ester;

52. [2,3,4,5-Tetrahydro-7-methylthio-l -[[2'-[[(methylamino)- carbony 1] amino] [1,1 ' -biphenyl] -4-y l]methy 1] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl]carbamic acid, [2-[2(R)-hydroxy- propyl]amino-2-methylpropyl] ester;

53. [2,3,4,5-Tetrahydro-7-fluoro-l -[[2'-[[(methylamino)- carbony 1] amino] [1,1 ' -biphenyl] -4-yl]methy 1] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl]carbamic acid, [2-[2(R)-hydroxy- propyl]amino-2-methylpropyl] ester;

54. [2,3,4,5-Tetrahydro-7-methoxy-l -[[2'-[[(methylamino)- carbonyl] amino] [1,1 ' -biphenyl] -4-yl]methy 1] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl] carbamic acid, [2-[2(R)-hydroxy- propyl]amino-2-methylpropyl] ester;

55. [2,3,4,5-Tetrahydro-7-trifluoromethyl-l -[[2'-[[(methyl- amino)carbonyl] amino] [1 ,1 '-biphenyl]-4-yl]methyl]-2-oxo- lH-l-benzazepin-3(R)-yl]carbamic acid, [2-[2(R)-hydroxy- propyl]amino-2-methylpropyl] ester;

56. [ 1 -[[2'-[(Ethylamino)carbonyl] [1,1 '-biphenyl]-4-yl]methyl- 2,3 ,4,5-tetrahy dro-2-oxo- 1 H- 1 -benzazepin-3 (R)-yl] carbamic acid, [2-[2(R)-hydroxypropyl]amino-2-methylpropyl] ester;

57. [1 -[[2'-[(Ethylamino)carbonyl][l ,1 '-biphenyl] -4-y l]methyl- 2,3,4,5-tetrahydro-7-fluoro-2-oxo-lH-l-benzazepin-3(R)- yl]carbamic acid, [2-[2(R)-hydroxypropyl]amino-2-methyl- propyl] ester;

58. [l-[[2'-[(Ethylamino)carbonyl][l,l'-biphenyl]-4-yl]methyl- 2,3,4,5-tetrahydro-7-trifluoromethyl-2-oxo-lH-l-benz- azepin-3(R)-yl] carbamic acid, [2-[2(R)-hydroxypropyl]- amino-2-methylpropyl] ester;

59. [l-[[2'-[(Ethylamino)carbonyl][l,l ^* -biphenyl]-4-yl]methyl- 2,3 ,4,5-tetrahy dro-7-methoxy-2-oxo- 1 H- 1 -benzazepin-3 (R) - yl] carbamic acid, [2-[2(R)-hydroxypropyl]amino-2- methylpropyl] ester;

60. [l-[[2 ^* -[(Ethylamino)carbonyl][l,l'-biphenyl]-4-yl]methyl- 2,3,4,5-tetrahydro-7-methylthio-2-oxo-lH-l-benzazepin- 3(R)-yl]carbamic acid, [2-[2(R)-hydroxypropyl]amino-2- methylpropyl] ester;

61. Λ^-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-7V'- [2,3,4,5-tetrahydro-2-oxo-l -[[2'-(lH-tetrazol-5-yl)[ 1,1'- biphenyl] -4-yl]methyl] - 1 H-benzazepin-3(R)-yl]urea;

62. -[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]- V'- [2,3,4,5-tetrahydro-7-methoxy-2-oxo-l-[[2 ^* -(lH-tetrazol-5- yl) [ 1 , 1 '-biphenyl] -4-yl]methyl] - 1 H-benzazepin-3 (R)-yl]urea;

63. Λ^-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-Λ '- [2,3,4,5-tetrahydro-7-methylthio-2-oxo-l-[[2'-(lH-tetrazol- 5-yl)[l,l'-biphenyl]-4-yl]methyl]-lH-benzazepin-3(R)-yl]- urea;

64. V-[2-[2(S),3-Dihydroxypropyl] amino-2-methylρropyl] - '- [2,3,4,5-tetrahydro-7-trifluoromethyl-2-oxo-l-[[2'-(lH- tetrazol-5 -yl) [1,1 '-biphenyl] -4-yl]methyl] - 1 H-benzazepin- 3(R)-yl]urea;

65. yV-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-yV'- [2,3,4,5-tetrahydro-7-fluoro-2-oxo-l-[[2'-(lH-tetrazol-5- yl) [ 1 , 1 '-biphenyl] -4-yl]methyl] - 1 H-benzazepin-3 (R)-yl]urea;

66. Λ^-[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino]carbonyl] amino] -2,3,4,5-tetrahydro-2- oxo- 1 H-benzazepin- 1 -y l]methyl] [1,1 '-biphenyl] -2-yl] -N'- methylurea;

67. -[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino]carbonyl] amino] -2,3 ,4,5-tetrahy dro-7- methoxy-2-oxo- 1 H-benzazepin- 1 -yl]methy 1] [1,1 '-biphenyl] - 2-yl]- V'-methylurea;

68. 7V-[4 ^* -[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methylthio-2-oxo- lH-benzazepin- 1 -yl]methyl] [1,1'- biphenyl] -2-yl]-7V'-methylurea;

69. Λ^-[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino]carbonyl] amino] -2,3 ,4,5-tetrahy dro-7- fluoro-2-oxo- 1 H-benzazepin- 1 -yl]methy 1] [1,1 '-biphenyl] -2- yl] - V'-methylurea;

70. -[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- trifluoromethyl-2-oxo- 1 H-benzazepin- 1 -y l]methyl] [1,1'- bipheny 1] -2-yl] -N '-methy lurea;

71. 7V-[[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-2- oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] -2-yl] - methyl] -W-methy lurea;

72. Λ -[[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methoxy-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] - 2-yl]methyl] -W-methylurea;

73. -[[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- fluoro-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] -2- yl]methy 1] - '-methylurea;

74. ^-[[4 ^* -[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- trifluoromethyl-2-oxo- 1 H-benzazepin- 1 -y l]methyl] [1,1'- biphenyl] -2-y l]methyl] -W-methylurea;

75. -[[4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methylthio-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1'- bipheny 1] -2-yl]methy 1] -W-methy lurea;

76. 4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo- 1H- 1 -benzazepin- 1 -yl]methyl] -Λ -ethyl[ 1 , 1 '-biphenyl]-2- carboxamide;

77. 4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-7- methylthio-2-oxo- 1 H- 1 -benzazepin- 1 -yl]methy 1] -TV- ethyl [1,1 '-biphenyl] -2-carboxamide;

78. 4 ^* -[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl] amino] carbony 1] amino] -2,3 ,4 ,5 -tetrahydro-7 - methoxy-2-oxo- 1H- 1 -benzazepin- 1 -yl]methy 1] -/V-ethyl[ 1,1'- biphenyl] -2-carboxamide;

79. 4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl] amino]carbony 1] amino] -2,3 ,4,5 -tetrahydro-7-fluoro- 2-oxo- 1 H- 1 -benzazepin- 1 -yl]methyl] -N-ethyl [1,1'- biphenyl] -2-carboxamide;

80. 4'-[[3(R)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4 ,5 -tetrahy dro-7 - trifluoromethyl-2-oxo- 1 H- 1 -benzazepin- 1 -yl]methyl] -TV- ethyl [1,1 '-biphenyl] -2-carboxamide;

81. [2,3,4,5-Tetrahydro-l-[[2'-[[(methylamino)carbonyl]- amino][l, -biphenyl]-4-yl]methyl]-2-oxo-lH-l- benzazepin-3(R)-yl]carbamic acid, [2-[2(S),3- dihydroxypropyl] amino-2-methylpropy 1] ester;

82. [2,3,4,5-Tetrahydro-7-methylthio-l-[[2'-[[(methylamino)- carbony 1] amino] [1,1' -biphenyl] -4-y l]methyl] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl]carbamic acid, [2-[2(S),3-dihydroxy- propyl]amino-2-methylpropyl] ester;

83. [2,3,4,5-Tetrahydro-7-fluoro-l -[[2'-[[(methylamino)- carbony 1] amino] [1,1 ' -biphenyl] -4-y l]methy 1] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl]carbamic acid, [2-[2(S),3-dihydroxy- propyl]amino-2-methylpropyl] ester;

84. [2,3,4,5-Tetrahydro-7-methoxy-l-[[2'-[[(methylamino)- carbonyl] amino] [1,1 ' -biphenyl] -4-yl]methyl] -2-oxo- 1 H- 1 - benzazepin-3(R)-yl]carbamic acid, [2-[2(S),3-dihydroxy- propyl]amino-2-methylpropyl] ester;

85. [2,3,4,5-Tetrahydro-7-trifluoromethyl-l -[[2'-[[(methyl- ammo)carbonyl] amino] [1 ,1 '-biphenyl]-4-yl]methyl]-2-oxo- lH-l-benzazepin-3(R)-yl] carbamic acid, [2-[2(S),3- dihydroxypropyl] amino-2-methylpropy 1] ester;

86. [1 -[[2'-[(Ethylamino)carbonyl][l ,1 '-biphenyl] -4-yl]methyl- 2,3,4,5-tetrahydro-2-oxo- 1H- 1 -benzazepin-3(R)-yl]carbamic acid, [2-[2(S),3-dihydroxypropyl]amino-2-methylpropyl] ester;

87. [l-[[2'-[(Ethylamino)carbonyl][l,r-biphenyl]-4-yl]methyl- 2,3 ,4,5-tetrahy dro-7-fluoro-2-oxo- 1 H- 1 -benzazepin-3 (R)- yl]carbamic acid, [2-[2(S),3-dihydroxypropyl]amino-2- methylpropyl] ester;

88. [l-[[2'-[(Ethylamino)carbonyl][l,l'-biphenyl]-4-yl]methyl- 2,3 ,4,5-tetrahydro-7-trifluoromethy 1-2-oxo- 1 H- 1 -benz- azepin-3(R)-yl]carbamic acid, [2-[2(S),3-dihydroxypropyl]- amino-2-methylpropyl] ester;

89. [l-[[2'-[(Ethylamino)carbonyl][l,l'-biphenyl]-4-yl]methyl- 2,3,4,5-tetrahydro-7-methoxy-2-oxo-lH-l-benzazepin-3(R)- yl]carbamic acid, [2-[2(S),3-dihydroxypropyl]amino-2- methylpropyl] ester;

90. [l-[[2'-[(Ethylamino)carbonyl][l,r-biphenyl]-4-yl]methyl- 2,3,4,5-tetrahydro-7-methylthio-2-oxo-lH-l-benzazepin- 3(R)-yl]carbamic acid, [2-[2(S),3-dihydroxypropyl]amino-2- methylpropyl] ester;

91. Λ^-(2-Amino-2-methylpropyl) W-[2,3,4,5-tetrahydro-4-oxo- 5-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,5- benzothiazepin-3(S)-yl]urea;

92. Λ^-(2-Amino-2-methylpropyl)-yV'-[2,3,4,5-tetrahydro-8- fluoro-4-oxo-5-[[2'-(lH-tetrazol-5-yl)[l ,l'-biphenyl]-4- yl]methyl]- 1 ,5-benzothiazepin-3(S)-yl]urea;

93. 7V-(2-Amino-2-methylpropyl)- '-[2,3,4,5-tetrahydro-8- trifluoromethyl-4-oxo-5-[[2'-(lH-tetrazol-5-yl)[l,r- biphenyl]-4-yl]methyl]-l,5-benzothiazepin-3(S)-yl]urea;

94. 7V-(2-Amino-2-methylpropyl)-7V'-[2,3,4,5-tetrahydro-8- methoxy-4-oxo-5-[[2'-(lH-tetrazol-5-yl)[l ,1 '-biphenyl] -4- yl]methyl]-l,5-benzothiazepin-3(S)-yl]urea;

95. ΛT-(2-Amino-2-methylpropyl)-7V'-[2,3,4,5-tetrahydro-8- methylthio-4-oxo-5-[[2'-(lH-tetrazol-5-yl)[l ,1 '-biphenyl] -4- yl]methyl]-l,5-benzothiazepin-3(S)-yl]urea;

96. -[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-4-oxo- 1 ,5-benzothiazepin-5-yl] - methyl] [1,1 '-biphenyl] -2-y l]-7V'-methy lurea;

97. A^-[4'-[[3(S)-[[[(2-Aιnino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahy dro-8-methylthio-4-oxo- 1 ,5-benzo- thiazepin-5-yl]methy 1] [1,1 '-biphenyl] -2-yl] -TV'-methy lurea;

98. Λ^-[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-8-methoxy-4-oxo-l,5-benzo- thiazepin-5-yl]methyl] [ 1 ,1 '-biphenyl]-2-yl]-7V'-methylurea;

99. _J /V-[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbony l] - amύιo]-2,3,4,5-tetrahydro-8-trifluoromethyl-4-oxo-l,5- benzothiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl] --V'- methylurea;

100. 7V-[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahy dro-8-fluoro-4-oxo- 1 ,5-benzo- thiazepin-5-yl]methy 1] [1,1 '-biphenyl] -2-yl] -TV'-methylurea;

101. yV-[[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-4-oxo- 1 ,5-benzothiazepin-5-yl] - methyl] [1,1 '-biphenyl] -2-y l]methyl] -./V'-methylurea;

102. Λ^-[[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahydro-8-methoxy-4-oxo-l ,5-benzo- thiazepin-5-yl]methyl] [ 1 ,1 '-biphenyl] -2-yl]methyl]-W- methylurea;

103. -[[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-8-trifluoromethyl-4-oxo-l,5- benzothiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl]methyl] -N'- methylurea;

104. 7V-[[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- aπιino]-2,3,4,5-tetrahydro-8-methylthio-4-oxo-l,5-beιιzo - thiazepin-5-yl]methyl][ 1 ,1 '-biphenyl]-2-yl]methyl]-7V'- methylurea;

105. yV-[[4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-8-fluoro-4-oxo-l,5-benzo- thiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl]methyl] -7V'- methylurea;

106. 4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-4-oxo-l,5-benzothiazepin-5-yl]- methyl]-yV-ethyl[ 1 , 1 '-biphenyl] -2-carboxamide;

107. 4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-8-fluoro-4-oxo-l,5-benzo- thiazepin-5-yl]methyl] -TV-ethyl [1 ,1 '-biphenyl] -2- carboxamide;

108. 4'-[ 3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3 ,4,5-tetrahydro-8-trifluoromethyl-4-oxo- 1 ,5- benzothiazepin-5-yl]methyl]- -ethyl[ 1 , 1 '-biphenyl] -2- carboxamide;

109. 4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-8-methoxy-4-oxo-l,5-benzo- thiazepin-5-yl]methy 1] -TV-ethyl [1,1 '-biphenyl] -2- carboxamide;

110. 4'-[[3(S)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-8-methylthio-4-oxo-l,5-benzo- thiazepin-5-yl]methyl] -TV-ethyl [1 , 1 '-biphenyl]-2- carboxamide;

111. 7V-[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]-Λ^'- [2,3,4,5-tetrahydro-4-oxo-5-[[2'-(lH-tetrazol-5-yl)[l,r- biphenyl] -4-yl]methyl] - 1 ,5-benzothiazepin-3(S)-yl]urea;

112. Λ^-[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl] -TV'- [2,3,4,5-tetrahydro-8-fluoro-4-oxo-5-[[2'-(lH-tetrazol-5- yl)[l,l'-biphenyl]-4-yl]methyl]-l,5-benzothiazepin-3(S)-yl]- urea;

113. -[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]-7V'-

[2,3,4,5-tetrahydro-8-trifluoromethyl-4-oxo-5-[[2'-(lH- tetrazol-5-yl)[l , 1 '-biphenyl] -4-y l]methyl] - 1 ,5-benzo- thiazepin-3 (S)-yl]urea;

114. TV-[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]-Λ '-

[2,3,4,5-tetrahydro-8-methoxy-4-oxo-5-[[2'-(lH-tetrazol-5 - yl) [ 1 , 1 '-biphenyl] -4-yl]methyl] - 1 ,5-benzothiazepin-3 (S)-yl] - urea;

115. TV- [2- [2(R)-Hydroxypropy 1] amino-2-methylpropy 1] -TV'- [2,3,4,5-tetrahydro-8-methylthio-4-oxo-5-[[2'-(lH-tetrazol- 5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,5-benzothiazepin-3(S)- yl]urea;

116. TV-[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl] -TV'- methylurea;

117. TV-[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5 -tetrahydro-8- methylthio-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1 , 1 '- biphenyl]-2-yl]-TV'-methylurea;

118. TV-[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahydro-8- methoxy-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [ 1 , 1 '- biphenyl] -2-yl] -TV'-methylurea;

119. TV-[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- trifluoromethy 1-4-oxo-l ,5-benzothiazepin-5-yl]methyl] [1 , 1 '- biphenyl] -2-yl] -TV'-methylurea;

120. TV-[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8-fluoro- 4-oxo- 1 ,5 -benzothiazepin-5 -y l]methyl] [1,1 '-biphenyl] -2-y 1] - TV'-methylurea;

121. TV-[[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1 , 1 '-biphenyl] -2-yl] - methyl] -TV'-methylurea;

122. TV-[[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5 -tetrahydro-8- methoxy-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1,1'- bipheny 1] -2-yl]methyl] -TV'-methylurea;

123. TV-[[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3 ,4,5 -tetrahydro-8- trifluoromethyl-4-oxo-l ,5-benzothiazepin-5-yl]methyl] [1 , 1 '- biphenyl] -2-yl]methyl] -TV'-methylurea;

124. TV-[[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] aminojcarbonyl] amino] -2,3 ,4,5 -tetrahydro-8- methylthio-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1,1'- biphenyl] -2-yl]methyl] -TV'-methylurea;

125. TV-[[4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino]carbonyl] amino] -2,3,4,5-tetrahydro-8-fluoro- 4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl] - methyl] -TV'-methylurea;

126. 4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-4-oxo-

1 ,5-benzothiazepin-5-yl]methyl]-TV-ethyl[l ,1 '-biphenyl]-2- carboxamide;

127. 4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl]aιnino]carbonyl]amino]-2,3,4,5-tetrahydro-8-fluoro- 4-oxo-l, 5-benzothiazepin-5-yl]methyl]-TV-ethyl[l,l'- biphenyl] -2-carboxamide;

128. 4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahy dro-8- trifluoromethyl-4-oxo-l,5-benzothiazepin-5-yl]methyl]-TV- ethyl[l ,1 '-biphenyl] -2-carboxamide;

129. 4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5 -tetrahydro-8- methoxy-4-oxo-l,5-benzothiazepin-5-yl]methyl]-TV- ethyl [1,1 '-biphenyl] -2-carboxamide;

130. 4'-[[3(S)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahy dro-8- methylthio-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] -TV- ethyl [1,1 '-biphenyl] -2-carboxamide;

131. TV-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-TV'- [2,3,4,5-tetrahydro-4-oxo-5-[[2 ^* -(lH-tetrazol-5-yl)[l ,1 ^* - biphenyl]-4-yl]methyl]-l,5-benzothiazepin-3(S)-yl]urea;

132. -[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-TV'- [2,3,4,5-tetrahydro-8-fluoro-4-oxo-5-[[2'-(lH-tetrazol-5- yl) [ 1 , 1 '-biphenyl] -4-yl]methyl] - 1 ,5-benzothiazepin-3 (S)-yl] - urea;

133. TV-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-TV'- [2,3,4,5-tetrahydro-8-trifluoromethyl-4-oxo-5-[[2'-(lH- tetrazol-5-yl) [1,1 '-biphenyl] -4-yl]methyl] - 1 ,5-benzo- thiazepin-3 (S)-yl]urea;

134. TV-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]- '- [2,3,4,5-tetrahydro-8-methoxy-4-oxo-5-[[2'-(lH-tetrazol-5- yl)[l , 1 '-biphenyl] -4-yl]methyl]-l ,5-benzothiazepin-3(S)-yl]- urea;

135. TV-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-TV'- [2,3,4,5-tetrahydro-8-methylthio-4-oxo-5-[[2'-(lH-tetrazol- 5-yl)[l ,l'-biphenyl]-4-yl]methyl]-l ,5-benzothiazepin-3(S)- yl]urea;

136. TV-[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahy dro-4- oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl] - TV'-methylurea;

137. TV-[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino]carbonyl] amino] -2,3 ,4,5-tetrahy dro-8- methylthio-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1 , 1 '- biphenyl] -2-yl] -TV'-methylurea;

138. TV-[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahy dro-8- methoxy-4-oxo-l ,5-benzothiazepin-5-yl]methyl] [1,1'- bipheny 1] -2-yl] -TV'-methylurea;

139. Λ^-[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- trifluoromethyl-4-oxo-l ,5-benzothiazepin-5-yl]methyl] [1 ,1 '- biphenyl] -2-yl] -TV'-methylurea;

140. TV-[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- fluoro-4-oxo- 1 ,5-benzothiazepin-5 -yl]methy 1] [1,1'- bipheny 1] -2-yl] -TV'-methylurea;

141. TV-[[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino]carbonyl] amino] -2,3 ,4,5-tetrahy dro-4- oxo-1 ,5-benzothiazepin-5-yl]methyl] [1,1 '-biphenyl] -2-yl] - methyl] -TV'-methylurea;

142. TV-[[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahydro-8- methoxy-4-oxo-l ,5-benzothiazepin-5-yl]methyl] [1 ,1 '- biphenyl] -2-yl]methyl] -TV'-methylurea;

143. TV-[[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- trifluoromethyl-4-oxo- 1 ,5-benzothiazepin-5-yl]methy 1] [1,1'- bipheny 1] -2-y l]methyl] -TV'-methylurea;

144. TV-[[4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- methylthio-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1 , 1 '- biphenyl] -2-yl]methyl] -TV'-methylurea;

145. TV-[[4 ^* -[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- memylpropyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- fluoro-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] [1,1'- bipheny 1] -2-yl]methy 1] -TV'-methylurea;

146. 4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2- methylpropyl] aminojcarbonyl] amino] -2,3 ,4,5-tetrahy dro-4- oxo-1 ,5-benzothiazepin-5-y l]methyl] -TV-ethyl[ 1 , 1 '-biphenyl] - 2-carboxamide;

147. 4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahydro-8-fluoro- 4-oxo-l ,5-benzothiazepin-5-yl]methyl]-TV-ethyl[ 1,1'- biphenyl] -2-carboxamide;

148. 4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl]amino]carbonyl]amino]-2,3,4,5-tetrahydro-8- trifluoromethyl-4-oxo-l,5-benzothiazepin-5-yl]methyl]-TV- ethyl[ 1 , 1 '-biphenyl] -2-carboxamide;

149. 4 ^* -[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl]amino]carbonyl] amino] -2,3 ,4,5-tetrahydro-8- methoxy-4-oxo-l,5-benzothiazepin-5-yl]methyl]-TV- ethyl[l , 1 '-biphenyl] -2-carboxamide; and

150. 4'-[[3(S)-[[[[2-[2(S),3-Dihydroxypropyl]amino-2-methyl- propyl] amino] carbonyl] amino] -2,3 ,4,5-tetrahy dro-8- methylthio-4-oxo- 1 ,5-benzothiazepin-5-yl]methyl] -TV- ethyl [1,1 '-biphenyl] -2-carboxamide.

Representative examples of the nomenclature employed are given below:

[2,3,4,5-Tetrahydro-7-memyl-l-[[2'-[[(memylamino)carbonyl ]amino]- [ 1 , 1 ' -biphenyl] -4-yl]methyl] -2-oxo- 1 H- 1 -benzazepin-3 (R)-yl] carbamic acid. (2-amino-2-methylpropyl) ester

4'-[[3(R)-[[[[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl] amino]- carbonyl] amino] -2,3 ,4,5-tetrahy dro-2-oxo- 1 H- 1 -benzazepin- 1 -yl] - methyl] -TV-ethyl π .1 '-biphenyll-2-carboxamide

TV-[2-[2(S),3-Dihydroxypropyl]amino-2-methylpropyl]-TV'-[ 2,3,4,5-tetra- hydro-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4-yl]methyl]-lH- benzazepin-3( ^' RVynurea

TV-2-[[4'-[[3(S)-[[[(2-amino-2-methylpropyl)amino]carbony l]amino]- 2,3,4 ,5-tetrahydro-8-methyl-4-oxo-l,5-benzothiazepin-5-yl]methyl] π .1 '-biphenvfl -2- ylllethyl-TV'-^-morpholino^urea

The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in the structural Formula I above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention. In the case of the asymmetric center represented by the asterisk in Formula I, it has been found that the compound in which the 3-amino substituent is above the plane of the structure, as seen in Formula la, is more active and thus more preferred over the compound in which the 3-amino substituent is below the plane of the structure. The asymmetric center will be designated according to the R/S rules as either R or S depending upon the value of X.

The instant compounds are generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain compounds containing an acidic function such as a tetrazole or carboxy can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.

The compounds (I) of the present invention are prepared from aminolactam intermediates such as those of Formula π. The preparation of these intermediates is described by Fisher, et ah, in U.S. Patent 5,206,235 and references cited therein. Preparation of compounds (I) of the present invention from intermediates of Formula II is described in the following Schemes.

π

In general, intermediates of Formula II are converted to the corresponding urea-, carbamate- or thiocarbamate intermediate IV as illustrated in Scheme 1. Activation of the amine component of intermediate II is achieved by a variety of reagents known in the literature and familiar to one skilled in the art. For example, as described in the following Schemes, reagents such as TV^V'-carbonyldiimidazole or its sulfur analog, TV,TV'-thiocarbonyldiimidazole, phosgene, triphosgene or 4- nitrophenylchloroformate are all commonly used to activate amines. Subsequent treatment of the activated amine with compound HI leads directly to ureas, carbamates or thiocarbamates.

SCHEME 1

π m

Intermediates of Formula IV wherein K is taken as -NR6b- (3) are prepared from amine I as shown in Scheme 2. The protected amine derivatives 1 are, in many cases, commercially available in t- butoxycarbonyl (BOC) or benzyloxycarbonyl (CBz) forms. It may be appreciated by one skilled in the art that other substituents may also be present that need to be protected during the ensuing chemical transformations. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis. T.W. Greene, John Wiley and Sons, New York, 1981. Amine 1 can be further elaborated to a new compound (2) which is substituted on the amino group. Reductive alkylation of I with an aldehyde is carried out under conditions known in the art; for example, by catalytic hydrogenation with hydrogen in the presence of platinum, palladium or nickel catalysts or with chemical reducing agents such as sodium cyanoborohydride in an inert solvent such as methanol or ethanol to give compound 2. Treatment of intermediate II with TV,TV'-carbonyldiimidazole in an inert solvent, such as methylene chloride or tetrahydrofuran (THF), rapidly leads to formation

of an activated species which is further reacted with amine 2 to give the desired urea product 3. Separation of unwanted side products, and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (W.C. Still, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923 (1978)) or by medium pressure liquid chromatography.

SCHEME 2

G is f-butoxycarbonyl or benzyloxycarbonyl

Alternatively, urea compounds of Formula 3 may also be prepared by using 4-nitrophenylchloroformate as the activating reagent as shown in Scheme 3. Thus, treatment of II with 4-nitrophenyl chloro- formate results in formation of a reactive 4-nitrophenyl carbamate intermediate which is reacted in situ with amine 2 to give the desired urea product 3.

SCHEME 3

G is f-butoxycarbonyl or benzyloxycarbonyl

Intermediates of Formula IV wherein K is -NH- (5) are prepared by a similar route from π. As illustrated in Scheme 4, amine I is converted to an isocyanate 4 by treatment with phosgene, or preferably, with a phosgene equivalent such as bts(tricMoromethyl)carbonate (triphosgene), in the presence of triethylamine in methylene chloride. Reaction of the isocyanate 4 with compound II gives the desired urea product 5.

SCHEME 4

R ⁵ R ⁵

I (CI ₃ CO) ₂ CO I

H ₂ N-A-N-G 0=C=N-A-N-G

Et ₃ N 1 4

G is f-butoxycarbonyl or benzyloxycarbonyl

A convenient preparation of a preferred intermediate 8 is shown in Scheme 5. Diamine 6, available from several commercial sources, is first treated with benzyl chloroformate which gives predominant reaction at the less hindered amine. Subsequent reaction of the remaining amino group with di-/-butyldicarbonate affords a differentially protected diamine intermediate, which is selectively de¬ blocked by hydrogenolytic removal of the benzylcarbamate group under mildly acidic conditions. Neutralization of the hydrochloride salt thus

formed gives the mono-protected diamine 7. Treatment of 7 with triphosgene as described above affords the isocyanate 8.

SCHEME 5

H ₃ C CH ₃ 1. benzyl chloroformate

\ / 2. di-f-butyldicarbonate, Et ₃ N

H ₂ N-CH ₂ - C-NH ₂

3. H ₂ , Pd(OH) ₂ /C, CH ₃ OH/HCI £ 4. Et ₃ N

H C CHq (CI ₃ CO) ₂ CO HqC CH

\ / ^{3 3} \ /

H ₂ N-CH ₂ -C-NHBOC CH Cl , Et N 0= C=N-CH ₂ - C-NHBOC Z S

Intermediates of Formula IV wherein K is O (10) are prepared by a route analogous to that described above for the preparation of urea compounds. As summarized in Scheme 6, amine II is first reacted with TV _^ V'-carbonyldiimidazole in an inert solvent, which step is followed by reaction with alcohol 9. The carbamate product 1O is isolated and purified as desribed previously.

SCHEME 6

10

Alternatively, carbamate compound 1O may also be prepared by using 4-nitrophenylchloroformate as the activating reagent as shown in Scheme 7. Thus, treatment of II with 4-nitrophenyl chloroformate results in formation of a reactive 4-nitrophenyl carbamate intermediate which is reacted in situ with alcohol 9 to give the desired carbamate product JO.

π

G is f-butoxycarbonyl or benzyloxycarbonyl

1Q

Thiocarbamate intermediates of Formula IV wherein K is S (12) are prepared by routes analogous to those described in Schemes 6 and 7 for the preparation of carbamate derivatives. As shown in Scheme 8, following activation of intermediate π by either of the methods described, reaction with thiol ϋ affords the thiocarbamate prduct 12.

SCHEME 8

π ιι

G is f-butoxycarbonyl or benzyloxycarbonyl

12

Intermediates of Formula VI are prepared as shown in Scheme 9 by treatment of the desired lactam intermediate IV with an alkylating agent V, wherein Y is a good leaving group such as Cl, Br, I, 0-methanesulfonyl or 0-(p-toluenesulfonyl). Alkylation of intermediates of Formula IV is conveniently carried out in anhydrous dimethyl formamide (DMF) in the presence of bases such as sodium hydride or potassium r-butoxide for a period of 0.5 to 24 hours at temperatures of 20-100°C. Substituents on the alkylating agent V may need to be protected during alkylation. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis. T.W. Greene, John Wiley and Sons, New York, 1981.

SCHEME 9

IV 1. NaH/DMF

Y is a leaving group G is f-butoxycarbonyl or benzyloxycarbonyl

VI

Alkylating agents V are, in some cases commercially available compounds or may be prepared as described in EPO publications 253,310; 291,969; 324,377 and the references cited therein.

Compounds of Formula I wherein R^a or R3b is a tetrazole are prepared as described in Scheme 10 by alkylation of IV with a suitably substituted alkylating agent V containing a nitrile as tetrazole precursor. Elaboration of nitrile JJ3 to the desired tetrazole product 14 is carried out by treatment with trimethyltin azide in refluxing toluene.

SCHEME 10

Y is a leaving group G is f-butoxycarbonyl or benzyloxycarbonyl

SCHEME 10 (CONT'D)

G is f-butoxycarbonyl or benzyloxycarbonyl

14

A useful method to prepare a preferred alkylating agent 19 is own in reaction Scheme 11 , and in U.S. Patent 5,039,814.

SCHEME 11

15

Λ/-bromosuccinimide

AIBN, CCI ₄ , reflux

13.

As outlined in Scheme 11 , benzonitrile is treated with sodium azide and zinc chloride to give 5-phenyltetrazole 15 which is converted to the N-trityl derivative 16 by treatment with triphenylmethyl chloride and triethylamine. The zinc reagent 17 was prepared by treatment with n-butyllithium followed by zinc chloride. Coupling with 4-iodotoluene using the catalyst bt triphenylphosphine)nickel(ll) dichloride gives the biphenyl product 18 in high yield. Treatment with N-bromosuccinimide in refluxing carbon tetrachloride, in the presence of a radical initiator such as benzoyl peroxide or 2,2'-azobisisobutyronitrile (AIBN), gives bromide 19.

Compounds of Formula I where R3a or R3b is a carbamate, semicarbazide or urea derivative, wherein this functionality is attached to the phenyl ring by a nitrogen atom, are prepared from intermediate 20. obtained by alkylation of TV with a derivative of Formula V wherein R3a or R3b is a nitro group as shown in Scheme 12.

SCHEME 12

IV 1. NaH/DMF

Y is a leaving group G is f-butoxycarbonyl or benzyloxycarbonyl

20

A useful method of synthesizing a preferred alkylating agent is shown in reaction Scheme 13.

SCHEME 13

24

Reaction of 4-tolylboronic acid 21 with 2-bromonitro- benzene 22 in the presence of a transition metal catalyst such as (tefrαfa ^' s)triphenylphosphine palladium(O) in a mixed ^' solvent system containing aqueous sodium hydroxide, water, 2-propanol and benzene at elevated temperatures for several hours gives the coupled product 23 in good overall yield. Chromatographic purification and separation of unwanted by-products is conveniently performed on silica, eluting with common organic solvents such as hexane, ethyl acetate and methylene chloride. Conversion of 23 to the bromide derivative 24 is accomplished by the aforementioned reaction with Λ^-bromosuccinimide.

As shown in Scheme 14, reduction of the nitro group of 20 is achieved by hydrogenation in the presence of a metal catalyst, such as palladium on carbon, in a protic solvent such as methanol or ethanol. It may be appreciated by one skilled in the art that for certain compounds

where catalytic hydrogenation is incompatible with existing functionality, alternative methods of reduction are indicated, such as chemical reduction with stannous chloride under acidic conditions. It should also be noted that the protecting group G in intermediate 20 must be compatible with the experimental conditions anticipated for reduction. For example, intermediate 20 wherein G is f-butoxycarbonyl (BOC) is stable to the conditions of catalytic reduction employed in the conversion to 25. Intermediate 25 may also be further elaborated to a new intermediate 26 by the aforementioned reductive alkylation conditions.

SCHEME 14

G is f-butoxycarbonyl

25

SCHEME 14 (CONT'D)

aldehyde sodium cyanoborohydride

5 G is -butoxycarbonyl

26

Elaboration of 26 to carbamate compound 27 is achieved by o reaction with the appropriate chloroformate reagent in pyridine or in methylene chloride with triethylamine as shown in Scheme 15.

SCHEME 15

2£

G is f-butoxycarbonyl

27

Transformation of amine intermediate 26 to urea derivatives is accomplished in several ways. Terminally disubstituted compounds 29 can be obtained directly by reaction of 26 with a disubstituted carbamoyl

chloride 28 in an inert solvent such as methylene chloride in the presence of triethylamine or 4-dimethylaminopyridine. In addition, mono- substituted compound 31 wherein either R5b or R 12b is hydrogen is obtained from 26 by reaction with an isocyanate 30 as shown in Scheme 16. Terminally unsubstituted urea 31, wherein Rl2b is hydrogen, is also prepared from amine 26 by reaction with trimethylsilyl isocyanate (30; R ¹² b is (CH3)3Si).

SCHEME 16

G is f-butoxycarbonyl

29

SCHEME 16 (CONT'D)

G is f-butoxycarbonyl

SI

Alternatively, amine 25 is converted to an isocyanate 32 by treatment with phosgene or an equivalent reagent such as btXtrichloro- methyl)carbonate (triphosgene) as indicated in Scheme 17. Subsequent reaction of 32 with primary or secondary amines in an inert solvent such as methylene chloride gives the corresponding urea derivative 29 in good yield. Isocyanate 32 is also converted to substituted semicarbazides 33 or

hydroxy- or alkoxyureas 34 by reaction with substituted hydrazines or hydroxy- or alkoxylamines, respectively.

SCHEME 17

or enzyloxycarbony

22

SCHEME 17 (CONT'D)

G or

SCHEME 17 (CONT'D)

G is f-butoxycarbonyl or benzyloxycarbonyl

33

SCHEME 17 (CONT'D)

G is f-butoxycarbonyl or benzyloxycarbonyl

34

Compounds of Formula I where R3a or R3b is a carbazate or carbamate derivative, where attachment to the phenyl ring is through the oxygen atom of the carbazate or carbamate linkage, are prepared from acetophenone intermediate 35 as indicated in Scheme 18.

SCHEME 18

G

G is f-butoxycarbonyl or benzyloxycarbonyl

22

SCHEME 18 (CONT'D)

3Z

G or

SCHEME 18 (CONT'D)

G or

a

Oxidative rearrangement of 35 through the use of a peroxy- carboxylic acid (Baeyer- Villager reaction) such as -chloroperbenzoic acid gives the ester 36 which is hydrolyzed in the presence of a strong base such as sodium or lithium hydroxide to give phenol 37. Reaction of 37 with an isocyanate 30 leads directly to carbamate 38. Additionally, treatment of 37 with Λ ,/V'-carbonyldiiιnidazole in dimethylformamide can

form an activated intermediate which will react with substituted hydrazine reagents to give the carbazate product 39.

Compounds of Formula I wherein R^a or R^b is

R5bRl2bNCON(Rl2a)CH2- R5bRl2bNCSN(Rl2a)CH ₂ - . R5bRl2cNN(Rl2b)CSN(Rl2a)CH2-, R5bRl2cNN(Rl2b

CON(Rl2a)CH2- or Rl3θCON(Rl2a)CH2- are prepared from the f -butyl ester intermediate 40 as described in Scheme 19. Removal of the ?-butyl ester through the use of trifluoroacetic acid gives the carboxylic acid 4L It may be appreciated by one skilled in the art that the protecting group G in 40 must therefore be compatible with the strongly acidic conditions employed for ester cleavage; hence G is taken as benzyloxycarbonyl. Conversion of the carboxylic acid 4 , to the benzylamine derivative 42 can be achieved by a five-step sequence consisting of: 1) formation of a mixed anhydride with isobutyl chloroformate; 2) reduction with sodium borohydride to the benzyl . alcohol; 3) formation of the mesylate with methanesulfonyl chloride; 4) formation of the azide by reaction with sodium azide, and finally, 5) reduction of the azide with tin(II) chloride. The benzylamine intermediate 42 can be further elaborated to 43 by the aforementioned reductive amination procedure.

SCHEME 19

G is benzyloxycarbonyl

41

SCHEME 19 (CONT'D)

o II

1. /Bu-O-C-CI, Λ/-methylmorpholine

2. sodium borohydride

3. CH ₃ S0 ₂ CI

4. sodium azide

5. SnCI ₂ , aqueous dioxane

G is benzyloxycarbonyl

42

SCHEME 19 (CONT'D)

^Q

^aldeh y ^{de 0} sodium cyanoborohydride

43

(Reactions of amine 43 with the appropriate reagents will o form urea-linked compounds 44 and 45, and carbamate-linked compound 46.) Terminally unsubstituted urea 44, wherein Rl2b i _s hydrogen, is also prepared from amine 43 by reaction with trimethylsilyl isocyanate (30; R ¹² b is (CH3)3Si).

SCHEME 20

G is benzyloxycarbonyl

44

SCHEME 20 (CONT'D)

G is benzyloxycarbonyl

45

SCHEME 20 (CONT'D)

G is benzyloxycarbonyl

46

As shown in Scheme 21 , hydrazide compound 47 can be prepared from intermediate 43 by a two-step procedure consisting of activation of the amine via treatment with Λ^'-carbonyldiimidazole followed by treatment with the appropriately substituted hydrazine derivative R5bRl2c (Rl2b)H.

SCHEME 21

Λ/./V-carbonyldiimidazole

43

G is benzyloxycarbonyl

47

A useful preparation of the protected benzylamine intermediate 52 is shown in Scheme 22. Metallation of 4-bromobenzyl t- butyldiphenylsilylether 48 with n-butyllithium followed by treatment with triisopropyl borate gives the aryl boronic acid 49. Reaction of 49 with 2-bromo- V-(/-butoxycarbonyl)benzylamine 50 in the presence of

tetra& s(triphenylphosphine)palladium(0) and sodium hydroxide in a mixed solvent system at elevated temperature gives the coupled product

51 in good yield. Desilylation and conversion to the ( -methanesulfonate

52 is achieved by treatment with tetrabutylammonium fluoride followed by methanesulfonyl chloride. Reaction of 52 with compounds of Formula IV is carried out using the conditions described in Scheme 9.

SCHEME 22

52

SCHEME 22 (CONT'D)

CH ₂ NHBOC

51

51 5Z

Compounds of Formula I wherein R3a or R3b i _s taken as R5bRl2bNCO are prepared by several methods. For example, as shown in Scheme 23, compound 53 wherein R^b and R 2b _are both hydrogen is conveniently prepared by hydrolysis of the nitrile precursor 13..

SCHEME 23

G is f-butoxycarbonyl or benzyloxycarbonyl

53

Thus, treatment of nitrile 13 with hydrogen peroxide and a strong base, such as potassium carbonate, in a polar solvent, such as dimethylsulfoxide at temperatures of 25°C to 150°C results in formation of the amide derivative 53. The precursor 13 is prepared from an

appropriate alkylating agent V, where R3a is cyano, as described in Scheme 10.

A useful method of preparing the alkylating agent 56 is outlined in Scheme 24

SCHEME 24

54

55 56

Thus, treatment of 4-(methylphenyl)trimethyl stannane 54 with 2-bromobenzonitrile in dimethylformamide at 100°C in the presence of bw-triphenylphosphine palladium(II) chloride results in coupling to form the biphenyl nitrile 55 in high yield. Conversion to bromide 56 is achieved by the aforementioned treatment with N-bromosuccinimide.

Compounds of Formula I wherein R3a or R3b is taken as R5bRl2bNCO- and R ^5b and/or Rl2b _are other than hydrogen (57) are prepared from the corresponding carboxylic acid derivative 41 as shown in Scheme 25.

SCHEME 25

G is benzyloxycarbonyl

5Z

Coupling of the carboxylic acid derivative 41 with R5 Rl2bNH j _s conveniently carried out by the use of a coupling reagent such as benzotriazol-l-yloxytris(dimethylamino)phosphonium hexa¬ fluorophosphate ("BOP") orbenzotriazol-1-yloxytripyrrolidino- phosphonium hexafluorophosphate ("PyBOP") in an inert solvent such as methylene chloride. The requisite carboxylic acid precursors are prepared as illustrated in Scheme 26 for the biphenyl compound 60.

SCHEME 26

59

SCHEME 26 (CONT'D)

G is benzyloxycarbonyl 50

Alkylation of IV with f-butyl 4'-bromomethyl-biphenyl-2- carboxylate 58 (prepared as described in EPO Publication 324,377) in the presence of sodium hydride as previously described in Scheme 9 gives the adduct 59 in high yield. Hydrolysis of the f-butyl ester to give the acid 60 is achieved by treatment with a strong acid, such as trifluoroacetic acid, in an inert solvent such as methylene chloride. It is noted that the protecting group G in this instance must be inert to strongly acidic conditions, for example G is benzyloxycarbonyl (CBz).

Conversion to compounds of Formula I wherein R4 is hydrogen is carried out by simultaneous or sequential removal of all protecting groups from intermediate VI as illustrated in Scheme 27.

SCHEME 27

Removal of benzyloxycarbonyl (CBz) groups can be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a platinum or palladium catalyst in a protic solvent such as methanol. In cases where catalytic hydrogenation is contraindicated by the presence of other potentially

reactive functionality, removal of benzyloxycarbonyl groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid. Removal of f-butoxycarbonyl (BOC) protecting groups is carried out by treatment of a solution in a solvent such as methylene chloride or methanol, with a strong acid, such as hydrochloric acid or trifluoroacetic acid. Conditions required to remove other protecting groups which may be present can be found in Protective Groups in Organic Synthesis T.W. Greene, John Wiley and Sons, NY. 1981.

As shown in Scheme 28, compounds of Formula I wherein R4 is hydrogen are elaborated to new compounds by reductive alkylation with an aldehyde by the aforementioned procedures. The products, obtained as hydrochloride or trifluoroacetate salts, are conveniently purified by reverse phase high performance liquid chromatography (HPLC) or by recrystallization.

SCHEME 28

Aldehyde, sodium cyanoborohydride

It is noted that the order of carrying out the foregoing reaction schemes is not significant and it is within the skill of one skilled in the art to vary the order of reactions to facilitate the reaction or to avoid unwanted reaction products.

The growth hormone releasing compounds of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. This includes use in the evaluation of many factors thought or known to influence growth

hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting states. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that somatostatin inhibits growth hormone release. Other hormones that are important and in need of study as to their effect on growth hormone release include the gonadal hormones, e.g., testosterone, estradiol, and progesterone; the adrenal hormones, e.g., cortisol and other corticoids, epinephrine and norepinephrine; the pancreatic and gastrointestinal hormones, e.g., insulin, glucagon, gastrin, secretin; the vasoactive intestinal peptides, e.g., bombesin; and the thyroid hormones, e.g., thyroxine and triiodothyronine. The compounds of Formula I can also be employed to investigate the possible negative or positive feedback effects of some of the pituitary hormones, e.g., growth hormone and endorphin peptides, on the pituitary to modify growth hormone release. Of particular scientific importance is the use of these compounds to elucidate the subcellular mechanisms mediating the release of growth hormone.

The compounds of Formula I can be administered to animals, including man, to release growth hormone in vivo. For example, the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, and to increase milk production in such animals. In addition, these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone. For example, the compounds of Formula I can be administered in vivo to children. Serum samples taken before and after such administration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly determining the ability of the patient's pituitary to release growth hormone.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutical

carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise a growth promoting agent in addition to at least one of the compounds of Formula I or another composition which exhibits a different activity, e.g., an antibiotic or other pharmaceutically active material.

Growth promoting agents include, but are not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prosta- glandins, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Patent No. 4,411,890.

A further use of the disclosed novel benzo-fused lactam growth hormone secretagogues is in combination with other growth hormone secretagogues such as GHRP-6, GHRP-1 or GHRP-2 as described in U.S. Patent Nos. 4,411,890; and publications WO 89/07110 and WO 89/07111 and B-HT 920 or in combination with growth hormone releasing factor and its analogs or growth hormone and its analogs. A still further use of the disclosed novel benzo-fused lactam growth hormone secretagogues is in combination with cc2 adrenergic agonists or β3 adrenergic agonists in the treatment of obesity or in combination with parathyroid hormone or bisphosphonates, such as MK- 217 (alendronate), in the treatment of osteoporosis. A still further use of the disclosed novel benzo-fused lactam growth hormone secretagogues is in combination with IGF-1 to reverse the catabolic effects of nitrogen wasting as described by Kupfer, et al., J. Clin. Invest., 21, 391 (1993).

As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. Thus, the administration of the compounds of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself. These varied uses of growth hormone may be summarized as follows: stimulating growth hormone release in elderly humans; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis; stimulation of the immune system; treatment of retardation; acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation, treating

renal failure or insufficiency resulting in growth retardation; treatment of physiological short stature, including growth hormone deficient children; treating short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of bum patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondrodysplasias, Noonans syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing, and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic response after a major operation; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS. Treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function; treatment of immunosuppressed patients; improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal hemeostasis in the frail elderly; stimulation of osteoblasts, bone remodelling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock and stimulation of wool growth in sheep.

The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than

inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.

Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/Kg of body weight daily are

administered to patients and animals, e.g., mammals, to obtain effective release of growth hormone.

The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.

EXAMPLE 1

Λ^-(2-Amino-2-methylpropyl)W-[2,3,4,5-tetrahydro-2-oxo-l -[[2"-(lH- tetrazol-5-yl)rLr-biphenyll-4-yllmethyll-lH-benzazepin-3(R)- yllurea

Step A: l-Benzyloxycarbonylamino-2-amino-2-methylpropane

To a cooled (0°C) solution of l,2-diamino-2-methylpropane (760 mg, 7.25 mmol) in 20 mL of dry methylene chloride under a nitrogen atmosphere was added benzylchloroformate (1.25 g, 7.32 mmol, 1.01 eq) dropwise. A white precipitate was formed and the reaction was stirred at room temperature overnight. The solvent was stripped and the resulting white solid was further dried under high vacuum to give a white sludge which was used in Step B without purification. H NMR (200 MHz, CDC13): δ 1.30 (d, 7 Hz, 6H), 3.28 (s, 2H), 5.10 (s, 2H), 7.20-7.46 (m, 5H).

Step B: 1 -Benzyloxycarbonylamino-2-f-butoxy carbonylamino-2- methylpropane

To a cooled (0°C) solution of crude 1 -benzyloxycarbonyl - amino-2-amino-2-methylpropane (2.07 g, 7.25 mmol) in 20 mL of dry methylene chloride under a nitrogen atmosphere was added triethylamine (1.54 g, 2.1 mL, 15 mmol, 2.5 eq) followed by di-f-butyldicarbonate (1.67 g, 1.1 eq). After stirring at 0°C for three hours, the reaction was filtered through celite and the filtrate was stripped under vacuum. The residue was purified by column chromatography on silica gel (eluant 20% acetone/hexanes) to give 4.12 g (62% in two steps) of the product as a white foam. iH NMR (200 MHz, CDCI3): δ 1.20 (s, 6H), 1.37 (s, 9H),

3.34 (d, 14 Hz, 2H), 4.68 (br s, 1H), 5.06 (s, 2H), 5.44 (br s, 1H), 7.21- 7.42 (m, 5H).

Step C: 1 -Amino-2- -butoxycarbonylamino-2-methylpropane, hydrochloride

A solution of 1 -benzyloxycarbonylamino-2-f-butoxy- carbonylamino-2-methylpropane (1.41 g, 4.47 mmol) in 10 mL of methyl alcohol containing 0.5 mL of concentrated hydrochloric acid was reduced under a hydrogen atmosphere at 40 psi using 200 mg of 20% palladium on carbon. The catalyst was filtered through Celite and the solution was stripped to give 900 mg (99.5%) of the product as a white solid. H NMR (200 MHz, CD3OD): δ 1.26 (s, 6H), 1.42 (s, 9H), 3.16 (s, 2H).

Step D: Λ^-(2-?-Butoxycarbonylamino-2-methylpropyl)- '-[2,3 ,4,5- tetrahydro-2-oxo-lH-l-benzazepin-3(R)-yllurea l-Amino-2-f-butoxycarbonylamino-2-methylpropane hydrochloride (777 mg, 3.46 mmol) was dissolved in 2 mL of methanol and to this solution was added triethylamine (357 mg, 3.53 mmol, 1.02 eq) dropwise. The reaction mixture was triturated with ether (100 mL) and the solid was filtered off through Celite. The evaporation of the filtrate gave 653 mg of corresponding free base as a colorless oil. The freshly prepared free base (439 mg, 2.33 mmol) was dissolved in 20 mL of dry methylene chloride, and to this solution was added triethylamine (472 mg, 4.66 mmol, 2 eq) followed by triphosgene (232 mg, 2.35 mmol, 1.01 eq). Gas evolution was observed and after 20 minutes of stirring, a solution of 444 mg (2.56 mmol, 1.1 eq) of 3(R)-amino-2,3,4,5- tetrahydro-lH-l-benzazepin-2-one (prepared by the method of Fisher, et al, U.S. Patent 5,206,235) in 5 mL of methylene chloride was added by syringe. The white suspension was stirred at room temperature under a nitrogen atmosphere for 2 hours and then the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (eluant ethyl acetate) to give the product as a white solid (664 mg, 73%). lH NMR (400 MHz, CDCl3): δ 1.20 (s, 6H), 1.39 (br s, 9H), 1.96 (m, 1H), 2.59-2.75 (m, 2H), 2.88 (m, 1H), 3.29 (td; 8, 4 Hz; 2H),

4.51 (m, IH), 4.89 (br s, IH), 5.7-6.7 (m, 2H), 6.96 (d, 4 Hz, IH), 7.08- 7.25 (m, 3H), 8.8 (br s, IH). FAB-MS: calculated for C20H30N4O4 390; found 391 (M+H, 30%).

Step E: -(2^Butoxycarbonylamino-2-methylpropyl)-/v ^" '-[2,3 ,4,5- tetrahydro-2-oxo- 1 -[[2'-(Λ^triphenylmethyl)tetrazol-5-yl- r 1.1 '-biphenyll -4-yllmethy 11 - 1 H-benzazepin-3(R)-yl1urea To a solution of 665 mg (1.7 mmol) of the intermediate obtained in Step D in 30 mL of dry tetrahydrofuran (THF)/dimethyl- formamide(DMF) (5:1) under a nitrogen atmosphere at room temperature was added 73 mg (1.87 mmol, 1.1 eq.) of 60% sodium hydride oil dispersion. After 30 minutes, a solution of 1.017 g (1.87 mmol, 1.1 eq) of -triphenylmethyl-5-[2-(4'-bromomethylbiphen-4-yl)] tetrazole in 10 mL of dry THF was added and the mixture was stirred for 3 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was removed under vacuum. Purification by column chromatography on silica gel (eluant 1:1 ethyl acetate/hexanes) afforded 776 mg ( 53%) of the product. H NMR (400 MHz, CDCI3): δ 1.18 (s, 6H), 1.38 (s, 9H), 1.80 (m, IH), 2.27-2.52 (m, 3H), 3.12-3.30 (m, 2H), 4.41 (m, IH), 4.72 (d, 8 Hz, IH), 4.96 (br s, IH), 5.08 (d, 8Hz, IH), 5.42 (br s, IH), 5.69 (br s, IH), 6.87-7.48 (m, 26H), 7.84 (dd; 5,1 Hz; IH).

Step F: V-(2-Amino-2-methylpropyl)- '-[2,3,4,5-tetrahydro-2-oxo- l-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-lH- benzazepin-3(R)-yllurea. trifluoroacetate

A solution of 776 mg (0.909 mmol) of the intermediate obtained in Step E in 10 mL of methanol was treated with 3 mL of 9 N hydrochloric acid and 5 mL of hexanes. After stirring at room temperature for 3 hours, the methanol layer was separated and concentrated under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (55/45), to give 514 mg

(89%) of the title compound as a white solid. IH NMR (400 MHz, CD3OD): δ 1.26 (s, 3H), 1.29 (s, 3H), 1.99 (m, IH), 2.34 (m, IH), 2.46 (m, IH), 2.56 (m, IH), 3.03 (d, 6 Hz, IH), 3.35 (d, 6 Hz, IH), 4.23 (dd; 6,4 Hz; IH), 4.94 (d, 8 Hz, IH), 5.20 (d, 8 Hz, IH), 7.03 (d, 5 Hz, 2H), 7.16-7.27 (m, 4H), 7.28-7.35 (m, 2H), 7.50-7.59 (m, 2H), 7.61-7.69 (m, 2H). FAB-MS: calculated for C29H32N8O2524; found 526 (M+H, 100%).

EXAMPLE 2

Λ^-[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl] -N'-[2,3 ,4,5-tetra- hydro-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]me thyl]-lH- benzazepin-3(R)-yllurea. trifluoroacetate

Step A: -[2-[2(T )-Benzyloxypropyl]amino-2-methylpropyl]-^ '- [2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,r- biphenyl]-4-yl]methyl]-lH-benzazepin-3(R)-yl]urea, trifluoroacetate

A solution of 118 mg (0.185 mmol) of 7V-(2-amino-2- methylpropyl)-7v"-[2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetra zol-5-yl)[l,l'- biphenyl] -4-yl]methyl] - 1 H-benzazepin-3 (R)-yl]urea, trifluoroacetate (Example 1) in 7 mL of dry methanol was treated with activated powdered molecular sieves (100 mg) followed by 840 mg (5.12 mmol, 28 eq) of freshly prepared 2(R)-benzyloxypropanal (prepared from ethyl D- lactate according to the procedure of Hanessian and Kloss, Tetrahedron Lett. 198526, 1261-1264) and the resulting mixture stirred at room temperature under a nitrogen atmosphere. After 5 minutes of stirring, a solution of sodium cyanoborohydride (1 mL of 1M solution in THF, 1 mmol, 5.1 eq) was added and the stirring was continued overnight. The solid was removed by filtration and washed with methanol (10 mL), and then the solution was treated with trifluoroacetic acid (1 mL) to quench the excess sodium cyanoborohydride used (CAUTION! Hydrogen cyanide gas is evolved.). The solvent was removed under vacuum and the residue was purified by reverse phase medium pressure liquid

chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (60/40), to give 52 mg (34%) of the product. lH NMR (400 MHz, CD3OD): δ 1.20 (d, 3 Hz, 3H), 1.26 (s, 3H), 1.41 (s, 3H), 1.97 (m, IH), 2.26-2.47 (m, 2H), 2.53 (m, IH), 2.92 (dd; 7,5 Hz; IH), 3.09 (d, 8 Hz, IH), 3.19 (dd; 7,2 Hz; IH), 3.47 (d, 8 Hz, IH), 3.79 (m, IH), 4.22 (dd; 5,3 Hz; IH), 4.48 (d, 6 Hz, IH), 4.60 (d, 6 Hz, IH), 4.81 (d, 7 Hz, IH), 5.23 (d, 7 Hz, IH), 7.00 (d, 4 Hz, 2H), 7.13-7.38 (m, 11H), 7.48-7.56 (m, 2H), 7.61-7.66 (m, 2H).

Step B: V-[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]-Λ^'- [2,3,4,5-tetrahydro-2-oxo-l -[[2'-(lH-tetrazol-5-yl)[ 1,1'- biphenyl] -4-yl]methyl] - 1 H-benzazepin-3(R)-yl]urea, trifluoroacetate

A solution of 52 mg (0.066 mmol) of the intermediate obtained in Step A in 2 mL of methanol containing trifluoroacetic acid (0.1 mL) was reduced under a hydrogen atmosphere at 40 psi using 20 mg of 10% palladium on carbon. The catalyst was removed by filtration through Celite and the solvent was removed under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (60/40), to give 18 mg (39%) of the title compound as a white solid. lH NMR (400 MHz, CD3OD): δ 1.20 (d, 3 Hz, 3H), 1.28 (s, 3H), 1.32 (s, 3H), 1.98 (m, IH), 2.28-2.49 (m, 2H), 2.55 (m, IH), 2.77 (dd; 6, 5 Hz; IH), 3.09 (d, 7 Hz, IH), 3.13 (dd; 6,1 Hz; IH), 3.49 (d, 7 Hz, IH), 3.91 (m, IH), 4.21 (dd; 6, 4 Hz; IH), 4.90 (d, 7 Hz, IH), 5.22 (d, 8 Hz, IH), 7.01 (d, 4 Hz, 2H), 7.02 (d, 4 Hz, 2H), 7.18 (d, 4 Hz, 2H), 7.27 (d, 15 Hz, 4H), 7.51-7.59 (m, 2H), 7.62-7.68 (m, 2H). FAB-MS: calculated for C32H38N8O3 582; found 583 (M+H, 90%).

EXAMPLE 3

V-[2-[2(S)-Hydroxypropyl]amino-2-methylpropyl]- '-[2,3,4,5-tetra- hydro-2-oxo-l -[[2'-(lH-tetrazol-5-yl)[ 1 ,1 '-biphenyl] -4-yl]methyl]-lH- benzazepin-3(R)-yllurea. trifluoroacetate

The title compound was prepared from Λ^-(2-amino-2- methylpropyl)-Λ^'-[2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetr azol-5-yl)[l,l'- biphenyl]-4-yl]methyl]-lH-benzazepin-3(R)-yl]urea, trifluoroacetate (Example 1) and 2(S)-benzyloxypropanal by the methods described in Example 2. FAB-MS: calculated for C32H38N8O3 582; found 583 (M+H, 80%).

EXAMPLE 4

-[4'-[[3(R)-[[[(2-Ammo-2-memylpropyl)ammo]carbonyl]amino] - 2,3 ,4,5-tetrahy dro-2-oxo- 1 H-benzazepin- 1 -yl]methyl] [1,1 '-biphenyl] -2- yll-TV'-methylurea. trifluoroacetate

Step A: 4-Methyl-2'-nitro-l .1 '-biphenyl

A vigorously stirred mixture of 4-tolylboronic acid (34 g, 0.25 mol) and 2-bromo-l -nitrobenzene (34 g, 0.168 mol) in a mixture of 5N sodium hydroxide (170 mL), water (57 mL), isopropanol (215 mL) and benzene (1080 mL) under a nitrogen atmosphere was treated with (tetrakis)triphenylphosphine palladium(0) (11.9 g). The stirred bilayer reaction mixture was heated at reflux for 3 hours. The cooled reaction mixture was filtered through Celite and the filter cake washed with fresh benzene. The organic layer was separated and washed with water (3x), dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the residue (46.1 g) purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (20:1) gave 28.05 g of the product. H NMR (400 MHz, CDCI3): δ 2.38 (s, 3H), 7.20 (m, 4H), 7.43 (m, 2H), 7.59 (t, IH), 7.8 (d, IH). EI- MS: calculated for C ₁₃ H _π N0 ₂ 213; found 213 (M+).

Step B: 4-Bromomethyl-2'-nitro- 1.1 '-biphenyl

A solution of 4-methyl-2'-nitro-l,l'-biphenyl (6.0 g, 28.2 mmol), Λ^-bromosuccinimide (4.99 g, 28.2 mmol) and AIBN (653 mg) in 75 mL of carbon tetrachloride was heated at reflux until a negative potassium iodide test was obtained (1.5 h). The reaction mixture was

cooled and filtered. The filtrate was evaporated under vacuum to yield 8.41 g of crude product. *H NMR revealed the product composition was approximatly 75% monobromo and 10% dibromo, in addition to 15% of unreacted starting material. ^l U NMR (200 MHz, CDC13): δ 4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, IH). EI-MS: calculated for Cl4HlθBrN 272; found 272,274 (M+).

Step C: 4-Hvdroxymethyl-2'-nitro- 1.1 '-biphenyl

A solution of 4-bromomethyl-2'-nitro- 1,1 '-biphenyl (7.27 g, 24.8 mmol) in acetic acid (50 mL) was treated with potassium acetate (4.88 g, 49.1 mmol). The reaction mixture was heated at reflux for 2 hours. After cooling, the reaction mixture was filtered and the precipitate was washed with acetic acid (2x). The filtrate was evaporated under vacuum and the residue was triturated with ethyl ether. The ether layer was washed consecutively with water, saturated aqueous sodium bicarbonate (3x) and water. The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was dissolved in methanol (50 mL) and treated with a 6-N methanolic potassium hydroxide solution (5 mL). After stirring for 1 hour at room temperature, thin layer chromatography indicated the absence of starting material. The reaction mixture was acidified with acetic acid and evaporated under vacuum. The residue was washed free of acetic acid by washing an etheral solution with aqueous sodium bicarbonate and water. After drying over magnesium sulfate, the ethereal solution was evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 2'-nitro-l,l'-bi-phenyl-4-carboxaldehyde (620 mg) followed by 4-hydroxymethyl-2'-nitro- 1,1 '-biphenyl (3.06 g, 13.4 mmol, 54%).

Step D: 4-(Tetrahydropyranyloxy)methyl-2'-nitro-l .1 '-biphenyl

A solution of 4-hydroxymethyl-2'-nitro- 1,1 '-biphenyl (3.06 g, 13.4 mmol) and 3,4-dihydropyran (1.8 mL, 20.1 mmol) in methylene chloride (50 mL) under a nitrogen atmosphere was treated

with pyridinium p-toluenesulfonate (336 mg, 1.34 mmol). After stirring for 3 hours at room temperature, thin layer chromatography indicated that no starting material remained. The reaction mixture was diluted with ethyl ether (300 mL). The ether extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the residue purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to give 4.47 g of the product.

Step E: 4-(Tetrahydropyranyloxy)methyl-2'-amino-l .1 '-biphenyl

A solution of 4-(tetrahydropyranyloxy)methyl-2'-nitro-l,l'- biphenyl (4.12 g, 13.2 mmol) in 100 mL of methanol was hydrogenated at 40 psi in the presence of 5% palladium on carbon. After 2 hours, uptake of hydrogen was complete. The reaction mixture was filtered through diatomacious earth, and the filter cake washed with methanol. The filtrate was evaporated under vacuum to yield 3.57 g of the product.

Step F: 4-(Tetrahydropyranyloxy)memyl-2'-[(me ylaιnino- carbonyDaminol -1.1 '-biphenyl

To a solution of 483 mg (1.71 mmol) of 4-(tetrahydro- pyranyloxy)methyl-2'-amino- 1,1 '-biphenyl in methyl isocyanate (6 mL) under nitrogen atmosphere was added 0.27 mL (1.9 mmol, 1.1 eq) of triethylamine. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated under vacuum and purified by preparative thin layer chromatography on silica gel (eluant 1:1 ethyl acetate/hexanes) affording 578 mg (99%) of the product as a white solid. IH NMR (400 MHz, CDCI3): δ 1.49-1.65 (m, 4H), 1.72 (m, IH), 1.83 (m, IH), 2.69 (d, 3 Hz, 3H), 3.54 (m, IH), 3.90 (m, IH), 4.48 (d, 6 Hz, IH), 4.70 (t, 2 Hz, IH), 4.79 (br s, IH), 4.80 (d, 6 Hz, IH), 6.16 (br s, IH), 7.11 (t, 4 Hz, IH), 7.20 (d, 5 Hz, IH), 7.29-7.36 (m, 3H), 7.40 (d, 4 Hz, 2H), 7.84 (d, 5 Hz, IH).

Step G: 4-Hydroxymethyl-2'-[(methylaminocarbonyl)amino]-l ,1 '- biphenyl

To a solution of 347 mg (1.02 mmol) of 4-(tetrahydro- pyranyloxy)methyl-2'-[(methylaminocarbonyl)amino]-l, -biphenyl in 8 mL of methanol was added 59 mg (0.340 mmol) of /7-toluenesulfonic acid. The reaction mixture was stirred at room temperature for 3 hours. One drop of triethylamine was added and the reaction mixture was concentrated under vacuum. The residue was filtered through 3 mL of silica gel (eluant: methylene chloride followed by ethyl acetate) to afford the product as a white solid. !H NMR (400 MHz, CDCI3): δ 2.70 (s, 3H), 4.65-4.75 (m, 3H), 6.10 (br s, IH), 7.12 (t, 5 Hz, IH), 7.20-7.25 (m, 2H), 7.30-7.37 (m, 3H), 7.41 (d, 4 Hz, 2H), 7.81 (d, 5 Hz, IH).

Step H: 4-Bromomemyl-2'-[(methylaminocarbonyl)amino] -1 , 1 '- biphenyl

To a solution of 260 mg (1.0 mmol) of 4-hydroxymethyl-2'- [(methylaminocarbonyl)amino]- 1,1 '-biphenyl in 100 mL of methylene chloride under a nitrogen atmosphere was added trimethylsilyl bromide (0.38 mL, 2.9 mmol, 2.9 eq). The reaction mixture was stirred at room temperature for six hours. Triethylamine (0.8 mL) was added and the reaction mixture was concentrated under vacuum. The residue was purified by preparative thin layer chromatography on silica gel (eluant: 99:1 ethyl acetate/methanol) to afford the product as a white solid. *H NMR (400 MHz, CDCI3): δ 2.75 (s, 3H), 4.50 (br s, IH), 4.52 (s, 2H), 6.01 (br s, IH), 7.14 (td; 3,1 Hz; IH), 7.20-7.25 (dd; 4, 1 Hz; IH), 7.30-7.36 (m, 3H), 7.47 (d, 4 Hz, 2H), 7.80 (d, 5 Hz, IH). FAB-MS: calculated for Cl5Hl5BrN2θ 319; found: 319, 321 (M+, 65%).

Step I: 7V-[4'-[[3(R)-[[[(2-f-Butoxycarbonylamino-2-methylpropyl)- amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH- benzazepin- 1 -y llmethyll IT .1 '-biphenyll -2-yll -TV'-methylurea To a solution of 70.9 mg (0.182 mmol) of 7V-(2-f-butoxy- carbonylamino-2-methylpropyl)-N'-I2,3,4,5-tetrahydro-2-oxo-l H-

l-benzazepin-3(R)-yl]urea (Example 1, Step D) in 3 mL of dry THF/DMF (5:1) under a nitrogen atmosphere at room temperature was added 8.9 mg (0.22 mmol, 1.2 eq.) of 60% sodium hydride oil dispersion. After 25 minutes, a solution of 63 mg (0.2 mmol, 1.1 eq) of 4- bromomemyl-2'-[(memylaminocarbonyl)amino]-l,r-biphenyl was added dropwise, and then the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was removed under vacuum. Purification by preparative thin layer chromatography on silica gel (eluant 2:1 ethyl acetate/hexane) afforded 95.3 mg ( 70%) of the product. iH NMR (400 MHz, CDCI3): δ 1.11 (s, 3H), 1.20 (s, 3H), 1.39 (s, 9H), 1.80-2.10 (m, 2H), 2.50 (m, IH), 2.60-2.72 (m, 4H), 3.17 (br s, 2H), 3.91 (br s, IH), 4.53 (d, 8 Hz, IH), 4.70 (br s, IH), 4.92 (d, 8 Hz, IH), 5.66 (br s, IH), 5.82 (br s, IH), 6.17 (br s, IH), 6.83-7.30 (m, 12H), 8.03 (d, 9 Hz, IH). FAB-MS: calculated for C35H44N6O5 628; found 529 (M+H, 45%).

Step J: -[4'-[[3(R)-[[[(2-Ammo-2-memylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-2-oxo- 1 H-benzazepin- 1 -yl] - methyl] IT .1 '-biphenyll -2-y l]-7V'-methylurea. trifluoroacetate A solution of 95 mg (0.13 mmol) of the intermediate obtained in Step I in 4 mL of dry methylene chloride was treated with trifluoroacetic acid (1.0 mL). After stirring at room temperature overnight, the reaction mixture was evaporated under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (57/43), to give 63 mg (77%) of the title compound as a white solid. iH NMR (400 MHz, CD3OD): δ 1.56 (s, 3H), 1.58 (s, 3H), 2.05 (m, IH), 2.37 (m, IH), 2.58-2.70 (m, 5H), 3.04 (d, 8 Hz, IH), 3.36 (d, 8 Hz, IH), 4.29 (dd; 6, 5 Hz; IH), 5.06 (d, 9 Hz, IH), 5.20 (d, 9 Hz, IH), 7.12 (m, 11H), 7.61 (d, 4 Hz, IH). FAB-MS: calculated for C30H36N6O3 528; found 530 (M+H, 100%).

EXAMPLE 5

Λ^-[4'-[[3(R)-[[[(2-Ammo-2-memylpropyl)amino]carbonyl]am ino]- 2,3,4 ,5-tetrahydro-2-oxo-lH-benzazepin-l-yl]methyl][l,l'-biphenyl ]-2- yll -Λ ^, -(2-hvdroxyethyl)urea. trifluoroacetate

Step A: V-(2-r-Butoxycarbonylamino-2-methylpropyl)-7V'-[2,3,4,5- tetrahydro-2-oxo- 1 -[ [2'-nitro[ 1 , 1 '-biphenyl] -4-yl]methyl] -

1 H-benzazepin-3 (R)- yllurea

To a solution of 440 mg (1.13 mmol) of Λ^-(2-r- butoxycarbonylamino-2-methylpropyl)-Λ^'-I2,3,4,5-tetrahydro -2-oxo-lH- l-benzazepin-3(R)-yl]urea (Example 1, Step D) in 10 mL of dry THF/DMF (5:1) under a nitrogen atmosphere at room temperature was added 59 mg (1.46 mmol, 1.3 eq.) of 60% sodium hydride oil dispersion. After 25 minutes, a solution of 409 mg (1.40 mmol, 1.24 eq) of 4- bromomethyl-2'-nitro-l,l'-biphenyl (Example 4, Step B) in 3 mL of dry THF was added and the mixture was stirred for 6 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was removed under vacuum. Purification by preparative thin layer chromatography on silica gel (eluant 2:1 ethyl acetate/hexane) afforded 447 mg (66%) of the product. *H NMR (400 MHz, CDCI3): δ 1.19 (s, 6H), 1.39 (s, 9H), 1.86 (m, IH), 2.41-2.52 (m, 3H), 3.15-3.32 (m, 2H), 4.44 (m, IH), 4.84 (br s, IH), 4.93 (d, 7 Hz, IH), 5.15 (d, 7 Hz, IH), 5.32 (br s, IH), 5.58 (br s, IH), 7.12-7.29 (m, 8H), 7.38 (dd; 4, 1 Hz; IH), 7.43 (dt; 4, 1 Hz; IH), 7.57 (t, 4 Hz, IH), 7.81 (d, 4 Hz, IH).

Step B: - -(2^Butoxycarbonylarnino-2-methylpropyl)-^ '-[2,3 ,4,5- tetrahy dro-2-oxo- 1 -[ [2'-amino[ 1 , 1 '-biphenyl] -4-yl]methy 1] -

1 H-benzazepin-3 (R)-y 11 urea

A solution of 447 mg (0.743 mmol) of the intermediate obtained in Step A in 20 mL of methanol with 5% palladium on carbon (68 mg) was treated with hydrogen by balloon for 16 hours. The catalyst was filtered off through Celite and the filtrate was evaporated under

vacuum to give the product as a white foam (390 mg). iH NMR (400 MHz, CDC13): δ 1.19 (s, 6H), 1.39 (s, 9H), 1.89 (m, IH), 2.42-2.64 (m, 3H), 3.23 (ddd; 17, 7, 3 Hz; 2H), 3.75 (m, 2H), 4.46 (m, IH), 4.81 (br s, IH), 4.95 (d, 7 Hz, IH), 5.12 (d, 7 Hz, IH), 5.30 (br s, IH), 5.52 (br s, IH), 6.71-6.80 (m, 2H), 7.05-7.36 (m, 10H).

Step C: V-[4'-[[3(R)-[[[(2-r-Butoxycarbonylamino-2-methylproρyl)- amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH- benzazepin-1 -yl]methyl] [1,1 '-biphenyl] -2-yl] -TV- [2-(2- propenylcarboethoxy)ethyl]urea

A solution of 91 mg (0.16 mmol) of the intermediate obtained in Step B in 5 mL of dry methylene chloride was treated with excess isocyanatoethylmethacrylate (90 mg, 5 eq) ovemight. The solvent was stripped and the residue was purified by preparative thin layer chromatography on silica gel (eluant 3:2 ethyl acetate/hexanes) to give 252 mg of the product contaminated with a possible polymeric material resulting from the acrylate reagent used. The crude material was used for the next step without further purification. iH NMR (400 MHz, CDCI3): δ 1.11 (s, 3H), 1.20 (s, 3H), 1.38 (s, 9H), 2.49-2.72 (m, 3H), 4.60 (d, 9 Hz, IH), 5.30 (d, 9 Hz, IH), 6.90-7.30 (m, 11H), 8.01 (d, 3 Hz, IH).

Step D: Λ^-[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-2-oxo- 1 H-benzazepin- 1 -yl] - methyl][ 1 , 1 '-biphenyl]-2-yl]-W-[2-(2-propenylcarbo- ethoxy)ethynurea. trifluoroacetate

A solution of the crude intermediate obtained in Step C in 5 mL of methanol was treated with 3 mL of 9 N hydrochloric acid and 5 mL of hexanes. After stirring vigorously at room temperature for 8 hours, the methanol layer was separated and concentrated under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (55/45), to give 28.2 mg (27% over two steps) of the product contaminated with possible polymeric material as a colorless oil. iH NMR (400 MHz, CD3OD): δ 1.28 (s, 3H), 1.30 (s, 3H), 1.97 (s, 3H),

2.05 (m, IH), 2.37 (m, IH), 2.58-2.73 (m, 2H), 4.28 (dd; 6,4 Hz; IH), 5.07 (d, 7 Hz, IH), 5.17 (d, 7 Hz, IH), 5.71 (d, 1 Hz, IH), 6.11 (s, IH), 7.11 (m, 11H), 7.62 (d, 4 Hz, IH).

Step E: Λ^-[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-l-yl]- methyl] [1,1 '-biphenyl]-2-yl]-N'-(2-hydroxyethyl)urea, trifluoroacetate

A solution of the intermediate obtained in Step D in 3 mL of methanol was treated with sodium methoxide in methanol (0.5 mL of a 4.3M solution) at room temperature. After stirring at room temperature for 3 hours, the reaction was quenched with 9 N HCl and then the solvent was stripped under vacuum. Purification by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (55/45), gave 16.3 mg (66% of the title compound as a white solid. iH NMR (400 MHz, CD3OD): δ 1.26 (s, 3H), 1.28 (s, 3H), 2.05 (m, IH), 2.31-2.42 (m, 2H), 2.58-2.73 (m, 2H), 3.09 (d, 7 Hz, IH), 3.20 (t, 3 Hz, 2H), 3.31 (d, 7 Hz, IH), 3.51 (t, 3 Hz, 2H), 4.28 (dd; 6,5 Hz; IH), 5.08 (d, 8 Hz, IH), 5.18 (d, 8 Hz, IH), 7.11- 7.38 (m, 11H), 7.52 (d, 4 Hz, IH). FAB-MS: calculated for C31H38N6O4 558; found 559 (M+H, 96%).

EXAMPLE 6

Λ^-(2-Amino-2-methylpropyl)-Λ^'-[2,3,4,5-tetrahydro-2-o xo-l-[[2'- (methylcarbonylamino)[l , 1 '-biphenyl]-4-yl]methyl]-lH-benzazepin- 3(R)-yllurea. trifluoroacetate

Step A: ΛK2^Butoxycarbonylammo-2-memylpropyl)-Λ '-[2,3,4,5- tetrahydro-2-oxo- 1 -[ [2'-nitro[ 1 , 1 '-biphenyl] -4-yl]methyl] - lH-benzazepin-3(R)-yl1urea

To a solution of 440 mg (1.13 mmol) of -(2-r-butoxy- carbonylamino-2-methylpropyl)- '-[2,3,4,5-tetrahydro-2-oxo-lH- 1 - benzazepin-3(R)-yl]urea (Example 1, Step D) in 10 mL of dry THF/DMF

(5:1) under a nitrogen atmosphere at room temperature was added 59 mg (1.46 mmol, 1.3 eq.) of 60% sodium hydride oil dispersion. After 25 minutes, a solution of 409 mg (1.40 mmol, 1.24 eq) of 4-bromomethyl-2'- nitro-l,l'-biphenyl (Example 4, Step B) in 3 mL of dry THF was added and the mixture was stirred for 6 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was separated, dried (MgSθ4), filtered and the solvent was removed under vacuum. Purification by preparative thin layer chromatography on silica gel (eluant 2:1 ethyl acetate/hexanes) afforded 447 mg (66%) of the product. lH MR (400 MHz, CDCl3): δ 1.19 (s, 6H), 1.39 (s, 9H), 1.86 (m, IH), 2.41-2.52 (m, 3H), 3.15-3.32 (m, 2H), 4.44 (m, IH), 4.84 (br s, IH), 4.93 (d, 7 Hz, IH), 5.15 (d, 7 Hz, IH), 5.32 (br s, IH), 5.58 (br s, IH), 7.12- 7.29 (m, 8H), 7.38 (dd; 1, 4 Hz; IH), 7.43 (dt; 1, 4 Hz; IH), 7.57 (t, 4 Hz, IH), 7.81 (d, 4 Hz, IH).

Step B: 7V-(2^Butoxycarbonylamino-2-methylpropyl)-7V'-[2,3,4,5- tetrahydro-2-oxo-l-[[2'-amino[l,l'-biphenyl]-4-yl]methyl]-

1 H-benzazepin-3 (R)-yllurea

A solution of 447 mg (0.743 mmol) of the intermediate obtained in Step A in 20 mL of methanol with 5% palladium on carbon (68 mg) was treated with hydrogen by balloon for 16 hours. The catalyst was filtered off through Celite and the filtrate was evaporated under vacuum to give the product as a white foam (390 mg). iH NMR (400 MHz, CDC13): δ 1.19 (s, 6H), 1.39 (s, 9H), 1.88 (m, IH), 2.42-2.64 (m, 3H), 3.23 (ddd; 17, 7, 3 Hz; 2H), 3.75 (m, 2H), 4.46 (m, IH), 4.81 (br s, IH), 4.95 (d, 7 Hz, IH), 5.12 (d, 7 Hz, IH), 5.30 (br s, IH), 5.52 (br s, IH), 6.71-6.80 (m, 2H), 7.05-7.36 (m, 10H).

Step C: Λ ^r -(2-r-Butoxycarbonylamino-2-methylpropyl)-7V'-[2,3 ,4,5- tetrahydro-2-oxo- 1 -[ [2'-(methylcarbony lamino) [ 1,1'- biphenyll -4- yllmethyll - 1 H-benzazepin-3 (R)-yllurea A solution of 64 mg (0.11 mmol) of the intermediate obtained in Step B in 1 mL of dry methylene chloride was added to a solution of acetic anhydride (1.00 mL of a 0.127 M solution in methylene

chloride, 0.127 mmol, 1.1 eq) in the presence of excess triethylamine at 0°C (wet ice bath). The reaction was warmed to room temperature and stirring was continued overnight. The solvent was removed under vacuum and the residue was purified by preparative thin layer chromatography on silica gel (eluant ethyl acetate) to give 51 mg (78%) of the product. iH NMR (400 MHz, CD3OD): δ 1.20 (s, 6H), 1.40 (s, 9H), 1.90 (m, IH), 1.98 (s, 3H), 2.44-2.64 (m, 3H), 3.26 (br t, 8 Hz, 2H), 4.45 (br s, IH), 4.75 (br s, IH), 4.99 (d, 9 Hz, IH), 5.15 (d, 9 Hz, IH), 5.20-5.50 (m, 2H), 7.07-7.36 (m, 11H), 8.18 (d, 5 Hz, IH).

Step D: -(2-Amino-2-methylpropyl)W-[2,3,4,5-tetrahydro-2-oxo- 1 -[[2'-(methylcarbonylamino)[ 1 , 1 '-biphenyl] -4-yl]methyl]- lH-benzazepin-3(R)-yllurea. trifluoroacetate

A solution of 51 mg (0.87 mmol) of the intermediate obtained in Step C in 3 mL of methanol was treated with 1 mL of 9 N hydrochloric acid. After stirring at room temperature for 6 hours, the solvent was removed under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (59.2/40.8), to give 51 mg (97%) of the title compound as a white solid. !H NMR (400 MHz, CD3OD): 1.26 (s, 3H), 1.28 (s, 3H), 1.90 (s, 3H), 2.03 (m, IH), 2.36 (m, IH), 2.52-2.68 (m, 2H), 3.05 (d, 7 Hz, IH), 3.35 (d, 7 Hz, IH), 4.28 (dd; 6, 4 Hz; IH), 5.13 (dd; 61, 7 Hz; 2H), 7.19-7.44 (m, 12H). FAB-MS: calculated for C30H35N5O3 513; found 514 (M+H, 100%).

EXAMPLE 7

7V-(2-Amino-2-methylpropyl)-Λ^'-[2,3,4,5-tetrahydro-2-ox o-l-[[2'- [[(acetoxymethyl)carbonyl] amino] [1,1 '-biphenyl] -4-y l]methyl] - 1H- benzazepin-3 (R)-yllurea. trifluoroacetate

Step A: Λ^-(2^Butoxycarbonylamino-2-methylpropyl)- '-[2,3,4,5- tetrahydro-2-oxo- 1 -[ [2'-[ [(acetoxymethyl)carbonyl] amino] - T 1.1 '-biphenyll -4-yllmethyll - 1 H-benzazepin-3 (R)-y llurea

A solution of 123 mg (0.215 mmol) of N-(2-t- butoxycarbonylamino-2-methylpropyl)-/> '-[2,3 ,4,5-tetrahydro-2-oxo- 1 - [[2'-amino [ 1 , l'-biphenyl] -4-yl]methyl] - 1 H-benzazepin-3(R)-yl]urea (Example 5, Step B) in 1 mL of dry methylene chloride was added to a solution of acetoxyacetyl chloride (1 mL of 0.24 M solution in methylene chloride, 0.24 mmol, 1.1 eq) in the presence of excess triethylamine at room temperature. After stirring for 15 min., the solvent was removed under vacuum and the residue was purified by preparative thin layer chromatography on silica gel (eluant 2:1 ethyl acetate/hexanes) to give 90 mg (69%) of the product iH NMR (400 MHz, CDCI3): δ 1.19 (s, 6H), 1.39 (s, 9H), 1.80 (s, 3H), 1.90 (m, IH), 2.47-2.70 (m, 3H), 3.27 (td; 7, 3 Hz; 2H), 4.46 (m, IH), 4.53 (s, 2H), 4.74 (br s, IH), 5.06 (s, 2H), 5.20- 5.45 (m, 2H), 7.13-7.39 (m, 8H), 8.00 (s, IH), 8.38 (d, 5 Hz, IH).

Step B: 7V-(2-Amino-2-methylpropyl)-Λ^'-[2,3,4,5-tetrahydro-2-oxo- 1 -[[2'-[[(acetoxymethyl)carbonyl]amino] [1,1 '-biphenyl]-4- yllmethyll- lH-benzazepin-3(R)-yl1urea. trifluoroacetate A solution of 51 mg (0.87 mmol) of the intermediate obtained in Step A in 3 mL methanol was treated with 1 mL of 9 N hydrochloric acid. After stirring at room temperature for 6 hours, the solvent was removed under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (59/41), to give 51 mg (97%) of the title compound as a white solid. !H NMR (400 MHz, CD3OD): δ 1.26 (s, 3H), 1.28 (s, 3H), 2.03 (m, IH), 2.36 (m, IH), 2.59 (m, 2H), 3.03 (d, 7 Hz, IH), 3.20 (s, 3H), 3.28 (d, 7 Hz, IH), 3.92 (s, 2H), 4.28 (dd; 6, 4 Hz; IH), 5.05 (d, 8 Hz, IH), 5.21 (d, 8 Hz, IH), 7.18-7.40 (m, 11H), 8.08 (d, 4 Hz, IH). FAB-MS: calculated for C32H37N5O5 571; found 571 (M+).

EXAMPLE 8

7v ^" -(2-Amino-2-methylpropyl)- '-[2,3,4,5-tetrahydro-2-oxo-l-[[2'- [[(hydroxymethyl)carbonyl]amino][l,l'-biphenyl]-4-yl]methyl] -lH- benzazepin-3(R)-yl1urea. trifluoroacetate

A solution of 55 mg (0.08 mmol) of V-(2-amino-2-methylpropyl)- Λ ^r '-[2,3,4,5-tetrahydro-2-oxo-l-[[2'-[[(acetoxymethyl)ca rbonyl]amino]- [1 ,r-biphenyl]-4-yl]methyl]-lH-benzazepin-3(R)-yl]urea, trifluoro¬ acetate (Example 7) in 1 mL of methanol was treated with a solution of sodium hydroxide (0.5 mL, 5 N in water) at room temperature. After stirring at room temperature for 24 hours, the reaction was neutralized to pH 7 by the addition of trifluoroacetic acid and then the solvent was removed under vacuum. Purification by reverse phase medium pressure liquid chromatography on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (60/40), gave 38.7 mg (75%) of the title compound as a white solid. iH NMR (400 MHz, CD3OD): δ 1.25 (s, 3H), 1.28 (s, 3H), 2.01 (m, IH), 2.34 (m, IH), 2.52-2.64 (m, 2H), 3.03 (d, 8 Hz, IH), 3.36 (d, 8 Hz, IH), 3.92 (s, 2H), 4.27 (m, IH), 5.04 (d, 7 Hz, IH), 5.21 (d, 7 Hz, IH), 7.17 (m, 11 H), 8.09 (d, 5 Hz, IH). FAB-MS: calculated for C30H35N5O4 529; found: 530 (M+H).