CA2147503A1

CA2147503A1 - Substituted dipeptide analogs promote release of growth hormone

Info

Publication number: CA2147503A1
Application number: CA002147503A
Authority: CA
Inventors: Judith M. Pisano; William R. Schoen; Matthew J. Wyvratt
Original assignee: Individual
Current assignee: Merck and Co Inc
Priority date: 1992-11-06
Filing date: 1993-10-29
Publication date: 1994-05-26
Also published as: AU676525B2; AU5546994A; WO1994011012A1; JPH08503213A; EP0669830A4; EP0669830A1

Abstract

There are disclosed certain novel compounds identified as substituted dipeptide analogs which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the pro-duction of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such substituted dipeptide analogs as the active ingredient thereof are also disclosed.

Description

WO 94/1 1012 PCI~/US93/105~1 ~1 47503 TITLE OF THE INVENTION
SUBSTITUTED DIPEPTIDE ANAL~GS PROMOTE RELEASE OF
GROWTH ~IORMONE

Growth hormone, which is secreted from the pituitary, stim~ tes growth of all tissues of the body that are capable of growing.
In addition, growth ho~none 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 lltili7~tion 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 lcnown to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylal~nine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as 20 weli as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypoth~l~mll~ 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-25 releasing hormone or all of these.
In cases where increased levels of growth hormone weredesired, the problem was generally solved by providing exogenous growth hormone or by ~rlmini~tering an agent which stiml~l~ted growth hormone production and/or release. In either case the peptidyl nature 30 of the compound necessitated that it be ~1mini~tered 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 WO 94/11012 PCI/US93/}05~1 ? 5 L~

hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease tr~n.cmi.~sion, 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 the peptides of U.S. Patent 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 ins~ant compounds are highly substituted dipeptide analogs for promoting the release of growth hormone which are stable under various physiological conditions which may be ~clmini~tered parenterally, nasally or by the oral route.

SUMMARY OF THE INVEN~ION
The instant invention covers certain substicuted dipeptide analogs which have the ability to stim~ te the release of natural or endogenou~ gr~wth h~mlone. The compolmds thlls have ~e ability to be used to treat conditions which require the stiiinulation of growth 20 hormone production or secretion such as in hllm~n~ with a deficiency of natural growth hormone or in ~nim~l~ used for food production where the stim~ tion of growth hormone will result in a larger, more produc-tive ~nim~l. Thus, it is an object of the instant invention to describe the diphenyl substituted dipeptide analogs. It is a further object of this 25 invention to describe procedures for the preparation of such com-pounds. A still further object is to describe the use of such compounds to increase the secretion of growth hormone in hurnans and ~nim~l~. A
still further object of this invention is to describe compositions cont~ining the substituted dipeptide analogs ~or the use of treating 30 hllm~n~ and ~nim~l~ so as to increase the level of growth hormone secretions. Further objects will become apparent from a reading of the following description.

WO 9~/11012 PCr/US93/10551 -- - 214~3 DESCRIPTION OF THE INVENTION
The novel substituted dipeptide analogs of the instant invention are best described in the following structural formula I:

(X)n la R2a~rl=~ O(C I 2)p ,R4 l O R3a~ (L)w--(C H2)q--N--C--C H--N--C--A--N~ R5 where L is ,~/
3b ~/ ~J R
1b~ R2b 20 nisOorl;
p is O to 6;
q is O to 4;
w is O or 1 ;

X is C=O, O, S(O)m, -CH-, -N-, -CH=CH-;
m is O to 2;

30 Rl, R2, R1a, R2a, Rlb, and R2b are independently hydrogen, halogen, Cl-C7 alkyl, C1-C3 perfluoroalkyl, Cl-C3 perfluoroalkoxy, -S(O)m R7a, cyano, nitro, R7bo(cH2)v-~ R7bCoo(cH2)v-7 R7boco-(cH2) R4R5N(CH2)V-, R7bCoN(R4)(cH2)v-~ R4R5NCo(cH2)v-~ R4R5-NCOO(CH2)V-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy, or hydroxy; R7a WO 9~1/11012 PCI/US93/~05~1 and R7b are independently hydrogen, Cl-c3 perfluoroalkyl, Cl-C6 aLkyl, substituted Cl-C6 alkyl, where the substitu.ents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or 5 hydroxy and v is O to 3;

R3a and R3b are independently hydrogen, R9, Cl-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9;
o R9 is N--N N--N
,N ~ " ~a R4a R7bo(CH2)V-, R7bCoo(cH2)v-~ R7boCo(cH2)v-~ R7bCo(CH2)V-, R7bo(cH2)vco-~ R4bR 1 2CN(CH2)V -, R 1 2aR 1 2~NCO(CH2)v-, R12aR12bNCS(CH2)v, R4bRl2aNN(Rl2b)co(cH2)v-~R4bR 1 2aNN(R 1 2b)cs(cH2)v-~ R4bR 1 2aNcoN(R 1 2C)(CH2)V-, 2 R4bR 1 2aNCSN(R 1 2C)(CH2)V-, R4bR 1 2aNN(R 1 7~b)CoN(R 1 2C)(CH2)V-,R4bR 1 2aNN(R 1 2b)CSN(R 1 2c)(cH2)v-~ R4bR 1 ~aNN(R 1 2b) COO(CH2)V-, R4bR12aNCoo(cH2)v-~ or R130CoN(Rl2c)(cH2) where v is O to 3;

25 ~12a, R12b and R12c are independently RSa~ ORsa~ or CoRsa; R12a and R12b, or R12b and R12C, or Rl2a and Rl2c~ or R4b and R12a, or R4b and Rl 2a~ or R4b and Rl2c~ or Rl 3 and Rl 2c~ can be taken together to form -(CH2)r-B-(CH2)S- where B is cHRl~ 0, S(O)m or NRlO~ m is 0, 1 or 2, r and s are independently O to 3 and R1 and Rl 0 30 are as defined;

R13 is Cl-C3 perfluoroalkyl, Cl-C6 alkyl, substituted Cl-C6 alkyl, where the substituents are hydroxy, -NR lOR 1 1, carboxy, phenyl or substituted phenyl; phenyl or substituted phenyl ~vhere the substituents WO 94/11012 PCr/US93/10551 2~503 on the phenyl are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy or hydroxy where RlO and Rl l are as defined;

R14 is hydrogen, Rl, R2 independently disubstituted phenyl, Cl -ClO
5 alkyl or substituted Cl-Clo alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(o)mR7a~ Cl-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl, Cl-C3 alkoxy, R 1, R2 independently disubstituted phenyl Cl -C5 alkanoyloxy, Cl-C5 alkoxycarbonyl, carboxy, formyl or -NRloRl 1 where Rl, R2, 10 and R1 l are as defined;

Rl5 is hydrogen, trifluoromethyl, Rl, R2 independently disubstituted phenyl, Rl, R2 independently disubstituted naphthyl, C3-C7 cycloalkyl, Cl-C1o alkyl, substituted Cl-C1o alkyl where the substituents are from 5 1 to 3 of hydroxy, fluoro, S(o)mR7a~ C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disub-stituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted naphthyl, Rl, R2 independently disubstituted naphthyl Cl-C3 aLkoxy, Cl-C5 alkanoyloxy, Cl-C5 alkoxycarbonyl, carboxy, formyl, 2 -NR l OR l l or R l, R2 independently disubstituted heterocycle, where the heterocycle is imidazole, thiophene, furan, pyrrole, oxazole, thiazole, triazole, tetrazole, pyridine, benzofuran, benzothiophene, benzimi-dazole, indole, 7-azaindole, oxindole or indazole; where Rl, R2, RlO
and Rl l are as defined above;

R4, R4a, R4b, R5 and R5a are independently hydrogen, phenyl, substituted phenyl, C1 -Clo alkyl, substituted C1 -ClO alkyl, C3-clo alkenyl, substituted C3-Clo alkenyl, C3-C1o alkynyl, or substituted C3-Clo aL~cynyl where the substituents on the phenyl, alkyl, alkenyl or 30 alkynyl are from l to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, R1, R2 independently disubstituted phenyl Cl-C3 aIkoxy, R1, R2 independently disubstituted phenyl, Cl-C20-alkanoyloxy, C l-C5 alkoxycarbonyl, carboxy, fo~nyl, or -NR l OR 1 1 where R l O and R 1 1 are independently hydrogen, Cl-C6 alkyl, phenyl, phenyl Cl-C6 alkyl, WO 9~/11012 PCI/US93/105~1 - C1-Cs-alkoxycarbonyl, C1-Cs-alkanoyl or C1-C6 alkyl; or R4 and R5 can be taken together to form -(CH2)rB(CH2)S- where B, r, s, Rl and R10 are as defined above;

R6 is hydrogen, Cl-C1o alkyl, phenyl or phenyl C1-C1o alkyl;

A is ~8 o --(CH2)x--C--(CH2)y R8a where x and y are independently 0-3;

R8 and R8a are independently hydrogen, Cl-Clo alkyl, trifluoromethyl, phenyl, substituted Cl-Clo aLkyl where the subs~ituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(o)mR7a~ Cl-C6 aLkoxy, C3-C7 cycloalkyl, Rl, R2 independently disubstitute~ phenyl Cl-C3 alkoxy, Rl, R2 independently disubstituted phenyl, Cl-Cs-alkanoyloxy, C1-Cs 20 alkoxycarbonyl, carboxy, formyl, or ~ oRl 1 where R10 and Rl 1 are as defined above; or R8 and R8a can be taken together to form -(CH2)t- where t is 2 to 6; and R8 and R8a can independently be joined to one or both of R4 and RS to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the 25 bridge contains from 1 to 5 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 3 o 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 WO 94/11012 PCr/US93/10551 ~ 2147~03 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 atom 5 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 o when in the above structural formula:

nisOor1;
p is O to 4;
q is O to 2;
15 wisOorl;

I

X is O, S(O)m, -N-, -CH=CH-;
20 misO~o2;

Rl, R2, Rla~ R2a7 Rlb~ and R2b are independently hydrogen, halogen, C1-C7 alkyl, Cl-C3 perfluoroalkyl, -s(o)mR7a~ R7bo(CH2)v-, R7bCoo(cH2)v-~ R7boco(cH2)v-~ phenyl or substituted phenyl where 25 the substituents are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy, or hydroxy;

R7a and R7b are independently hydrogen, Cl-c3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl; phenyl 30 andvisoto2;

R3a and R3b are independently hydrogen, R9, Cl-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9;

WO 9 1/1 1012 PCI/US93/105~1 ,3 R9 is as defined above;

R12a, Rl2b and Rl2c are independently RSa~ OR Sa~ or CoR5a; R12a and R12b, or R12b and R12C, or R13 and R12b or R12a and R4b can be 5 taken together to form -(cH2)r-B-(cH2)s- where B is CHR1, O, S(O)m or NR10~ m is 0, 1 or 2, r and s are independently 0 to 3, R1 is as defined above and R10 is hydrogen, C1-C6 alkyl, phenyl C1-C6 alkyl or C1 -C5 alkanoyl-C1 -C6 alkyl;

o R13 is C1-C3 perfluoroalkyl, Cl-C6 alkyl, substituted C1-C6 alkyl, where the substituents 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, Cl-C6 aLkyl, Cl-C6 alkoxy or hydroxy, R14 and R15 are as defined above, R4, R4a, R4b, R~ and R5a are independently hydrogen, phenyl, substl-tuted phenyl, Cl-Clo alkyl, substituted Cl-Clo alkyl, where the 20 substituents on the alkyl or phenyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, Rl substituted or Rl, R2 indepen-dently disubstituted phenyl C1-C3 alkoxy, Rl substituted or R1, R2 independently disubstituted phenyl, C1-C20-aLkanoyloxy, Cl-CS
alkoxycarbonyl, carboxy or formyl;

R4 and R5 can be taken together to form -(CH2)rB(CH2)S- where B is CHRl, O, S(O)m or N-R10, r and s are independently 1 to 3 and R1 and R10 are as defined above;

3 R6 is hydrogen, Cl -Clo alkyl or phenyl Cl -Cl o aLkyl;

WO 94/11012 PCr/US93/10551 ~ 21~75~3 Ais ~8 --(CH2)x--C--(CH2)y--. R8a where x and y are independently 0-2;

R8, R8a and R8b are independently hydrogen, Cl-Clo alkyl, substituted o C1-Clo alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(o)mR7a~ C1-C6 alkoxy, Rl, R2 independently disubstituted phenyl, C1-Cs-alkanoyloxy, C1-Cs alkoxycarbonyl, carboxy, formyl, -NRlORl 1 where R10 and Rl 1 are independently hydrogen, Cl-C6 aLkyl, or Cl-C5 alkanoyl-Cl-C6 alkyl;
or R8 and R8a can be taken together to form -(CH2)t- where t is 2 to 4;
and R8 and R8a can independently be joined to one or both of R4 and R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
20 and pharmaceutically acceptable salts thereof.

Additional preferred compounds are realized in the above structural formula when:
nisOor l;
25 pisOto3;
q is O to 2;
wisOor 1;
X is 0, S(O)m or -CH=CH-;
misOor 1;
Rl, R2, R1a, R2a, Rlb, and R2b are independently hydrogen, halogen, C1-C7 alkyl, Cl-C3 perfluoroalkyl, -S(O)mR7a~ R7bo(cH2)v-~R7bCoo(cH2)v-~ R7boco(cH2)v-~ phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 aLkoxy, or hydroxy;

2~

R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted Cl-C6 alkyl, where the substituents are phenyl and v is O to 2;

5 R3a and R3b are independently hydrogen, R9, Cl-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9;

R9 is as defined above;

R12a, Rl2b and R12c are independently R5a or OR5a. R12a and R12b, or R12b and Rl2c~ or R13 and Rl2b or Rl2a and R4b can be taken together to form -(CH2)r-B-(CH2)S- where B is CHR1, O, S(O)m or NR1 0, m is 0, 1 or 2, r and s are independently O to 2, Rl is as defined above and R10 is hydrogen, Cl-c6 alkyl or Cl-cs alkanoyl-Cl-C6 5 aLkyl;

R13 is Cl-C6 alkyl, substituted Cl-C6 alkyl, where the substituents are phenyl or sllbstituted phenyl phenyl or sllbstib~ted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, Cl-20 C6 alkoxy or hydroxy;

R14 and R15 are as defined above;

R4, R4a, R4b~ R5 and Rsa are independently hydrogen, C1-C1o alkyl, 25 substituted C1-C1o alkyl, where the substituents on the alkyl are from 1 to 5 of hydroxy, Cl-C6 alkoxy, fluoro, Rl substituted or Rl, R2 independently disubstituted phenyl, C1-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy;

30 R6 is hydrogen or Cl-Clo alkyl;

~147~D~

A lS
~8 --(CH2)x--C--(CH2)y R8a where x and y are independently 0-2;

R8, R8a and R8b are independently hydrogen, C1-Clo alkyl, substituted o C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(o)mR7a~ Cl-C6 alkoxy, Rl substituted or Rl, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; or R8 and R8a can independently be joined to one or both of R4 and R5 to form alkylene bridges between the tennin~l nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 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 O to 2;
qis 1;
w is 1 ;
X is 0, S(O)m;
misOor 1;

R1, R2, Rla7 R2a~ Rlb~ and R2b are independently hydrogen, halogen~
Cl-C7 alkyl, Cl-C3 perfluoroalkyl, -S(O)mR7a, R7bo(cH2)v-~
R7bCoo(cH2)v-~ phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, Cl-C6 aL~yl, Cl-C6 alkoxy, or hydroxy;
R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is O or 1;

WO 9~/t1012 PCI/US93/10551 R3a and R3b are independently hydrogen, R9, or C1-C6 alkyl substituted with R9;

R9 is as defined above;

R12a, Rl2b and Rl2c are independently RSa. Rl2a and Rl2b~ or R12b and R12C, or R13 and R12b or R12a and R4b can be taken together to form -(CH2)r-B-(CH2)S- where B is CHRl, O, S(O)m or NR10, m is 0, 1 or 2, r and s are independently O to 2, R1 is as defined above and R10 is hydrogen, Cl-C6 alkyl or C1-Cs alkanoyl Cl-C6 alkyl;

R13 is C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents 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, C1-C6 alkoxy or hydroxy;

R14 and RlS are as defined above;

R4, R4a, R4b, R5 and RSa are independently hydrogen, C1-C1o alkyl, substituted Cl-Clo alkyl, where the substituents on the alkyl are from 1 to 3 of hydroxy, Cl-C3 aLkoxy, fluoro, Rl substituted or Rl, R2 inde-pendently disubstituted phenyl, Cl-C20 alkanoyloxy, C1-Cs alkoxy-carbonyl or carboxy;

R6 is hydrogen;

Ais ~8 3 o --(CH2)x--Cl--(CH2)y R8a where x and y are independently 0-1:

~ 2I47~3 R8, R8a and R8b are independently hydrogen, C1-C1o alkyl, substituted C1-C1o alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(o)mR7a~ Cl-C6 alkoxy, Rl substituted or Rl, R2 independently disubstituted phenyl, Cl-C5-alkanoyloxy, C1-Cs 5 alkoxycarbonyl, carboxy; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; and R8 and R8a can independently be joined to one or both of R4 and R5 to form aLkylene bridges between the terminal nitrogen and the alkyl portion o~ the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

Representative preferred growth hormone releasing compounds of the present invention include the following:
1. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(lH-tetrazol-5-yl)[l ,1 '-biphenyl]-4-yl]methyl] -benzene-b~lt~n~mide 2. (R)-oc-[(2-Amino-2-methyl-l-oxopropyl)amino]-N-[[2'-(lH-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]-methyl]benzene-but~n~mide 3. (R)-o~-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]benzenebut~n~mi(le 4. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]benzeneb--t~n~mitle 5 . (R)-oc-[(3-Amino-3-methyl- 1 -oxobutyl)amino] -N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]-benzenepentana-mide WO 9~/1101~ PCI/US93/~05~1 6. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino] -N-[[2'-(lH-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]-methyl]benzene-pent~n~mide 7 . (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl- 1-oxobutyl]amino]-N-[[2'-( 1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]benzenepent~n~mide 8. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-o oxobutyl]amino]-N-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]benzenepent~n~mide 9 . (R)-a-[(3-Amino-3 -methyl- 1 -oxobutyl)amino] -N-[[2'-( 1 H-l 5 tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]-lH-indole-3-propanamide 10. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-( 1 H-tetrazol-5-yl)[ 1,1 '-biphenyl] -4-yl] -methyl] -1 H-indole-3-propanamide 1 1. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-(1 H-tetrazol -5-yl)[ 1, 1 '-biphenyl]-4-yl]methyl]- 1 H-indole-3-propanamide 12. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl] -4-yl]methyl]- 1 H-indole-3-propanamide 13 . (R)-a-[(3 -Amino-3 -methyl- 1 -oxobutyl)amino] -N-[[2'-( 1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]me~hyl]-3-[(phenyl-methyl)oxy]propanamide 21~7~

14. (R)-o~-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-( 1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl] -methyl]-3-[(phenyl-methyl)oxy]propanamide 15. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl] -3-[(phenylmethyl)oxy]-propanamide 16. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-(lH-tetrazol-S-yl)rl,l'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy] -propanamide 17 . (R)-a-[(3-Amino-3-methyl- 1 -oxobutyl)amino] -N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]-methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]-propanamide 18. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino] -N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]-methyl] -3-[[(2,6-difluorophenyl)methyl]oxy]-propanamide 19. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]pro-panamide 20. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-(lH-tetrazol-5-yl)[1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]-propanamide 21. (R)-4'-[[[2-[(3-Amino-3-methyl- 1 -oxobutyl)amino]- 1 -oxo-4-phenylbutyl]amino]methyl]-N-ethyl[ 1,1 '-biphenyl]-2-carboxamide WO 91/11012 PCI/US93/105~1 2~

22. (R)-4'-[[[2-[(2-Amino-2-methyl- 1 -oxopropyl)-amino]- 1-oxo-4-phenylbutyl]amino]methyl]-N- ethyl[ 1,1 '-biphenyl]-2-carboxamide 23. (R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl~amino-3-methyl-1-oxobutyl]amino]- 1 -oxo-4-phenylbutyl]-amino]methyl] -N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 24. (R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl- 1-o oxobutyl]amino]- 1 -oxo-4-phenylbutyl]-amino]methyl]-N-ethyl[ 1,1 '-biphenyll-2-carboxamide 25 . (R)-4'-[[[2-[(3-Amino-3-methyl- 1 -oxobutyl)amino]- 1 -oxo-l 5 5-phenylpentyl]amino]methyl]-N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 26. (R)-4'-[[[2-[(2-Amino-2-methyl- 1 -oxopropyl)-amino]- 1-oxo-5-phenylpentyl]amino]methyl] -N-ethyl[ 1,1 '-biphenyl] -2-carboxamide 27. (R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl~amino-3-methyl-1-oxobutyl]amino]- 1 -oxo-5-phenylpentyl]-amino]methyl]-N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 28. (R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]- 1 -oxo-5-phenylpentyl]-amino]methyl] -N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 29. (R)-4'-[[[2-[(3-Amino-3-methyl- 1 -oxobutyl)amino]- 1 -oxo-3 3-(1 H-indole-3-yl)propyl]amino]methyl]-N-ethyl[ 1,1'-biphenyl] -2-carboxamide WO 94/1 1012 PCr/US93/10551 ~7~

30. (R)-4'-[[[2-[(2-Amino-2-methyl- 1 -oxopropyl)-amino]- 1-oxo-3-( 1 H-indole-3 -yl)propyl] amino] -methyl] -N-ethyl[ 1, 1 '-biphenyl] -2-carboxamide 31. (R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-l -o~o-3-(lH-indole-3-yl)propyl]amino]-methyl]-N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 32. (R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-o oxobutyl] amino] -1 -oxo-3 -(1 H-indole-3-yl)propyl] -amino]methyl] -N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 33 . (R)-4'-[[[2-[(3-Amino-3-methyl- 1 -oxobutyl)amino]- 1 -oxo-3-[(phenylmethyl)oxy]propyl]amino]methyl]-N-ethyl[ 1, 1'-1 5 biphenyl]-2-carboxamide 34. (R)-4'-[[[2-[(2-Amino-2-methyl-1-oxopropyl)-amino]-1-oxo-3-[(phenylmethyl)oxy]propyl]amino] -methyl] -N-ethyl[ 1,1 '-biphenyl]-2-carboxamide 35. (R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]- 1 -oxo-3-[(phenylmethyl)-oxy]propyl]-amino]methyl] -N-ethyl [ 1,1 '-biphenyl] -2-carboxamide 36. (R)-4'-[[[2-r[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]- 1 -oxo-3-[(phenylmethyl)-oxy]propyl]-amino]methyl]-N-ethyl[ 1,1 '-biphenyl] -2-carboxamide 37 . (R)-4'-[ [[2-[(3-Amino-3-methyl- 1 -oxobutyl)amino] -1 -oxo-3 3-[[(2,6-difluorophenyl)methyl]oxy]propyl]-amino]methyl]-N-ethyl[ 1,1 '-biphe~yl]-2-carboxamide WO 94/l 1012 PCl/US93/~0551 38. (R)-4'-[[[2-[(2-Amino-2-methyl- 1 -oxopropyl)-amino]- 1-oxo-3-[[(2,6-difluorophenyl)methyl]oxy]-propyl]amino] -methyl] -N-ethyl[ 1,1 '-biphenyl] -2-carboxamide 39. (R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]arnino-3-methyl-1-oxobutyl]amino]-1 -oxo-3-[[(2,6-difluoro-phenyl)methyl]-oxy]propyl]amino]methyl]-N-ethyl-[ 1,1 '-biphenyl]-2-carboxamide o 40. (R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-l -oxo-3-[[(2,6-difluoro-phenyl)methyl]-oxy]propyl]amino]methyl]-N-ethyl-[ 1,1 '-biphenyl]-2-carboxamide 41. (R)-a-[(3-Arnino-3-methyl-1-oxobutyl)arnino]-N-[[2'-[[(methylamino)carbonyl]amino] [ 1,1 '-biphenyl]-4-yl]me~yl]benzenebllt~n~mide 42. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-2 o [ [(methylamino)carbonyl] amino] [ 1,1 '-biphenyl] -4-yl]methyl]benzeneb-lt~n~mi~le 43. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-2 5 amino] [ l, l '-biphenyl] -4-yl]methyl]benzeneb lt~n~mi de 44. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino] [ 1,1 '-biphenyl]-4-yl]methyl]benzenebllt~n~mide 45 . (R)-a-[(3-Amino-3 -methyl- 1 -oxobutyl)amino] -N-[ [2'-[[(methylamino)carbonyl]amino] [ 1,1 '-biphenyl]-4-yl]methyl]benzenepent~n~mide WO 9~/1 tO12 PCI/US93/10551 .

2~75 46. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-[ [(methylamino)carbonyl] amino] [ 1 ,1 '-biphenyl] -4-yl]methyl]benzenepent~n~mide 47. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino][l ,1 '-biphenyl]-4-yl]methyl]benzenepent~n~mide 48. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-o oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-arnino] [ 1,1 '-biphenyl]-4-yl]methyl]benzenepent~n~mide 49. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[( methylamino)carbonyl]amino][1 ,1 '-biphenyl]-4-yl]methyl]-1 H-indole-3-propanamide 50. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino] -N-[[2'-[[(methylamino)carbonyl]amino][l ,1 '-biphenyl]-4-yl]methyl]- 1 H-indole-3-propanamide 51. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino] [ 1,1 '-biphenyl]-4-yl]methyl] -1 H-indole-3 -propanamide 52. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino][ 1,1 '-biphenyl]-4-yl]methyl]-1 H-indole-3-propanamide 53. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methylamino)carbonyl]amino] ~1,1 '-biphenyl]-4-yl]methyl] -3-[(phenylmethyl)oxy] -propanamide WO 94/ltO12 PCI/US93/10551 54. (R)-a-[(2-Amino-2-methyl- 1-oxopropyl)amino]-N-[[2'-[[(methylamino)carbonyl]amino] [ 1,1 t-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy] -propanamide 55. (R)-a-[[3-[2(R)-HydrOXypropyl]amillo-3-methyl- 1-oxobutyl]amino] -N-[[2'-[[(methylamino)carbonyl]-amino] -[ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propa-namide o 56. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino] [ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propanamide 57. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methylamino)carbonyl]amino] [ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]-propanamide 58. (R)-a-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[(methylamino)carbonyl]amino] [ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl] oxy] -propanamide 59. (R)-a-[[3-[2(R)-HydrOXypropyl]amillo-3-met oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino] [ 1,1 '-biphenyl] -4-yl]methyl] -3 -[ [(2,6-difluorophenyl)methyl]oxy]propanamide 60. (R)-a-[r3-[2(S),3-Dihydroxypropyl]amino-3-methyl- 1-oxobutyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino]-[ 1,1 '-biphenyl]-4-yl]methyl] -3-[ [(2,6-difluorophenyl)-methyl]oxy]propanamide WO 94/1 1012 PCltUS93/10551 ~ 2~ ~ 7~

61 . (R)-a-[(3-Amino-3 -methyl- 1 -oxobutyl)amino]-N-[ [2'-hydroxymethyl[ 1,1 '-biphenyl] -4-yl]methyl]-benzene-bllt~n~mide 62. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-benzene-bllt~n~mide 63. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-o oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]benzenebllt~n~mide 64. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-hydroxymet,hyl[ 1,1 '-biphenyl]-4-yl]methyl]benzenebllt~n~mide 65. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxymethyl[l ,1 '-biphenyl]-4-yl]methyl]-benzene-pent~n~mide 66. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-benzene-pent~n~mide 2 5 67. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl- 1-oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]met,hyl]benzenepent~n~mide 68 . (R)-a-[ [3-[2(S),3-Dihydroxypropyl]amino-3-methyl- 1-3 oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]benzenepent~n~mide WO 94/11012 PCI/US93/105~1 69. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxymethyl [ 1 ,1 '-biphenyl] -4-yl]mlethyl] -1 H-indole-3 -propanamide 70. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]mlethyl]- 1 H-indole-3-propanamide 71. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl- 1-o oxobutyl]amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]- 1 H-indole-3-propanamide 72. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide 73. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propanamide 74. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-hydroxymethyl[ 1,1'-biphenyl]-4-yl]m!ethyl]-3-[(phenyl-methyl)oxy]propanamide 75. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl] -3-[(phenylmethyl)oxy]propanamide 76. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-3 oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide WO 94/1 1012 PCI /US93/105~1 77. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide 78. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide 79. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl- 1-o oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]-propanamide 80. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-hydroxymethyl[ 1,1 '-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]-propanamide 81. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-2 0 [[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-yl]methyl]benzeneb-lt~n~mide 82. (R)-a-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-2 5 yl]methyl]benzenebllt~n~mi(le 83 . (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl- 1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl] [ 1,1 '-biphenyl] -4-yl]methyl]benzene-3 bllt~n~mide WO 9-1/11012 PCI/US93/~0551 84. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino] -N-[[2'-[[[(methylamino)carbon-yl]-amino]methyl] [ 1,1 '-biphenyl] -4-yl]methyl]-benzene-bllt~n~mide 85. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl] -4-yl]methyl]benzenepent~n~mide o 86. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[~2'-[[[(methylamino)carbonyl]amino]methyl]-[l ,1 '-biphenyl]-4-yl]methyl]benzenepent~n~mide 87. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl] [ 1,1 '-biphenyl] -4-yl]methyl]benzene-pent~n~mide 88. (R)-a-[[3-[2(S),3-Dihydroxypropyl]~mino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbon-yl]amino]methyl][ 1,1 '-biphenyl]-4-yl~methyl]ben-zenepent~n~mide 89. (R)-oc-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(met,hylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-yl]methyl]- 1 H-indole-3-propanamide 90. (R)-a-[(2-Arnino-2-methyl- 1 -oxopropyl)amino] -N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-yl]methyl]- 1 H-indole-3-propanamide 2 1 ~ 3 91. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][ 1 ,1 '-biphenyl] -4-yl]methyl] -1 H-indole-3-propanamide 92. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbon-yl]amino] -methyl] [ 1,1 '-biphenyl] -4-yl]methyl]- 1 H-indole-3-propanamide 93 . (R)-a-[(3-Amino-3-methyl- 1 -oxobutyl)amino]-N-[ [2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)-oxy]propanamide 94. (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino] -N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)-oxy]propanamide 95. (R)-a-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl] [ 1,1 '-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide 96. (R)-a-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbon-yl]-amino]methyl] [ 1,1 '-biphenyl]-4-yl]methyl] -3-[(phenyl-methyl)oxy]propanamide 97. (R)-a-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl]-4-yl]methyl] -3-[[(2,6-difluoro-phenyl)-methyl]oxy]propana-mide WO 94/1 1012 PCr/US93/10551 98. (R)-o~-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[ 1,1 '-biphenyl] -4-yl]methyl]-3-[[(2,6-difluoro-phenyl)methyl]oxy]-propanamide 99. (R)-oc-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl] [ 1,1 '-biphenyl]-4-yl]methyl] -3-[[(2,6-difluorophenyl)methyl]oxy]propanamide 100. (R)-o~-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbon-yl]amino]methyl] [ 1,1 '-biphenyl] -4-yl~methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide Representative examples of the nomenclature employed are given below:
CH
,O, ~ ~ 3 ~CH2~NH CH2 NH2 HN o ,N=N
CH2~NH

WO 94/11012 PC~/US93/105~1 21~73~3 (R)-a-[(3-Amino-3-methyl- 1 -oxobutyl)amino]-N-[[2'-( 1 H-tetrazol-S-yl)~ 1.1 '-biphenyll -4-vllmethyllbenzenepropanamide o ~,H CH3' CH3 HN O O

CH2~NHCH3 (R)-a-[(2-Amino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl~amino] [ 1 ,1 '-biphenyl]-4-yl]-methyl]-1H-imidazole-4-yl-propanamide ~ o CH3~ ~CH3 CH2~NH 2 H H~.C~OH

HN O
CH2~¢~NHCH3 (R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl~amino-3-methyl- 1 -oxobutyl3-30 amino]-1-oxo-3-(lH-indole-3-yl)propyl~amino]-methyl~-N-methyl[l11'-biphenyll -2-carboxamide WO 9~/11012 PCI/US93/10551 ~t~

,o, CH3~ ,CH3 C~ ,C~ N_CHz~ ,CH20H
[~3 CH2~S'CH2~ NH 2 H H~.C~oH

CH2~2oH
W

(S)-oc-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-l -oxobutyl]amino] -N-[[2'-hydroxymethyl[ 1, l '-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)-thiolpropanamide The compounds of the instant invention all have at least one 5 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 20 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 Ia, is more active and thus more preferred 5 over the compound in which the 3-arnino substituent is below the plane of the structure. This center will be designated according to the R/S
rules as either R or S depending upon the values of X, n, p and R15.

WO 94/11012 ~ PCl`/US93/10551 I

(X)n R3a~ (L)w--~C H2)q--,N - C - C--N, - C--A--N

The instant compounds are generally isolated in the form of their ph~rm~ceutically 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, 15 trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain compounds cont~inin~ an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, m~nesium and the like, as well as from organic bases.
Compounds I of the present invention are prepared from amino acid intermediates II as described in the following reaction schemes.
Arnino acid intermediates 1 are, in some cases, commer-cially available in the form of their N-t-butoxycarbonyl or N-benzyloxycarbonyl derivatives. These intermediates can also be prepared by a variety of methods described in the literature and f~mili~r to one skilled in the art. For example, the Strecker synthesis may be employed for the construction of racemic amino acid inter-mediates. Resolution can be achieved by classical methods, for example separation of diastereomeric salts by fractional cryst~lli7~tion. Alterna-tively, a chiral amino acid synthesis may be employed using the procedures described by R.M. Williams and M.N. Im (J. Amer. Chem.
Soc., 113, 9276-9286, 1991.). Conversion of the free amino acid product to its N-t-butoxycarbonyl (BOC) derivative can be achieved by a number of methods known in the art, for example, treatment with di-WO 9~/t1012 PCI/US93/10551 2~5~

t-butyl dicarbonate in an inert solvent such as melhylene chloride.
Benzyloxycarbonyl (CBz) protected derivatives are obtained by treatment of the amino acid with, for example, benzyl chloroformate.

Rl5 Rl 15 (Xl)n PhCH20H, EDC (Xl)n O~ (C72)P DMAP, CH2,C12 (CHI2)p ,C--CH--H- BOC PhCH20- ,C,--CH--H- BOC

CF3COOH, CH2C12 (Xl)n or HCI, THF (c72)p PhCH2O- ,C,--CH--NH2-HX
o 2 5 3 aldehyde, I
sodium cyano- (Xl)n borohydride (CH, 2)p PhCH20- ,C, ~CH--~H2 As shown in Scheme 1, formation of the benzyl ester 2 is carried out by treatment with benzyl alcohol in the presence of a coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), in methylene chloride with a catalytic amount of WO 9~/1 1012 PCI'/US93/10551 21~7~

4-dimethylaminopyridine. Removal of the BOC protecting group through the use of trifluoroacetic acid in methylene chloride or hydrochloric acid in tetrahydrofuran gives the amine salt 3. Reductive alkylation with an aldehyde and a mild reducing agent, such as sodium 5 cyanoborohydride, leads to the desired intermediate rl.
Attachment of the amino acid sidechain to intermediates of formula II is accomplished by the route shown in Scheme 2. Coupling is conveniently carried out by the use of an appropriately protected amino acid derivative, such as that illustrated by formula III, and a coupling reagent such as benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate ("BOP") in an inert solvent such as methylene chloride. 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.
5 Mitra, J. Org. Chem., 43, 2923 (1978)) or by medium pressure liquid chromatography. Removal of the benzyl ester by hydrogenolysis or by saponification in the presence of a strong base, such as sodium hydroxide, affords the product IV. It may be appreciated by one skilled in the art that the protecting group G must be selected to be compatible 20 with the conditions employed for removal of the specific class of ester present in 4. Hence, as illustrated for the benzyl ester 4, G is taken as t-butoxycarbonyl. It may further be appreciated that other combinations of protecting group G and ester functionality may be employed; for example, the benzyloxycarbonyl protecting group is inert to the 25 standard conditions of aqueous sodium hydroxide employed to hydrolyze methyl or ethyl esters.

WO 94/11012 PCI/US93/105~1 .

S~3 R1s R, 4 (X)n HO--C--A--N--G
(CHl 2)p BOP, triethylamine PhCH20- ,C,--CH--NH methylene chloride ll (X)n H2, catalyst (CHI2)p ,R4 NaOH, CH30H
PhCH20- ,C,--CH--N--C-A--N--G

(X)n G is t-butoxycarbonyl (CH2)p R4 "
HO-C--CH--N--C-A--N--G

IV
The protected amino acid derivatives III are, in many cases, 3 0 commercially available in t-butoxycarbonyl (BOC) or benzyloxy-carbonyl (CBz) forms. A useful method to prepare the preferred sidechain 2 is shown in Scheme 3.

WO 94/1 1012 PCr/US93/10551 ~ ~I47~3~-CH~C~ + O-C=NSO2Cl ether, ~ 3 6 NaH2 3~ ~CH3 BOC20 F¦ CH3 O CH3~ /CH3 8 LiOH~ HO,C--CH2--C--NHBOC

Reaction of isobutylene with N-chlorosulfonyl-isocyanate 5 in diethyl ether gives the azetidinone derivative 6. Removal of the chlorosulfonyl group with aqueous sodium sulfite followed by reaction with di-t-butyl-dicarbonate gives the BOC-protected intermediate 8.
Alk~line hydrolysis gives the protected amino acid derivative 2 in good 2 5 overall yield.
Attachment of the substituted phenyl sidechain V is achieved as shown in Scheme 4. Using the aforementioned BOP
reagent, coupling is conveniently carried out in an inert solvent, such as methylene chloride, to give compounds of formula VII in protected 3 o form.

W O 94/11012 PC~r/US93/105~1 S C~DE~EE 4 (X)n (C H2)q (CH2)p 1 1 ~4 O ~6 ~/~
IV
V

~15 BOP, triethylamine (X)n methylene chloride o(CH2)p R4 R14_N-C--CH--~--C--A--N-G
(CH2)q R6 (L)w R1a i~ Vll 2~a/~JR3a G is t-butoxycarbonyl or benzyloxycarbonyl The substituted phenyl sidechains V are prepared from the corresponding aLkylating agent VI by displacemel[lt of the leaving group Y with sodium azide as shown in Scheme 5. Reduction of the azide product by hydrogenation in the presence of a transition metal catalyst, or alternatively by reaction with triphenylphosphine followed by hydrolysis, gives the desired amine derivative 10. Conversion to the desired intermediate V is achieved by the a~orementioned reductive alkylation procedure.

WO 9~/1 1012 PCr/US93/10551 1. NaN3, DMF l H2 (C72)q 2. H2, catalyst (c72)q (L) or (L)w R2a~Rl3a Ph3P, H20 R2a~R3a Vl 10 NH2 l HR14 (CH2)q aldehyde (C l z)q sodlum J~
R2a~R3a cyanoborohydride R

V

Y is a leaving group As illustratrated in Scheme 6 an alternative route involves coupling of intermediate IV with R14NH2 using one of the coupling reagents described previously, followed by aLkylatiQn of the amide bond with VI. Alkylation is carried out in an inert solvent, such as dimethylformamide, using a strong base such as sodium hydride or potassium t-butoxide at temperatures of 0-100C. ALkylating agents VI
are, in some cases, commercially available or may be prepared by the procedures described in the following schemes.

WO 94/11012 PCI/US93/105~1 Rl5 (X)n R14NH2, BOP
(CH2)p R4 triethylarnine ll I methylene chloride HO-C--CH--N-C--A--N-G
ll l IV

IRl5 (X)n (C72)p o ~4 R 14_ N {~ - CH--N--C--A--N--G

IVa 1. NaH, DMF i)n 2 0 IVa 2. (C72)P o ~4 Y Rl4--N-C-CH--N-C--A--N-G
(C 1 2)q (C 1 2)q R6 ~)w (l)W

Vl Vll G is t-butoxycarbonyl or benzyloxycarbollyl Alkylating agents VI are, in some cases cornmercially available compounds or may be prepared by methods described in the literature and familiar to one skilled in the art.

WO 94/11012 PCr/US93/10551 Compounds of formula I wherein R3a or R3b is a tetrazole Cl.~.) are prepared as described in Scheme 7 by reaction of IV with a suitably substituted intermediate 11 cont~ining a nitrile as tetrazole precursor. Elaboration to the desired product 13 is carried out by 5 treatment with trimethyltin azide in boiling toluene.

NHRl4 ~15 (CH2)q HO-C--~CH--N--C -A--N--G R1 a ~
R6 R2a ~ CN

BOP, triethylamine methylene chloride WO 9~/1 1012 PCr/US93/10551 .

q ~

SCHEME 7 (cont'd) I

(X)n (C72)P R IR4 R14_N--C--CH--N--C -A--N--G
(CH2)q (L)w (CH3)3snN3 ~J~ toluene, heat R1a ' --CN
n2a n 12 (X)n 0( 72)p R4 Il 11 1 2 0 (CH2)q R6 (L)w 2 ~/~ N-N

G=t-butoxycarbonyl or benzyloxycarbonyl WO 94/11012 PCI/US93/}0551 ~ 7~D3 A useful method to prepare the preferred intermediate 18 is shown in Scheme 8, and in U.S. Patent 5,039,814.

N=N
~ NaN3, ZnCI2 ~N,NH

N=N
Ph3CCI, Et3N ~ ,N-CPh3 1. nBuLi 2. ZnCI2 ClZn N= N
~f ~ ,N--CPh3 2s 16 WO 9~/11012 PCr/US93/105~1 4~

SCHEME 8 (cont'd) ,N-CPh3 ¢~

17 Ni(PPh3)2Cl2 CH2Br N-bromosuccinimide ¢~ N=N
AIBN ~ ,N--CPh3 2~
As outlined in Scheme 8, benzonitrile is treated with sodium azide and zinc chloride to give 5-phenyltetrazole 14 which is converted to the N-trityl derivative 15 by treatment with triphenyl-methyl chloride and triethyl~mine. The zinc reagent 16 was prepared 25 by treatment with n-butyl lithium followed by zinc chloride. Coupling with 4-iodotoluene using the catalyst bis(triphenylphosphine)nickel(II) dichloride gives the biphenyl product 17 in high yield. Reaction with N-bromosuccin~mide and AIBN gives bromide 18. Conversion to the requisite amine derivative V is achieved by the procedure described in 30 Scheme 5.
Compounds of Formula I wherein R3a or R3b are taken as R4RSNco can be prepared by several methods. For example, as shown in Scheme 9, compound 20 wherein R4 and R5 are both hydrogen is conveniently prepared by hydrolysis of a nitrile precursor 19.

WO 94/11012 PCI`/US93/105~1 ~ 1 ~ 7 ~ ~ 3 I

(X)n o (CH2)p R4 (CHI 2)q R16 (L)w K2C03, H22 0 ~ DMSO
`1 /~
R2a (X)n o(CHI2)p R, 4 (CHI 2)q R16 (L)w R1a~ CN--NH2 R2a 3o Thus, treatment of the nitrile 19 with hydrogen peroxide and a strong base, such as potassium carbonate, in a polar solvent, such as dimethylsulfoxide at temperatures of 25C to 150C results in formation of the amide derivative 20.
A useful method of preparing the intermediate 23 is outlined in Scheme 10.

.

,4.q;~g`

CH3 Br ~ CN Pd(pph3)2cl2 + ~ DMF, 100C

Sn(CH3)3 CH3 CH2Br NBS 1~1 ¢~CN AIBN ~CN

Thus, treatment of 4-(methylphenyl)l:rimethyl st~nn~ne 21 with 2-bromobenzonitrile in dimethylformamide at 100C in the presence of bis-triphenylphosphine palladium (II) chloride results in 2 coupling to forrn the biphenyl nitrile 22 in high yield. Conversion to bromide 23 is achieved by treatment with N-bromosuccinimide and a radical initiator, such as azobisisobutyronitrile (AIBN), in refluxing carbon tetrachloride. Conversion to the requisite amine derivative V is achieved by the procedure described in Scheme 5.
Compounds of Formula I wherein R3a or R3b are taken as R4R5NCo and R4 and/or R5 are other than hydrogen are prepared from the corresponding carboxylic acid derivatives 24 as shown in Scheme 11 .

WO 9~/11012 2 PCI/US93/10551 (X)n o (CHl 2)p R4 (CH2)q R6 (L)w R4R5NH
~ BOP
~J CH2cl2 R2a (X) n 2 0 R (C I 2)p 8 R, 4 (CH, 2)q R6 (L)W

2 5 R 1 a--~--CN--N R4R5 R2a Coupling of the carboxylic acid derivative 24 with R4R5NH is conveniently carried out by the use of a coupling reagent such as benzotriazol-l-yloxytris-(dimethylamino)phosphoniurn hexafluorophosphate ("BOP") in an inert solvent such as methylene chloride.

WO 9~/11012 PCltUS93/10551 .

l ~ Q s3 The requisite carboxylic acid precursors can be prepared as illustrated in Scheme 12 for the biphenyl compowld 24.

7 ~ ~ ~

(X~n ~
5 (CHI2)p 1l R4 + ~
HO- IC--CH--N-C-A-N-G ~,COOtBu IV

(X)n BOP,triethylamine ~~ 7 P R IR4 methylene chlonde l I

¢~

2 o ¢~cootBu 27 G is benzyloxycarbonyl Rl 15 (X)n CF3COOH o(CH2)p R4 (CH2)q R6 [~

~,COOH
24 ~

WO 94/11012 PCr/US93/105~1 .

A convenient method to prepare the useful intelmediate 30 is shown in Scheme 13. Metallation of 4-iodotoluene with t-butyl-lithium in tetrahydro-furan, followed by treatment with zinc chloride gives the intermediate zinc reagent 28. Coupling of 28 with t-butyl 2-5 bromobenzoate in the presence of bis(triphenylphosphine)nickel(II)chloride affords the biphenyl product 29 in high yield. Bromination to give the desired intermediate 30 is carried out under the aforementioned conditions. Conversion to the requisite amine derivative V is achieved by the procedure described in Scheme 5.

CH3 CH3 Br 1. 2 t-BuLi, THF, -78C ~ ~CO2tBu 2. ZnCI2, ether ~
ZnCI _ Ni(PPh3)2CI2 CH3 CH2Br ¢~ N-bromosuccinimide CCI4, AIBN, heat 2 5 ~CO2tBU ~CO2tBu 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 32, obtained by reaction with a derivative 31 wherein R3a or R3b is a nitro ~roup as shown in Scheme 14.

WO 94/1 1012 PCT/US93/~0551 NHRl4 R15 (cHl2)q (X)n t (c72)p 8 IR R1a~
HO- ,C,--CH--IN--C--A--N-G + 2/`~ N2 IV

1 5 (X)n lo~ (C72)p 0 ~4 BOP, triethylamine R14_N-C--CH--N-C-A-N-G
methylene chloride (CHI 2)q R6 2 0 (L)w R1a~

R2a NO2 G is t-butoxycarbonyl A useful method of synthesizing a preferred intermediate 36 is shown in reaction Scheme 15.

WO 94/t 1012 PCI/US93/10551 ~ NO2 PdgPh3)4, NaO~

2-propanol, B(OH)2 benzene heat 1~1 o ~3 34 CH2Br 1 5 N-bromosuccinimide CCI4, AIBN, heat 0, NO2 Reaction of 4-tolylboronic acid 33 w~.th 2-bromo-nitroben~ene 34 in the presence of a transition mel-al catalyst such as 25 (tetrakis)triphenylphosphine p~ m (O) in a mi.xed solvent system cont~ining aqueous sodium hydroxide, water, 2-propanol and benzene at elevated temperatures for several hours gives the coupled product 35 in good overall yield. Chromatographic purification and separation of unwanted by-products is conveniently performed on silica, eluting with 3 0 common organic solvents such as hexane, ethyl acetate and methylene chloride. Conversion of 3~ to the bromide derivative 36 is accomplished by treatment with N-bromosuccinimide in refluxing carbon tetrachIoride in the presence of a radical initiator such as benzoyl peroxide or 2,2-azobisisobutyronitrile (A:rl3N). Conversion to WO 94tl1012 PCI/US93/105~1 ~ 21 ~ 7~ ~3 the requisite amine derivative V is acheived by the procedure described in Scheme 5.
As shown in Scheme 16, reduction of the nitro group of 32 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 32 must be compatible with the experimental conditions anticipated for reduct-ion. For example, intermediate 32 wherein G is t-butoxycarbonyl (BOC) are stable to the conditions of catalytic reduction employed in the conversion to ~7. Intermediate 37 may also be further elaborated to 15 new intermediate 38 by reductive aLt~ylation with an aldehyde by the aforementioned procedures.

WO 94/11012 PCr/US93/105~1 rl5~

- so -Rl5 I

(X)n o (CH2)p IR4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 (L)w H2, PcVC
o Rla~ CH30H

(X)n o (CH2)p IR4 ll l ll R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 R1a ' J
2/~ NH
37 G is t-butoxycarbonyl wo g~ 012 21 ~ 7~ ~ 3 PCr/l iS93/10551 SCHEME 16 (cont'd) F~15 (X)n O (CH2)p o ~4 R14_N-C--CH--IN-C--A--N-G
(CHI 2)q R6 aldehyde R1a_ ] sodium cyanoborohydride F~15 (X)n 20 R (CI H2)p 0 ~4 R14_N-C--CH--N-C--A--N-G
(CHl2)q R6 (L)w 2 5f~ NH R12b 38 G is t-butoxycarbonyl Elaboration of 37 to carbamate compounds is achieved by reaction with the appropriate chloroformate reagent in pyridine or in methylene chloride with triethyl~mine as shown in Scheme 17.

WO 9~/11012 PCI/US93/10551 t~3 - 52 -~7~15 (X)n ,O, (7H2)p ,O, ~4 (CHI 2)q R6 (IL)w R13-~
o R1a~ pyridine or R2a NH2 methylene chloride/Et3N

~15 (X)n R (7H2)P R ~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 (L)W
R~ ~R13 Transformation of amine intermediate 37 to urea derivatives is accomplished in several ways. Terrnin~lly disubstituted compounds 40 can be obtained directly by reaction of 37 with a disubstituted carbamoyl chloride in an inert solvent such as methylene chloride in the presence of triethylamine or 4-dimethylaminopyridine.

WO94/11012 ~ 3 4 7~D3 PCI/US93/~0551 .

In addition, monosubstituted compounds 41 wherein either R4b or R12a is hydrogen are obtained from 37 by reaction with an isocyanate as shown in Scheme 18.

~15 (X)n 1 o o (CH2)p R lR4 R14_N-C--CH--N-C--A--N-G
(c72)q R6 ~4b ~w Rl2a~
R~a ~ NH2 methylene chloride/Et3N

4-dimethylaminopyridine (X)n R (CH2)p R ~4 R14_N-C--CH--I -C--A--N-G
2S (CH2)q R6 (L)W

R1a~ 4b 3 0 ~ R

WO 94/1101~ PCI`/US93/10551 ?~ 4~ ~ 54 -SCHEME 18 (cont'd) F~15 (X)n R (CIH2)p R 1~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 1 o (L)w R1a--~ R12a-N=C=O r 2~/~\NH rnethylene chloride/Et3N
4-dimethylaminopyridine ~15 (X)n R (CIH2)p R ~4 R14_N-C--CH--N-C--A--N-G

(CHI 2)q R6 (L)W

~2~ R 1 2a Alternatively, amine 37 is converted to an isocyanate 42 by treatment with phosgene or an equivalent reagent such as bis(trichloro-methyl)carbonate (triphosgene) as indicated in Scheme 19. Subsequent reaction of 42 with primary or secondary amines in an inert solvent WO 94/ltO12 PCI/US93/105~1 2117~

such as methylene chloride gives the corresponding urea derivates 43 in good yield. Isocyanate 42 is also converted to substituted semi-carbazides 44 or hydroxy- or alkoxyureas 45 by reaction with substituted hydrazines or hydroxy- or alkoxylamines, respectively.

I

(X)n ,0 (Cl H2)p o ~4 R1 _N-C--CH--IN-C--A--N-G
(CH2)q R6 (L)w R1a~ ~ (Cl3c0)2Co J methylene chloride R2a NH2 triethylamine ~15 (X)n 14 ~0, (CH2)p 0 ~4 R --N-C--CH--I -C--A--N-G
(CHI 2)q R6 (L)W

R2a~N=C=O G is t-butoxycarbonyl or 42 benzyloxycarbonyl WO 9~/11012 PCI/US93/10551 ~ 4~ 56 -SCHEME 19 (cont'd) ~15 (X)n ,0l (CI H2)P R F'~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 1 0 (L)w R1a~ R4bR12aNH
2a ~ N=C=O methylene chloride R

F~15 (X)n R (CIH2)p R F~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 2 5 (L~w R2a~lNH~N` R12a G is t-butoxycarbonyl O or 3 0 43 benzyloxycarbonyl wos4/ll0l2 21~7- ~3 PCI/US93/10551 SCHEME 19 (cont'd) ~15 (Xl)n ,o, (CI H2)P R ~4 R14_N-C--CH--N-C--A--N-G
(C72)q R6 (L)w R1a~ R4bR12aNN(R12b)H
J methylenechloride ~15 (xl)n ,o, (Cl H2)p 0 ~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 (L)w ~ H~f N 4b G is t-butoxycarbonyl 44 benzyloxycarbonyl WO 91/11012 PCI/US93/105~1 SCHEME 19 (cont'd) 7~15 (X)n ,o (Cl H2)p O ~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 (L)w R1a~ R4b(R5ao)NH
2~/~\NH methylene chloride ~15 (X)n o (Cl H2)p O ~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 (L)w R1a~ ol R5a R2a HN~N~ R4b G is t-butoxycarbonyl O or benzyloxycarbonyl 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 intermediates 46 as indicated in Scheme 20.

~0 9~/11012 PCI/US93t10551 ~15 (X)n ,01 (7H2)P 1~4 R14_N-C--CH--N-C--A--N-G
(cHl2)q R6 (L)w Rla--~I m-chloroperbenzoic acid methylene chloride R2a o~ 3 ~15 (xl)n 20,O, (Cl H2)p o ~4 R14_N-C--CH--N-C--A--N-G
(CHI 2)q R6 (L)w ~O~cH

WO 94/11012 PCr/US93/10551 ~3~

SCHEME 20 (cont'd) ~15 (X)n R (CI H2)P R ~4 R --N-C--CH--N-C--A--N-G
(c72)q R6 (L)w R1a~q R12a N=C=O
2~/~\;OH methylene chloride/Et3N
4-dimethylaminopyridine LiOH48 I

(X)n 20 o (Cl H2)p 0 ~4 R14_N-C--CH--N-C--A--N-G
(c72)q R6 (L)w R1a--~1 R2a/~ ~N`R12a 49 o G ist-butoxycarbonyl benzyloxycarbonyl WO94/11012 2I ~ 7~ ~3 PCI'/US93/105~1 SCHEME 20 (cont'd) R1~
I

(X)n o (Cl H2~P ~~ ,R4 R14_N--C--CH--N--C-A--N--G
(CHI 2)q R6 (L)W
R1a~ 1. N, N'-carbonyldiimidazole /~ 2. R4bR12aNN(R12b~H
R2a OH methylenechloride lS

Rl 15 (xl)n 2~ ~o~ (Cl H2~P ,R4 R14_N--C--CH--N--C-A--N--G
(CHl 2)q R6 (L)W
2 S R 1 a~ R 1 Zb O G is t-butoxycarbonyl benzyloxycarbonyl Oxidative rearrangement of 46 through the use of a peroxy-carboxylic acid (Baeyer-Villager reaction) such as m-chloroperbenzoic acid gives the ester 47 which is hydrolyzed in the presence of a strong base such as sodium or lithium hydroxide to give phenol 48.

WO 94/11012 PCI/US93/105~1 .

Reaction of 48 with an isocyanate leads directly to carbamate analogs 49. Additionally, treatment of 48 with N,N'-carbonyldiimidazole in dimethylformamide can form an activated intermediate which will react with substituted hydrazine reagents to give 5 carbazate products 50.
Compounds of formula I wherein R3a or R3b contains the linkage -CH2N(R12b)- can be prepared from the t-butyl ester inter-mediate 51 as described in Scheme 21. Removal of the t-butyl ester through the use of trifluoroacetic acid gives the carboxylic acid 24. It may be appreciated by one skilled in the art that the protecting group G
in 51 must therefore be compatible with the strongly acidic conditions employed for ester cleavage, hence G is taken as benzyloxycarbonyl.
Conversion of the carboxylic acid to the benzyl~mine derivative 52 can be achieved by a five-step sequence consisting of: 1) formation of a 15 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 52 can be further elaborated to 53 by the 20 aforementioned reductive ~min~tion procedure.

WO 94/t 1012 2~7~

F~15 (I)n R(CIH2)p O r4 (CH2)q 1~

(L)w R1a~ ~ COOtBu R2a CF3COOH
51 methylene chloride Flt15 (I )n R ( IcH2)p R ,R4 R14--IN-C-CH--Nl--C--A--N-G
(CH2)q R

(L)w R 1 a --C"
l/~J OH
D2a n 24 G is benzyloxycarbonyl WO 9~/ 11 0 1 2 PCrt US93/ 1 055 1 SCHEME 21 (Cont'd) 1. iBu-O-C-CI, N-methyl-morpholine 24 2. sodium borohydride .

3. CH3SO2CI
4. sodium azide 5. SnCI2, aqueous dioxane I

(I )n O (CH2)p R4 (C 112)q R 6 (L~W
Rla ~J--CH2NH2 R2a 52 G is benzyloxycarbonyl 2s WO 94/1 1012 PCr/US93/105~1 21~7~

SCHEME 21 (Cont'd) ~15 . (I)n R (CI H2)p o ~4 (C lH2)q (L)w R1a~ CH2NH2 R2a aldehyde 5? sodium cyanoborohydride IRl5 2 0 ( I )n O (CH2)p R4 (CH2)q R6 (L)W

R1a ~ CH2NHR12b R2a ~ G is benzyloxycarbonyl WO 94/tlO12 PCI/US93/105~1 . .

~ ~ 4~ ~

Reaction of amine 53 with the appropriate reagents to form urea-linked compounds 54 and 55 carbamate-linked compounds 56, and amide-linked structures 57 are illustrated in Scheme 22.

~ 67 2I47~

G--Z G
~ I-Z
0=0 ~ ~0 --Z
~'I -- N
tr x~
O=~
Z~
G G
G

A
,~
O o V~ _ ~ al G- I G
":
O= C~
~D G
0 Z~
U~ c C`J ~
G--X--c )--c~
O=
~_N_3 ~t -- =/
C~
tr WO 94/11012 PCr/US93/105~1 ~ I ~
~--Z
C~l I

Z
O = ~ O
CL z--G G--z G X--C)--C) G ~ G
~ G
Z
O a) C`l o ~I 0~
~I~ N I C) G--Z
~ I Z
~t I G ~ LLI
~--Z

O= ( ) D
CD ~

a:--X--c~--c~ I
=~ I 3~ ~ N

r G

~VO 9~/ 1 1 0 1 2 6~ ~ 4 7 ~ ~ r Pcr/ US93/ 1 055 1 C~
1 ~ ~ Z t~
O
O = (.) ~C O
Q Z-G a-z L C I
~:--X~
O=~ ~
Z--I_~ ~ ~ ~¦
~,,1 _ ~ =,,\
G G
z ~ ~ a) c~
~--Z

O=
Q Z--G I

tr: X--C~
O=

r c G (~

WO 9~/11012 PCI/US93/10551 ?~ ~ 4~ ~

G--lZ ~D
~ G
O=c~ ~ ~0 <L~ G- Z
Q Z-G
' I = I
G--X--C~

G ~c Z

~L ~
.L O Z -) ~ O=C~
v~ I Q-.
(~ G m G--Z
~t O = ~ N
Q ~- G
G X--C )--( ) o=~

C~l G (~ .

WO 94/11012 PCI/US93/105~1 ~ 21~7~1~3 A useful preparation of the protected benzylamine intermediate 62 is shown in Scheme 23. Metallation of 4-bromobenzyl t-butyldimethylsilylether 5~ with n-butyllithium followed by treatment 5 with trimethyl borate gives the aryl boronic acid 59. Reaction of 59 with 2-bromo-N-(t-butoxycarbonyl)benzylamine 60 in the presence of tetrakis(triphenylphosphine)palladium(0) and barium hydroxide in aqueous 1,2-dimethoxyethane at elevated temperature gives the coupled product 61 in good yield. Desilylation is carried out by treatment with tetra-n-butylammonium fluoride; conversion to the O-methanesulfonate 62 is achieved by reaction of the intermediate benzyl alcohol with methanesulfonic anhydride. Conversion to the requisite amine derivative V is achieved by the procedure described in Scheme 5.

SCHE~IE 23 CH20Si(CH3)2t-Bu CH20Si(CH3)2t-Bu ~ 1. n-C4H9Li, ¢~

Br THF B(OH)2 2. B(OGH3)3 Br di-t-butyl- Br ,~CH2NH2 dicarbonate ~,CH2NHBOC
3 0 ~ chloride W

WO 94/11012 PCr/US93/105~1 2~ 72-SCHEME 23 (Cont'd) Br CH20Si(CH3)2t-Bu ~CH2NHBOC

B(OH)2 ~iQ 59 1 o CH20Si(CH3)2tBu Pd(PPh3)4 Ba(OH)2 ~
aqueous dimethoxy- 1 CH2NHBOC
ethane, heat ~ ~
CH20Si(CH3)2tBu ~
ll l ~ 1. (n-c4Hs)4NF
~ CH2NHBOC 2. (CH3S02)20, (c2H~)3N

BOC is t-butoxycarbonyl ~,CH2NHBOC
30 ~

~ 21~7~0~

Conversion to the final products of formula I wherein R5 is hydrogen, is carried out by simlllt~neous or sequential removal of all protecting groups from intermediate VII as illustrated in Scheme 24.
Removal of benzyloxycarbonyl groups can be achieved by a number of 5 methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a pl~tinum 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. Catalytic hydrogenation is also employed in the removal of N-triphenylmethyl (trityl) protecting groups. Removal of t-butoxy-carbonyl (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.

WO 94/11012 PCI/US93t105~1 IRl5 ( I )n O (CH2)p R4 R14--N--C-CH--IN--C-A--N--(, (CH2)q R6 (L)w R3a Removal of protecting groups J
R1a R2a Vll ~:~15 ( I )n R (CI H2)P R F~4 (CH2)q R6 (L)w R1a l/~\
3 0 R2a R3a Compounds of formula I wherein R4 and R5 are each hydrogen can be further elaborated by reductive alkylation with an ~1~7~

aldehyde by the aforementioned procedures or by alkylations such as by reaction with various epoxides as shown in Scheme 25. The products, obtained as hydrochloride or trifluoroacetate salts, are conveniently purified by reverse phase high performance liquid chromatography 5 (HPLC) or by recrystallization.

( lx)n o (CH2)p R4 (C ~2)q (-)w Aldehyde, sodium cyanoborohydride R1a~ or epoxides 2 o /~\
R2a R3a ~15 (X)n R1a R2~l=~ R (CI H2)P R ,R4 3 <~(L)w--(CH2)q ,N-C-CH--N--C--A--N

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.

2~ 3 The growth hormone releasing compounds of Formula I
are useful in yitro 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 horrnones, e.g., testosterone, estradiol, and progesterone; the adrenal hormones, e.g., cortisol and other corticoids, pinephrine and norepinephrine; the pancreatic and gastrointestinal horrnones, e.g., insulin, ~lllc~on, gastrin, secretin; the vasoactive intestinal peptides, e.g., bombesin; and the thyroid hormones, e.g., thyroxine and triiodothyronine. The compounds of Formula I c,m also be employed to investigate the possible negative or positive feedb~ck 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 mech~nisms me~ tin~ the release of growth hormone.
The compounds of Formula I can be ~lmini~tered to ~nim~l.s, including man, to release growth hormone in vivo. For example, the compounds can be ~lministered to commercially important ~nim~lc such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, and to increase milk produc-tion in such ~nim~l.s. In addition, these compounds can be ~lministered 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 ~(lmini~tered in vivo to children.
Serum samples taken before and after such ~lminictration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly WO 9~/11012 2 1 ~ 7 ~ 9 3 PCI/US93/lOS51 }

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 ph~rm~ceu-tical 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 prostaglan-dins, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, 15 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 still further use of the disclosed novel substituted dipeptide analogs is in combination with other growth hormone secretagogues such as GHRP-6, GHRP-1 as described in U.S. Patent 20 Nos. 4,411,890; and publications WO 89/07110 and WO 89/07111 and B-HT920 or growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins including IGF-l and IGF-2.
A still further use of the disclosed novel substituted dipeptide analogs is in combination with a2 adrenergic agonists or 133 adrenergic agonists in 2 the treatment of obesity or in combination with parathyroid hormone or bisphosphonates, such as MK-217 (alendronate), in the treatment of osteoporosis.
As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. Thus, the ~lmini~tration of the compounds of this invention for purposes of stim~ ting 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 sllmm~rized as follows: stimulating growth hormone release in elderly humans; Prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimlll~tion of the immune WO 94/1 1012 PCI/US93/~0551 ~,~4~ ~

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 5 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 hospit~li7~tion of burn patients; Treatment of intrauterine growth o retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; Induction of pulsatile growth hormone release; Replacement of growth hormone in stressed patients; Treatment of osteochondrodys-plasias, Noonans syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing, and psychosocial deprivation; treatment 5 of pulmonaly 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 incllldin~ nesidioblastosis; Adjllvant treatment for ovulation induction; To stimulate thymic development and 20 prevent the age-related decline of thymic function; Treatment of immunosuppressed patients; Improvement in muscle strength, mobility, m~intenance of skin thickness, metabolic homeostasis, renal hemeostasis in the frail elderly; Stim~ tion of osteoblasts, bone remodelling, and cartilage growth; Stimlll~tion of the immlme system in companion 25 ~nim~l~ and treatment of disorders of aging in companion ~nim~
Growth promotant in livestock; and stimulation of wool growth in sheep.
The compounds of this invention can be ~lmini~tered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or 3 subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of ~(lmini~tration and can be formulated in dosage forms appropriate for each route of ~c~mini~tration.
Solid dosage forms for oral ~lmini~tration include capsules, tablets, pills, powders and granules. In such solid dosage WO 94/1 1012 PCr/US93/105~1 ~ 7 r~ ~ 3 forms, the active compound is admixed with at least one inert pharma-ceutically 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 m~nesium 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 ~minilstration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs cont~inin~ inert diluents cornmonly 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 ~mini~tration 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 he~ting 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 ~dmini~stration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
3 Compositions for nasal or sublingual a~lministration 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 WO 94/1 1012 PCr/US93/10551 4~ ~3 selected dosage depends upon the desired therapeutic effect, on the route of a-lmini~tration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg. of body weight daily are ~lminictered to patients and ~nim~l~, e.g., m~mm~l~, to obtain effective 5 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.

o EXAMPLE 1 (R)-a-[(3-Amino-3-methyl- 1 -oxobutyl)amino] -N-l [2'-(1 H-tetrazol-5 -yl)r l ~ l '-biphenyll -4-yllmethyllbenzene-bllt~n~mide, trifluoroacetate Step A: 5-Phenyltetrazole Z~nc chloride (3.3 g, 24.3 mmol, 0.5 eq) was added to 15 mL of N,N-dimethylformamide in small portions ~hile m~int~inin~ the temperature below 60C. The sllspension of zinc chloride was cooled to room temperature and treated with S.0 g of benzonitrile (48.5 mmol, 1.0 eq) followed by 3.2 g of sodium azide (48.5 mmol, 1.0 eq). The heterogeneous mixture was heated at 115C with agitation for 18 hours.
The mixture was cooled to room temperature, water (30 mL) was added and the mixture acidified by the addition of 5.1 ml_ of concentrated hydrochloric acid. The mixture was cooled to 0C and aged for one hour, then filtered and the filter cake washed with 15 mL of cold 0.1N
HCl then dried at 60C under vacuum to afford 6.38 g (43.7 mmol, 90%) of the product.

Step B: 5-Phenyl-2-trityltetrazole 3 To a suspension of 5.0 g (34.2 mmol) of 5-phenyltetrazole in 55 mL of acetone was added 5.0 mL of triethyl,lmine (3.6 g, 35.6 mrnol, 1.04 eq). After 15 minutes, a solution of 10.0 g of triphenyl-methyl chloride (35.9 mmol, 1.05 eq) in 20 mL of tetrahydrofuran was added and the mixture stirred at room temperature for one hour.

21~7~

Water (75 mL) was slowly added and the mixture stirred for one hour at room temperature. The product was collected by filtration, washed with 75 mL of water and dried at 60C under vacuum to give 13.3 g (34.2 mmol, 100%) of the product.

Step C: N-Triphenylmethyl-5-r2-(4'-methylbiphen-4-yl)ltetrazole A solution of zinc chloride (6.3 g, 46.2 mmol, 0.6 eq) in 35 mL of tetrahydrofuran was dried over molecular sieves. 5-Phenyl-2-trityltetrazole (30.0 g, 77.3 mmol, 1.0 eq) was dissolved in 300 mL of dry tetrahydrofuran and the solution gently stirred while being degassed three times by alternating vacuum and nitrogen purges. The stirred solution was cooled to -15C and treated slowly with 50.5 mL of 1.6 M
n-butyllithium in hexane (80.0 mmol, 1.05 eq) so as to m~int~in the temperature below -5C. The solution was m~int~ined at -5 to -15C
15 for 1.5 hours then treated with the dried zinc chloride solution and allowed to warm to room temperature.
In a separate flask, 4-iodotoluene (20.17 g, 92.5 mmol, 1.2 eq) and bis(triphenylphosphine)nickel(II)dichloride (1.5 g, 2.3 mmol, 0.03 eq) were dissolved in 60 mL of tetrahydrofuran, then degassed and 20 left under an atmosphere of nitrogen. The mixture was cooled to 5C
and treated with 1.5 mL of 3.0 M solution of methylm~gnesium chloride in tetrahydrofuran (4.5 mmol, 0.06 eq) so as to keep the temperature below 10C. The solution was warmed to room tempera-ture and added, under nitrogen purge, to the arylzinc solution. The 25 reaction mixture was stirred vigorously for 8 hours at room tempera-ture then quenched by the slow addition of a solution of 10 mL of glacial acetic acid (1.6 mmol, 0.02 eq) in 60 mL of tetrahydrofuran at a rate so that the temperature was m~int~ined below 40C. The mixture was stirred for 30 minutes and 150 mL of 80% saturated aqueous 30 sodium chloride was added; the reaction mixture was extracted for 30 minutes and the layers allowed to separate. The organic layer was removed and washed with 150 mL of 80% saturated aqueous sodium chloride buffered to pH >10 by the addition of arnmonium hydroxide.
The organic phase was removed and concentrated under vacuurn to WO 9~/11012 PCIJUS93/10551 '~ - 82 -approximately 50 mL then 250 mL of acetonitrile was added. The mixture was again concentrated under vacuum to S0 mL and acetonitrile added to make the final volume 150 mL. The resulting slurry was cooled at 5C for 1 hour then filtered and washed with S0 mL of cold 5 acetonitrile followed by lS0 mL of distilled water. The filter cake was air dried to a free flowing solid then further dried under vacuum at 50C for 12 hours to afford 30.0 g (62.8 mmol, 81 %) of the product. lH NMR (200 MHz, CDC13): 2.?8 (s,3H), 6.9-7.05 (m, lOH), 7.2-7.5 (m, 12H), 7.9 (m, lH).

Step D: N-Triphenylmethyl-5-[2-(4'-bromomethylbiphen4-yl)ltetrazole A solution of 3.15 g (6.6 mmol) of N-triphenylmethyl-S-[2-(4'-methylbiphen-4-yl)]tetrazole in 25 mL of mlethylene chloride was treated with 1.29 g (7.25 mmol, 1.1 eq) of N-bronnosuccinimide, 80 mg (05 mmol, 0.07 eq) of ArsN~ 200 mg of sodium ~cetate and 200 mg of acetic acid. The mixture was heated at reflux for 16 hours then cooled arld washed with saturated aqueous sodium bicarbonate. The organic layer was removed, dried over sodium sulfate, fil~ered and concentrated to a minimllm volume by atmospheric distillation. Methyl t-butyl ether was added and distillation continued until almost all the methylene chloride was removed the the total volume reduced to approximately 12 mL and 12 mL of hexanes was then added. The mixture was kept at room temperature for 2 hours and the product isolated by filtration, washed with hexanes then dried under vacuum at 50C to give 2.81 g (5.04 mmol, 76%) of the product. lH NMR (200 MHz, CDC13): 4.38 (s, 2H), 6.9-8.0 (m, 23H). NMR indicates presence of approximately 1 % of the starting material and 7% of the dibromo derivative.

Step E: N-Triphenylmethyl-5-[2-(4'-azidomethylbiphen-4-yl)ltetrazole To 5.57 g (10 mmol) of N-triphenylrnethyl-5-[2-(4'-bromomethylbiphen-4-yl)]tetrazole in 20 mL of dimethyl sulfoxide was added 614 mg (12.5 mmol, 1.25 eq) of pulverized lithium azide. The WO 94/1 1012 PCI/US93/~05~1 2I~7~3 reaction was stirred at room temperature for 4 hours, during which time a thick precipitate formed. The precipitated solids were collected by filtration and washed with methanol, water, and then methanol again, and dried under vacuum for 16 hours to yield 4.06 g (78%) of the product as a white solid. lH NMR (200 MHz, CDC13): 3.46 (s, 2H), 6.82-7.55 (m, 22H), 7.95 (m, lH).

Step F: N-Triphenylmethyl-5-[2-(4'-aminomethylbiphen-4-yl)ltetrazole To a solution of 4.06 g (7.8 mmol) of N-triphenylmethyl-5-[2-(4'azidomethylbiphen-4-yl)]-tetrazole in 15 mL of tetrahydrofuran was added 2.05 g (7.8 mmol, l eq) of triphenylphosphine in small portions. The mixture was stirred at room temperature for 2 hours, at which time 0.2 mL of water was added and the reaction mixture stirred for 16 hours. The reaction mixture was concentrated to dryness under vacuum and the crude product chromatographed on a silica flash column, eluting with chloroform, to give 1.5 g (3.03 mmol, 39%) of the product. 1H NMR (200 MHz, CDC13): 2.21 (br s, 2H), 3.75 (s, 2H), 6.80-7.94 (m, 22H), 7.94 (m, lH).

Step G: (R)-oc-[t-Butoxycarbonylamino]-N-[[2'-(~-triphenyl-methyl-tetrazol-5-yl)[ l,1 '-biphenyl]-4-yl]methyl]benzene-butanamide To a solution of 30.5 mg (0.11 mmol) of N-BOC-D-25 homophenyl~l~nine in 1 mL of methylene chloride at room temperature under a nitrogen atmosphere was added 54 mg (0.11 mmol, l eq) of N-triphenylmethyl-5-[2-(4'aminomethylbiphen-4-yl)]tetrazole (Step F), 25 mg (0.13 mmol, 1.2 eq) of 1-(3-dimethylaminopropyl)-3-ethylcarbodii-mide hydrochloride and 13 mg (0.13 mmol, 1.2 eq) of triethyl~mine.
The reaction was stirred at room temperature for 16 hours, then transferred to a separatory funnel and washed with 2 mL of 5% aqueous citric acid and 2 mL of saturated aqueous sodium bicarbonate. The organic layer was removed, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was chromato-graphed on a silica flash column, eluting with hexane/ethyl acetate (5:1), to give 29 mg (35%) of the product. lH NMR (200 MHz, CDC13):
1.43 (s, 9H), 2.05 (m, 2H), 2.67 (t, 8Hz, 2H), 4.0~ (m, lH), 4.32 (m, lH), 4.99 (m, lH), 6.19 (m, lH), 6.78-7.15 (m, 27H), 7.95 (m, lH).

Step H: (R)-a- [t-Butoxycarbonylamino] -N- [ [2'-(1 H-tetrazol-5 -yl)r 1.1 '-biphenyll-4-yllmethyll-benzene-b-1t~n~mide A solution of 29 mg (0.038 mmol) o~ the intermediate obtained in Step G in 1 mL of methanol was hydrogenated at room o temperature and one atmosphere over 4 mg of 20% palladium hydroxide on carbon for two hours. The reaction mixture was then filtered through Celite to remove the catalyst, the solvent removed under vacuum and the residue flash chromatographed on silica to yield 19 mg (95%) of the title compound. lH NMR (200 MHz, CD30D):
1.43 (s~ 9H), l.9S (m, 2H), 2.64 (m, 2H), 4.00 (m, lH), 4.34 (t, 5Hz, 2H), 7.00-7.30 (m, 8H), 7.50 (m, SH). FAB-MS: calculated for C2gH32N603 512; found 513 (M+l, 24%).

Step I; (R)-a-Amino-N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4yllmethyll-benzenebut~n~mide. hydrochloride A solution of 19 mg (0.037 mmol) of the intermediate obtained in Step H in 1 mL of methanol was treated with one drop of concentrated hydrochloric acid. The mixture was stirred at room temperature for 16 hours then evaporated to dryness under vacuum.
5 The crude product was purified on reverse phase HPLC on C18, eluting with methanol/0.1% aqueous trifluoroacetic acid ~linear gradient: 60%
me~anol to 80% methanol over 10 minlltes], to yield 14 mg (84%~ of the product. lH NMR (200 MHz, CD30D): 2.11 (m, 2H), 2.64 (m, 2H), 3.89 (t, 6Hz, lH), 4.42 (s, 2H), 7.05-7.32 (m, 8H), 7.58 (m, SH).
30 FAB-MS: calculated for C24H24N6O 412; found 413 (M+1,100%).

Step J: 2 2-Dimethylbutanedioic acid~ 4-methyl ester 2,2-Dimethylsuccinic acid (20 g, 137 mmol) dissolved in 200 mL of absolute methanol at 0C was treated clropwise with 2 mL of WO 9 1/1 1012 2 1 ~ 7 ~ O ~ PCI/US93~105~1 concentrated sulfuric acid. After the addition was complete, the mixture was allowed to warrn to room temperature and stir for 16 hours. The mixture was concentrated under vacuum to 50 mL and slowly treated with 200 mL of saturated aqueous sodium bicarbonate.
5 The mixture was washed with hexane (3x) and the aqueous layer removed and cooled in an ice bath. The mixture was acidified to pH 2 by slow addition of 6N HCI then extracted with ether (8x). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was dried at room temperature under vacuum to afford 14.7 g (91.8 mmol, 67%) of the product as a viscous oil that slowly solidified upon standing. lH NMR (200 MHz, CDC13): 1.29 (s, 6H), 2.60 (s, 2H), 3.65 (s, 3H).

Step K: 3-Benzyloxycarbonylamino-3-methylbutanoic acid, methyl ester To 14.7 g (91.8 mmol) of 2,2-dimethylbutanedioic acid-4-methyl ester in lS0 mL of benzene was added 13 mL of triethylamine (9.4 g, 93 mmol) followed by 21.8 mL of diphenylphosphoryl azide 20 (27.8 g, 101 mmol). The mixture was heated under nitrogen at reflux for 45 minutes then 19 mL (19.9 g, 184 mmol) of benzyl alcohol was added and refluxing continued for 16 hours. The mixture was cooled, filtered and the filtrate concentrated to a minimum volume under vacuum. The residue was redissolved in 250 mL of ethyl acetate, 25 washed with water, saturated aqueous sodium bicarbonate (2x) and brine. The organic layer was removed, dried over m~nesium sulfate, filtered and the filtrate concentrated to a minimllm volume under vacuum. The crude product was purified by medium pressure liquid chromatography on silica, eluting with hexane/ethyl acetate (4:1), to afford 18.27 g (68.9 mmol, 75%) of the product. lH NMR (200 MHz, CDCl3): 1.40 (s, 6H), 2.69 (s, 2H), 3.63 (s, 3H), S.OS (s, 2H), 5.22 (br s, lH), 7.32 (s, 5H).

Step L: 3-Benzyloxvcarbonylamino-3-methylbutanoic acid WO 9~/11012 PCI/US93/105~1 .

A solution of 18.27 g (68.9 mmol) of 3-benzyloxycar-bonylamino-3-methylbutanoic acid methyl ester in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N NaOH
(102 mmol). The mixture was stirred at room temperature for 16 5 hours then transferred to a separatory funnel and washed with hexane (3x). The aqueous layer was removed, cooled to 0C and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl. This mixture was extracted with ether (6x); combined extracts were washed with lN
HCl and brine, then dried over magnesium sulfate, filtered and solvent removed under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product. lH NMR (200 MHz, CDCl3): 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 (br s, lH), 7.3 (s, SH).

Step M: 3-Benzyloxycarbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester A solution of 2.93 g (11.7 mrnol, 0.~5 eq) of 3-benzyl-oxycarbonylamino-3-methylbutanoic acid in S mL of methylene chloride at room temperatllre was treated with 1.61 g (14.0 mmol) of N-hydroxysuccinimide followed by 2.67 g (14.0 Enmol, l eq) of 1(3-20 dirnethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 16 hours then tr~msferred to a separatory furmel, washed with water and dilute aqueous sodium bicarbonate. The organic layer was removed, dried over magnesium sulfate, filtered, and solvents removed under vacuum. The crude 25 product was chromatographed on a silica flash column, eluting with hexane/ethyl acetate (1:1), to give 3.9 g (qll~ntit~tive) of the product.
1H NMR (200 MHz, CDCl3): 1.51 (s, 6H), 2.80 (s, 4H), 3.12 (s, 2H), 5.13 (s, 2H), 7.37 (s, SH). FAB-MS: calculated f~r C17H20N2o6 348;
found 349 (M+l, 40%).

Step N: (R)-a-[(3-Benzyloxycarbonylamino-3-methyl-1-oxo-butyl)amino]-N-[[2'-(1 H-tetrazol-S-yl)-[ l, l '-biphenyl]-4yllmethyllbenzenebutanamide WO g4/1 1012 PCI/US93/10551 21~7~3 A solution of 12 mg (0.023 mmol) of the intermediate obtained in Step I in 0.5 mL of methylene chloride at room temperature was treated with 9.2 mg (0.027 mmol, 1.2 eq) of 3-benzyloxy-carbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester (Step M) and 3.5 mg (0.027 mmol, 1.2 eq) of diisopropylethyl~mine.
The reaction mixture was stirred at room temperature for 48 hours.
Solvents were emoved under vacuum and the crude residue was purified on HPLC to give 14 mg of product. lH NMR (200 MHz, CD30D):
1.29 (s, 3H), 1.36 (s, 3H), 1.90 (m, 3H), 2.45 (m, 3H), 4.31 (m, lH), 4.72 (d, 20Hz, lH), 5.02 (d, 20Hz, lH), 7.00-7.62 (m, 18H). FAB-MS:
calculated for C37H39N704 645; found 646 (M+l, 100%).

Step O: (R)-oc-[(3-Amino-3-methyl- 1 -oxobutyl)amino] -N-[[2'-(1 H-tetrazol-5-yl)[1,1 '-biphenyl] -4-yl]methyl]benzenebutana-mide~ tri-fluoroacetate A solution of 14 mg (0.21 mmol) of the intermediate obtained in Step N in 1 mL of methanol was hydrogenated at room temperature and one atmosphere over l mg of 20% palladium hydroxide on carbon for 16 hours. The reaction mixture was filtered 20 through Celite and the filtrate concentrated under vacuum and the residue chromatographed on reverse phase high pressure liquid chromatography on C18, eluting with methanol/0.1% aqueous trifluoroacetic acid (linear gradient; 65% methanol increased to 85%
over 10 minllt~s), to give 10 mg (72%) of the title compound. lH NMR
25 (200 MHz, CD30D): 1.32 (s, 3H), 1.36 (s, 3H), 1.81 (m, lH), 1.95 (m, 2H), 2.26 (m, lH), 2.52 (s, lH), 2.63 (m, lH), 4.34 (m, lH), 4.76 (d, 14Hz, lH), 4.95 (d, 14Hz, lH), 7.01-7.70 (m, 13H). FAB-MS:
calculated for C29H33N7O2 511; found 512 (M+l, 100%).

E~XAMPLE 2 (R)-a-[(3-Amino-3-methyl- 1 -oxobutyl)amino] -N-[[2'-(1 H-tetrazol-5-yl)rl.l'-biphenvll-4-yllmethyllbenzene-propanamide. trilCluoroacetate wo 94/11012 Pcr/US93/~0551 The title compound was prepared from N-BOC-D-phenylalanine by the methods described in Example 1. lH NMR (200 MHz, CDCl3): 1.27 (s, 3H), 1.40 (s, 3H), 2.49 (d, l5Hz, lH), 2.62 (d, 15Hz, lH), 3.10 (m, 2H), 4.44 (m, 2H), 4.80 (m, lH), 7.16 (s, 4H), 7.35 (s, 5H); 7.70 (m, 4H). FAB-MS: calculated ~or C28H3 lN702 497;
found 498 (M+1,100%).

(R)-oc-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(lH-tetrazol-5-yl)[1,1 '-biphenyl]-4-yl]methyl]- 1 H-indole-3-propanamide, trifluoroacetate Step A: (R)-oc-[t-Butoxycarbonylamino]-N-[12'-(~-triphenyl-me~yl-tetrazol-5-yl)[ 1,1 '-biphenyl]- ~-yl]methyl]-(Nim-fo~nyl)indole-3 -propanamide Prepared from N-triphenylmethyl-5-[2-(4'-aminomethyl-biphen-4-yl)]tetrazole and Nim-fo~nyl-Na-BOC D-tryptophan by the procedure described in E~xarnple 1, Step G. lH NMR (200 MHz, CDCl3): 1.40 (s, 9H), 3.18 (br s, 2H), 4.24 (br s, 2H), 4.48 (m, lH), 5.24 (s, lH), 6.28 (s, lH), 6.70-7.70 (m, 27H), 7.90 (m, lH), 8.82 (br s, lH).

Step B: (R)-a-[t-Butoxycarbonylamino]-N-[[2'-(lH-tetrazol-5-yl)[1,1 '-biphenyl] -4-yl]methyl]-(Nim-formyl)indole-3-propanamide Prepared from the intermediate obtained in Step A by the procedure described in Example 1, Step H. lH NMR (200 MHz, CD30D): 1.38 (s, 9H), 3.14 (m, 3H), 6.90-7.70 (m, 13H), 9.02 (br s, 30 lH). FAB-MS: calculated for C30H31N704 553; found 554 (M+ 1,40%).

WO 94/11012 21~ 7 ~ O ~ PCI/US93/~05~1 . , Step C: (R)-o~-Amino-N-[[2'-(1 H-tetrazol-5-yl)[ l,1 '-biphenyll-4-yl]methyl] -(Nim-formyl)indole-3 -propanamide, trifluoroacetate A solution of 80 mg (0.14 mmol) of the intermediate 5 obtained in Step B in 4 mL methylene chloride was treated with l mL of anisole followed by 4 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 hour, then all volatiles were removed under vacuum. The residue was purified by reverse phase high pressure liquid chromatography on C18, eluting with methanol/0.1% aqueous trifluoroacetic acid (45:55), to give 64 mg (77%) of the product. lH NMR (200 MHz, CD30D): 3.26 (m, 2H), 4.11 (t, 6Hz, lH), 4.28 (m, 2H), 6.99 (s, 4H), 7.28-7.70 (m, 9H), 8.75 (br s, lH). FAB-MS: calculated for C26H23N7O2 465; found 466 (M+1, 22%).

Step D: 4.4-Dimethylazetidin-2-one A 3-neck 3L round bottom flask equipped with a magnetic stirrer, thermometer, cold finger condenser and nitrogen bubbler was charged with lL of ether. The flask was cooled to -65C and into it was 20 condensed 500-600 mL of isobutylene. The cold finger condenser was replaced with a dropping funnel and 200 mL (325 g, 2.30 mol) of chlorosulfonyl isocyanate was added dropwise over 1.5 hours. The mixture was m~int~ined at -65C for 1.5 hours then the dry ice/acetone cooling bath replaced with methanol/ice and the internal temperature 25 slowly increased to -5C at which time the reaction initi~ted and the internal temperature rose to 15C with evolution of gas. The internal temperature remained at 15C for several minutes then dropped back down to -5C and the mixture stirred at -5C for 1 hour. The methanol/ice bath was removed and the reaction mixture warmed to 30 room temperature and stirred overnight.
The reaction mixture was transferred to a 3-neck 12L
round bottom flask fitted with a mechanical stirrer and diluted with 2L
of ether. The well-stirred reaction mixture was treated with 2L of saturated aqueous sodium sulfite. After 1 hour, an additional lL of W O 94/11012 PC~r/US93/~0551 ~4~ ~3 saturated aqueous sodium sulfite was added followed by sufficient sodium bicarbonate to adjust the pH to approximately 7. The mixture was stirred another 30 minutes then the layers allowed to separate. The ether layer was removed and the aqueous layer reextracted with 2 x lL
of ether. The combined ether extracts were washed once with 500 mL
of saturated aqueous sodium bicarbonate and once with 500 mL of saturated aqueous sodium chloride. The ether layer was removed, dried over m~nesium sulfate, filtered and concentrated under vacuum to give 33 g of a pale yellow oil. The aqueous layer was made basic by the o addition of solid sodium bicarbonate and extracted with 3 x lL of ether.
The combined ether extracts were washed and dried as described above, then combined with the original 33 g of pale yellow oil and concen-trated under vacuum to give 67.7 g of product. ~urther extraction of the aqueous layer with 4 x lL of methylene chlor;de and washing and drying as before gave an additional 74.1 g of product. Still further extraction of the aqueous layer with 4 x lL of methylene chloride gave an additional 21.9 g of product. The combined product (163.7 g, 1.65 mol, 72%) was used in Step E without purification. lH NMR (200 MHz, CDCl3): 1.45 (s, 6H), 2.75 (d, 3Hz, 2H), 5.9 (br s, lH).

Step E: N-(t-Butoxycarbonyl)-4.4-dimethvla7etidin-2-one A 5L, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was charged with 88.2 g (0.89 mol) of 4,4-dimethylazetidin-2--one, 800 mL of methylene chloride, 150 mL of triethyl~mine (1.08 mol) and 10.9 g (0.089 mol) of 4-dimethylaminopyridine. To the stirred solution at room temperature was added dropwise over 15 minlltes a solution of 235 g (1.077 mol) of di-t-butyl-dicarbonate in 300 mL of methylene chloride. The reaction mixture was stirred at room temperature overnight then diluted with lL of methylene chlo ride and washed with 500 mL of saturated aqueous ammonium chloride, 500 mL of water, and 500 mL of saturated aqueous sodium chloride. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated ~VO 94J11012 21 ~ 7~ D 3 PCT/US93/10~1 under vacuum to afford 180.3 g of crude product as an orange solid.
The material was used directly in Step F without purification.
1H NMR (200 MHz, CDC13): 1.50 (s, 9H), 1.54 (s, 6H), 2.77 (s, 2H).

5 Step F: 3-t-Butoxycarbonylamino-3-methylbutanoic acid A 3L, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was charged with 180.3 g (0.89 mol) of N-(t-butoxycarbonyl)-4,4-dimethylazetidin-2-one dissolved in lL of tetrahydrofuran. The solution was cooled to 0-o 5C and treated dropwise with 890 mL of l.OM aqueous lithiumhydroxide over 30 minutes. The reaction mixture was stirred at 0-5C
for 2 hours then diluted with lL of ether and lL of water. The layers were allowed to separate and the aqueous layer was reextracted with an additional lL of ether. The aqueous layer was acidified by the addition 5 of lL of saturated aqueous sodium bisulfate, then extracted with 1 x lL
and 2 x 500 mL of ether. The combined organic layer and ether extracts were washed with 500 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to give 173 g of a yellow oil that solidified upon standing. The material 20 was slurried with warm hexane then filtered and dried under high vacuum to afford 168.5 g (0.775 mol, 87%) of product as a white solid.
lH NMR (200 MHz, CDC13): 1.39 (s, 6H), 1.44 (s, 9H), 2.72 (s, 2H).
FAB-MS: calculated for C1oH1gNO4 217; found 218 (M+H, 54%).

25 Step G: (R)-oc-[(3-t-Butoxycarbonylamino-3-methyl-1-oxo-butyl)amino]-N-[[2'-(lH-tetrazol-5-yl)-[1,1 '-biphenyl]-4-yllmethvll -(Nim -formyl)-indole-3-propanamide A solution of 64 mg (0.11 mmol) of the intermediate obtained in Step C in 1 mL of methylene chloride at 0C was treated 30 with 25 mg (0.12 mmol, 1.1 eq) of dicyclohexylcarbodiimide and the resulting solution stirred at 0C for 30 minutes. A solution of 53 mg (0.24 mmol, 2 eq) of 3-t-butoxycarbonylamino-3-methylbutanoic acid and 12 mg (0.12 mmol, 0.017 mL, 1.1 eq) of triethylamine in 1 mL of methylene chloride was added and the mixture stirred for 5 hours al WO 94/11012 PCr/US93/105~1 , --2~s~3 room temperature. The reaction mixture was evaporated to dryness under vacuum and the residue was dissolved in 1 mL of anisole and treated with 4 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes the concentrated under vacuum. The 5 residue was taken up in methanol and the solids removed by filtration.
The filtrate was concentrated under vacuum; the residue was purified by reverse phase high pressure liquid chromatography on C18 to yield 31 mg (42%) of the product. lH NMR (200 MHz, CD30D): 1.14 (s, 3H), 1.25 (s, 3H), 2.37 (d, 15Hz, lH), 2,48 (d, 15Hz, l ~I), 3.11 (m, 2H), 4.26 (m, 2H), 4.72 (m, lH), 6.92-7.70 (m, 13H), 8.55 ~br s, lH).
FAB-MS: calculated for C31H32NgO3 564; found 565 (M+1, 80%).

Step H: (R)-a-[(3-Amino-3-methyl- 1 -oxobutyl)amino]-N-[[2'-(1 H-tetrazol-5 -yl) [1,1 '-biphenyl] -4-yl]methyl] - 1 H-indole-3 -propanamide. trifluoroacetate A solution of 31 mg (0.046 mmol) of the intelmediate obtained in Step G in 1 mL of methanol was treated with 0.2 mL of concentrated hydrochloric acid and the resulting mixture heated at 65C
for 1.5 hours. All volatiles were removed under ~acuum and the 20 residue purified by reverse phase high pressure liquid chromatography on C18, eluting with methanol/0.1% aqueous trifluoroacetic acid (50:50), to give 20 mg (67%) of the title compound. lH NMR (200 MHz, CD30D): 1.15 (s, 3H), 1.28 (s, 3H), 2.38 (d, 16Hz, lH), 2.50 (d, 16Hz, lH), 3.19 (m, 2H), 4.20 (d, 14Hz, lH), 4.32 (d, 14Hz, lH), 4.73 5 (t, 7Hz, lH), 6.90-7.70 (m, 13H). FAB-MS: calculated for C30H32N8o2 536; found 536 (70%).

(R)-2-[(3-Amino-3-methyl- 1 -oxobutyl)amino]-N-phenyl-N-[ [2'-(1 H-tetrazol-5-yl)r l . l '-biphenyll-4-yllmethyll-butanamide~ trifluoroacetate Step A: (R)-2-(t-Butoxycarbonylamino)-N-phenyl-butanamide -~ 7 ~ ~ ~

Prepared from N-BOC-D-2-arninobutanoic acid and aniline by the method described in Example 1, Step G. lH NMR (200 MHz, CDC13): 1.00 (t, 6Hz, 3H), 1.45 (s, 9H), 1.82 (m, 2H), 4.30 (m, lH), 5.59 (d, 7Hz, lH), 7.00-7.62 (m, 5H), 8.90 (br s, lH). FAB-MS:
calculated for C15H22N2O3 278; found 279 (M+1, 40%).

Step B: (R)-2-(t-Butoxycarbonylamino)-N-phenyl-N-[[2'-(~-triphenylmethyl-tetrazol-5-yl)-[1,1'-biphenyl] -4-yl]methyl] -butanamide A solution of 70 mg (0.25 mmol) of (R)-2-(t-butoxy-carbonylamino)-N-phenyl-but~n~mide in 0.5 mL of dry dimethyl-formamide was treated with 10 mg (0.25 mmol, l eq) of 60% sodium hydride oil dispersion. The mixture was stirred at room temperature for 20 minutes, then treated with a solution of 140 mg (0.25 mmol, l 5 eq) of N-triphenylmethyl-5-[2-(4'-bromomethylbiphen-4-yl)]tetrazole (Example 1, Step D) in 0.5 mL of dry dimethylformamide. The mixture was stirred at room temperature for 2 hours, then quenched by the addition of 2 mL of water. The mixture was extracted several times with ethyl acetate; the combined extracts were washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate then dried over magnesium sulfate, filtered and the filtrate dried under vacuum. The crude material was chromatographed on a flash silica column, eluting with hexane/ethyl acetate (1:1), to give 91 mg (48%) of the product. lH
NMR (200 MHz, CDC13): 0.74 (t, 6Hz, 3H), 1.32 (s, 9H), 1.58 (m, 25 2H), 4.20 (m, lH), 4.79 (s, 2H), 6.82-7.60 (m, 27H), 7.86 (m, lH).

Step C: (R)-2-(t-Butoxycarbonylamino)-N-phenyl-N-[[2'-(lH-tetrazol-5-yl)-~1.1'-biphenyll -4-yllmethyllbutanamide Prepared from the intermediate obtained in Step B by the 3 procedure described in Example 1, Step H. 1 H NMR (200 MHz, CDC13): 0.74 (t, 6Hz, 3H), 1.36 (s, 9H), 1.55 (m, 2H), 4.13 (m, lH), 4.70 (d, 14Hz, lH), 5.02 (d, 14Hz, lH), 5.22 (m, lH), 7.00-7.62 (m, 12H), 8.01 (m, lH). FAB-MS: calculated for C29H32N6O3 512; found 513 (M+l, 100%).

~VO 9~/11012 PCT/US93/lOS;i Step D: (R)-2-Amino-N-phenyl-N-[[2'-(1H-tetrazol-5-yl)[l,l'-biphenyll-4-yllmethyllbut~n~mide. hydrochloride Prepared from the intermediate obtained in Step C by the method described in Example 1, Step I. 1H NMR (200 MHz, CD30D):
0.83 (t, 7Hz, 3H), 1.68 (m, 2H), 3.80 (m, lH), 4.81 (d, 14Hz, lH), 5.01 (d, 14Hz, lH), 7.00-7.70 (m, 13H). FAB-MS: calculated for C24H24N60 412; found 413 (M+1, 100%).

Step E: 3-t-Butoxycarbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 3, Step F) and N-hydroxysuccinimde by the procedure describe in Example 1, Step M. lH NMR (200 MHz, CDCl3): 1.41 (s, 9H), 1.43 (s, 6H), 2.82 (s, 4H), 3.07 (s, 2H), 4.72 (br s, lH).

Step F: (R)-2-[(3-t-Butoxycarbonylamino-3-methyl-1-oxobutyl)-amino]-N-phenyl-N-[ [2'-(1 H-tetra-zol-5 -yl) [1,1 '-biphenyl] -4yllmethyll -but~n~mi de Prepared as in Example 1, Step N from (R)-2-amino-N-phenyl-N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]b~lt~n~mide, hydrochloride and 3-t-butoxycarbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester. lH NMR (200 MHz, CD30D): 0.74 (t, 7Hz, 3H), 1.32 (s, 6H), 1.40 (s, 9H), 1.58 (m, 2H), 2.4S (d, 13Hz, lH), 2.58 (d, 13Hz, lH), 4.29 (m, lH), 4.78 (d, 14Hz, lH), 4.9~ (d, 14Hz, lH), 6.97-7.79 (m, 13H). FAB-MS: calculated for C34H41N704 611; found 612 (M+l, 100%).

Step G: (R)-2-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-phenyl-N-[[2'-(lH-tetrazol-5-yl)[ l,1 '-biphenyl] 4-yl]methyl]-butanamide. -trifluoroacetate The title compound was prepared from the intermediate obtained in Step F by the procedure described in Example 3? Step H.
1H NMR (200 MHz, CD30D): 0.72 (t, 7Hz, 3H), 1.32 (s, 3H), 1.40 (s, WO 94/1 1012 PC~/US93/~05~1 77~

3H), 1.58 (m, 2H), 2.51 (m, 2H), 4.28 (m, lH), 4.73 (d, 14Hz, lH), 4.99 (d, 14Hz, 1 H), 6.95-7.83 (m, 1 3H). FAB-MS: calculated for C29H33N7O2 51 1; found 512 (M+1, 100%).

E~AMPLE 5 2-[(3-Amino-3-methyl- 1 -oxobutyl)amino]-N-[[2'-(1 H-tetrazol-5-yl)r1.1'-biphenyll-4-yllmethyllacetamide. trifluoroacetate Step A: 2-t-Butoxycarbonylamino-N-[[2'-(~-triphenylmethyl-tetrazol-5-yl)~ 1~1 '-biphenyll-4-yll-methyllacetamide Prepared from N-triphenylmethyl-5-[2-(4'-aminomethyl-biphen-4-yl)]tetrazole (Example 1, Step F) and N-BOC-glycine by the procedure described in Example 1, Step G. lH NMR (200 MHz, CDC13): 1.43 (s, 9H), 3.72 (d, SHz, 2H), 4.32 (d, 6Hz, 2H), 5.06 (m, lH), 6.30 (m, lH), 6.82-7.68 (m, 22H), 7.95 (m, lH).

Step B: 2-t-Butoxycarbonylamino-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyll -4-yllmethyll acetamide Prepared from the intermediate obtained in Step A by the procedure described in Example 1, Step H. 1H NMR (200 MHz, CD30D): 1.42 (s, 9H), 3.69 (s, 2H), 4.38 (d, 6Hz, 2H), 6.90-7.28 (m, 4H), 7.42-7.69 (m, 4H). FAB-MS: calculated for C21H24N603, 408;
found 409 (M+1, 20%).

Step C: 2-Amino-N-[[2'-(1 H-tetrazol-5-yl)[ 1,1 '-bi-phenyl]-4-yllmethyllacetamide~ hydrochloride Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Step I. lH NMR (200 MHz, 30 CD30D): 3.84 (s, 2H), 4.35 (s, 2H), 7.10-7.83 (m, 8H). FAB-MS:
calculated for C1 6H1 6N60 308; found 309 (M+1, 100%).

WO 9~/11012 PCI/US93/10551 .

Step D: 2-[(3-Benzyloxycarbonylamino-3-melthyl-1-oxo-butyl)-amino] -N-[[2'-( l H-tetrazol-5-yl)[1,1 '-biphenyl]-4yl] -methyll acetamide Prepared from the intermediate obtained in Step C and 3-5 benzyloxycarbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester by the procedure described in Example 1, Step N. lH NMR (200 MHz, CD3OD): 1.37 (s, 6H), 2.60 (s, 2H), 3.79 (s, 2H), 4.33 (s, 2H), 5.00 (s, 2H), 6.95-7.65 (m, 13H). FAB-MS: calculated for C26H33N7O4 507; found 508 (M+1, 20%).

Step E: 2-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(lH-tetrazol-5-yl)[1,1 '-biphenyl]-4-yl]methyl]acetamide, trifluoroacetate Prepared from the intermediate obtained in Step D by the procedure described in Example 1, Step O. 1H N~R (200 MHz, CD30D): 1.38 (s, 6H), 2.52 (s, 2H), 3.89 (s, 2H), 4.38 (s, 2H), 7.00-7.70 (m, 8H). FAB-MS: calculated for C21H25N7O2 407; found 408 (M+ 1,100%).

(R)-o~-[(2-Arnino-2-methyl- 1 -oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino] [1,1 '-biphenyl] -4-yl]-methyl] - 1 H-indole-3-propanamide~ trifluoroacetate Step A: N-(t-Butoxycarbonyl)-D-tryptophan benzyl ester Finely divided t-butoxycarbonyl-D-tryptophan (3 g, 10 mmol) was suspended in methylene chloride and benzyl alcohol (1.08 mL, 10 mmol) and 4-dimethylaminopyridine (0.1" g, 1 mmol) were 3 added and stirred at room temperature. Solid 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) was then added in three roughly equal portions over 5 minutes. The reaction mixture was stirred for 3 hours at room temperanlre during which time the reaction mixture became a homogeneous solut;on. The reaction WO 94/11012 PCrtUS93/10551 21 i7~

mixture was poured into water (100 mL) and extracted with methylene chloride (2 x 50 mL). The combined methylene chloride layers were washed with 5% aqueous citric acid solution (100 mL) and 5% aqueous sodium bicarbonate solution (100 mL). The resulting methylene 5 chloride layer was dried over magnesium sulfate, filtered and evaporated under vaccum to give an off-white solid. This solid material was chromatographed on silica gel using ethyl acetate~exanes (2:3 v/v) as eluant. This afforded 3.56 g (91%) of the desired benzyl ester as a white amorphous powder.
lH NMR (400 MHz, CDCl3): 1.42 (s, 9H), 3.27 (d, 2H), 4.69 (m, lH), 5.17 (ABq, 2H), 6.78 (br s, lH), 7.15-7.42 (m, 8H), 7.53 (d, lH), 7.97 (br s, lH).

Step B: D-Tryptophan benzyl ester N-(t-Butoxycarbonyl)-D-tryptophan benzyl ester (3.5 g, 8.87 mmol) was dissolved in methylene chloride (10 mL) and stirred at room temperature and trifluoroacetic acid (20 mL) was added dropwise to the ester. The reaction mixture was stirred at room temperature for one hour during which time the reaction darkened. The reaction 20 mixture was directly evaporated under vacuum to give a white solid.
This solid was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform (2 x 25 mL) and the combined chloroform layers were dried over potassium carbonate. Filtration and concentration of the 25 chloroform solution under vacuum gave a pale yellow oil (3.14 g, 82%) which was mainly ~e desired product.
lH NMR (400 MHz, CDC13): 1.58 (s, 9H), 3.09 (dd, lH), 3.27 (dd, lH), 3.88 (m, lH), 5.10 (s, 2H), 6.93 (br s, lH), 7.15-7.39 (m, 8H), 7.59 (d, lH), 8.03 (br s, lH).

Step C: (R)-a-[(2-t-Butoxycarbonylamino-2-methyl-1-oxopropyl)-aminol-lH-indole-3-propanoic acid. benzyl ester Crude D-tryptophan benzyl ester (1.0 g, 3.40 mmol), 1-hydroxybenztriazole hydrate (0.63 g, 4.1 mmol) and t-butoxycarbonyl-7 ~
, o~-methylalanine (0.84 g, 4.11 mmol) were stirredi together at room temperature in chloroform (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol) was added to this mixture in a single portion. The reaction mixture was stirred at 5 room temperature for 4 hours and worked up by pouring into water (50 mL). The chloroform layer was separated and washed with 5% aqueous citric acid solution (25 mL) and 5% aqueous sodium bicarbonate solution (25 mL). The chloroform layer was dried over magnesium sulfate, filtered and evaporated under vacuum to 2fford a thick oily foam. Chromatography on silica gel using ethyl acetate/hexanes (2:3 v/v) afforded a yellow foam (0.822 g 50%). lH ~R (400 MHz, CDCl3): 1.30 (s, 9H), 1.39 (s, 6H), 3.29 (m, 2H), 4.88 (m, lH), 5.03 (s, 2H), 6.88 (br s, lH), 7.05-7.35 (m, 8H), 8.53 (d, lH), 7.98 (br s, lH).

Step D: (R)-oc-[(2-t-Butoxycarbonylamino-2-methyl-1-oxopropyl)-aminol - 1 H-indole-3 -propanoic acid The benzyl ester (0.82 g, 1.71 mmol) obtained in Step C
and 10% palladium on carbon (150 mg) were stirred together in ethyl 20 acetate (5 mL). The solution was degassed and a hydrogen atmosphere introduced over the reactants using a balloon for 32 hours. The reaction products were isolated by filtering the reaction mixture through a Celite plug. The plug was washed with additional ethyl ac~tate (3 x 10 mL). The combined filtrates were evaporated under 25 vacuum to afford the product (680 mg, 102%). l~I NMR (400 MHz, CDCl3): 1.30 (s, 9H), 1.41 (s, 6H), 3.32 (dd, lH), 3.42 (m, lH), 4.87 (br s, lH), 6.82 (d, lH), 7.13-7.35 (m, 8H), 7.60 ~d, lH), 8.28 (br s, lH).

3 Step E: 4-Methyl-2'-nitro-1 1'-biphenyl A vigorously stirred mixture of 34 g (0.25 mol) of 4-tolylboronic acid and 34 g (0.17 mol) of 2-bromo-1-nitrobenzene in a mixture of 170 mL of 5N sodium hydroxide, 57 mL of water, 215 mL
of 2-propanol and 1080 mL of benzene was treated with 11.9 g of wo 94/llO12 Pcr/uss3/los~l ~1~7~0~

(tetrakis)triphenylphosphine palladium(0). The two-phase mixture was heated at reflux for three 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), to give 28.05 g of the product. lH NMR (400 MHz, CDCl3):
2.38 (s, 3H), 7.20 (m, 4H), 7.43 (m, 2H), 7.59 (t, lH), 7.8 (d, lH).
EI-MS: calculated for C13H1 lNO2 213; found 213 (M+).

Step F: 4-Bromomethyl-2'-nitro-1~1'-biphenyl Prepared from 4-methyl-2'-nitro-1,1'-biphenyl by the procedure described in Example 1, Step D. 1H NMR (200 MHz, CDC13): 4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, lH).

Step G: 4-Azidomethyl-2'-nitro-1~1'-biphenyl Prepared from 4-bromomethyl-2'-nitro-1,1'-biphenyl by the procedure described in Example 1, Step E. lH NMR (200 MHz, CDCl3): 4.39 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (d, lH).

Step H: 4-Aminomethyl-2'-nitro-1.1'-biphenyl Prepared from 4-azidomethyl-2'-nitro-1,1'-biphenyl by the procedure described in Example 1, Step E. lH NMR (200 MHz, 25 CDCl3): 3.90 (s, 2H), 7.2-7.7 (m, 7H), 7.83 (d, lH).

Step I: (R)-a-[(2-t-Butoxycarbonylamino-2-methyl-1-oxopropyl)-amino]-N-[[(2'-nitro)[ 1,1 '-biphenyl]-4-yl]methyl]-1H-indole-3 -propanamide The acid (338 mg, 0.87 mmol) from Step D and 4-aminomethyl-2'-nitro-1,1'-biphenyl (200 mg, 0.87 mmol) and triethylamine (0.245 mL, 1.76 mmol) were dissolved in methylene chloride (8 mL) and stirred at room temperature. Benzotriazolyl-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (388 mg, WO 94/11012 PCr/US93/105~1 ?~4r~

0.87 mmol) was added in a single portion. The reaction mixture was stirred togerther for 3.5 hours then the reaction was quenched by adding saturated aqueous sodium chloride (10 mL) and extracted with methylene chloride (3 x 20 mL). The combined extracts were dried 5 over magnesium sulfate, filtered and evaporated under vacuum. The resulting thick gum was chromatographed on silica gel using ethyl acetate/hexanes (1 :2 v/v) to give 297 mg (50%) of an orange semi-solid.
1H NMR (400 MHz, CD3OD): 1.08 (s, 9H), 1.26 (s, 3H), 1.32 (s, 3H), 3.29 (dd, lH), 3.43 (dd, lH), 4.35 (m, 2H), 4.64 (m, lH), 7.00-7.20 (m, 7H), 7.34 (d, lH), 7.42 (m, lH), 7.53 (t, lH), 7.61 (d, lH), 7.67 (t, lH), 7.83 (d, lH), 8.22 (s, lH).

Step J: (R)-a-[(2-t-Butoxycarbonylamino-2-methyl-1-oxopropyl)-arnino]-N-[[(2'-amino)[1,1 '-biphenyl]-4-yl]methyl]-lH-l 5 indole-3-propanamide The amide (142 mg, 0.24 mmol) from Step I was dissolved in ethanol (5 mL) and 10% palladium on carbon (15 mg) was added.
The ethanolic mixture was degassed and a hydrogen atmosphere introduced and m~int~ined above the reaction mixture for 2.5 hours 20 using a balloon. The hydrogenation catalyst was removed by filtration through a Celite pad. The pad was washed carefu~ly with methylene chloride (4 x 5 mL). The combined filtrates were evaporated under vacuum to give a powdery white foam (124 mg, 92%). lH NMR (400 MHz, CD30D): 1.09 (s, 9H), 1.26 (s, 3H), 1.31 (s, 3H), 3.29 (m, lH), 2S 3.43 (dd, lH), 4.36 (m, 2H), 4.62 (m, lH), 6.87 (m, 2H), 7.00-7.45 (m, lOH), 7.60 (d, lH), 8.20 (s, lH). FAB-MS: calculated for C33H3gNsO4 569, found 570 (M+l).
Step K: (R)-a-[(2-t-Butoxycarbonylarnino-2-1nethyl-l-oxopropyl)-amino~-N-[~2'-[[(methylamino)-carbonyl]amino][l ,l '-biphenvll-4-yllmethvll- 1 H-indole-3-~ropanamide The amine (25 mg, 0.04 mmol) from Step J was dissolved in methylene chloride and methyl isocyanate (0.009 mL, 0.15 mmol) was added to the amine. The reaction mixture was stirred together at WO 9~/1 1012 PCI/US93/10551 21~7~3 room temperature for 2.5 hours then the volatiles were removed directly under vacuum. The resultant residue was chromatographed on silica gel using ethyl acetate/hexanes (4: 1 v/v) to afford the desired product (23 mg, 82%). lH NMR (200 MHz, CD30D): 1.10 (s, 9H), 1.24 (s, 3H), 1.30 (s, 3H), 2.64 (d, 3H), 3.33 (ABq, 2H), 4.33 (m, 2H), 4.60 (m, lH), 6.23 (m, lH), 6.96-7.45 (m, 11H), 7.58 (d, lH), 7.68 (m, lH), 8.20 (m, lH). FAB-MS: calculated for C3sH42N6Os 626; found 627 (M+l).

Step L: (R)~ [(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[(methylaminocarbonyl)amino] [1,1 '-biphenyl] -4-yl]methyl] -lH-indole-3-propanamide~ trifluoroacetate The intermediate obtained in Step K (15 mg, 0.023 mmol) and anisole (0.01 mL, 0.09 mmol) were dissolved in methanol (0.5 mL) 15 and hexanes (0.5 mL). To this solution 0.5 mL of 9 N aqueous hydro-chloric acid was added. The reactants were stirred at room temperature for 30 minutes then the hexane layer was removed using a pipette. The aqueous methanolic layer was evaporated at atmospheric pressure using a fast stream of nitrogen at room temperature. The solid material thus 20 obtained was purified by reverse phase medium pressure liquid chroma-tography on C8, eluting with methanol/0.1% aqueous trifluoroacetic acid (85:15 v/v). ~his afforded 11.3 mg (0.018 mmol, 74%) of the title compound. 1H NMR (400 MHz, CD30D): 1.38 (s, 3H), 1.56 (s, 3H), 2.66 (s, 3H), 3.18 (dd, lH), 3.33 (dd, lH), 4.35 (ABq, 2H), 4.78 (t, lH), 25 6.98-7.47 (m, lOH), 7.62 (d, lH), 7.64 (d, lH). FAB-MS: calculated for C30H34N6o3 526; found 527 (M+l).

Claims

WHAT IS CLAIMED IS:

1. A compound having the formula:

where L is n is 0 or 1;
p is 0 to 6;
q is 0 to 4;
w is 0 or 1;

;

m is 0 to 2;

R1, R2, R1a, R2a, R1b, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(O)m-R7a, cyano, nitro, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, R4R5N(CH2)v-, R7bCON(R4)(CH2)v-, R4R5NCO(CH2)v-, R4R5-NCOO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy and v is 0 to 3;

R3a and R3b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9;

R9 is , , R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, R7bCO(CH2)v-, R7bO(CH2)vCO-, R4bR12cN(CH2)v-, R12aR12bNCO(CH2)v-, R12aR12bNCS(CH2)v-, R4bR12aNN(R12b)CO(CH2)v-, R4bR12aNN(R12b)CS(CH2)v-, R4bR12aNCON(R12c)(CH2)v-, R4bR12aNCSN(R12c)(CH2)V-, R4bR12aNN(R12b)CON(R12c)(CH2)v-, R4bR12aNN(R12b)CSN(R12c)(CH2)v-, 4bR12aNN(R12b)-COO-(CH2)v-, R4bR12aNCOO(CH2)v-, or R13OCON(R12c)(CH2)v-, where v is 0 to 3;

R12a, R12b and R12c are independently R5a OR5a, or COR5a; R12a and R12b, or R12b and R12c, or R12a and R12c, or R4b and R12a, or R4b and R12a, or R4b and R12c, or R13 and R12c, can be taken together to form -(CH2)r-B-(CH2)s- where B is CHR1,O,S(O)m or NR10, m is 0, 1 or 2, r and s are independently 0 to 3 and R1 and R10 are as defined;

R13 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are hydroxy, -NR10R11, 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 where R10 and R11 are as defined;

R14 is hydrogen, R1, R2 independently disubstituted phenyl, C1-C10 alkyl or substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NR10R11 where R1, R2, R10 and R11 are as defined;

R15 is hydrogen, trifluoromethyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, C3-C7 cycloalkyl, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disub-stituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted naphthyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, -NR10R11 or R1, R2 independently disubstituted heterocycle, where the heterocycle is imidazole, thiophene, furan, pyrrole, oxazole, thiazole, triazole, tetrazole, pyridine, benzofuran, benzothiophene, benzimi-dazole, indole, 7-azaindole, oxindole or indazole; where R1, R2, R10 and R11 are as defined above.

R4, R4a, R4b, R5 and R5a are independently hydrogen, phenyl, substituted phenyl, C1-C10 alkyl, substituted C1-C10 alkyl, C3-C10 alkenyl, substituted C3-C10 alkenyl, C3-C10 alkynyl, or substituted C3-C10 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, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, or -NR10R11 where R10 and R11 are independently hydrogen, C1-C6 alkyl, phenyl C1-C6 alkyl, C1-C5-alkoxycarbonyl or C1-C5-alkanoyl-C1-C6 alkyl; or R4 and R5 can be taken together to form -(CH2)rB(CH2)s- where B, r, s, R1, R10 as defined above;

R6 is hydrogen, C1-C10 alkyl, phenyl or phenyl C1-C10 alkyl;

A is where x and y are independently 0-3;

R8 and R8a are independently hydrogen, C1-C10 alkyl, trifluoromethyl, phenyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, or -NR10R11 where R10 and R11 are as defined above; or R8 and R8a can be taken together to form -(CH2)t-where t is 2 to 6; andR8 and R8a can independently be joined to one or both of R4 and R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

2. A compound of Claim 1 wherein:

n is 0 or 1;
p is 0 to 4;
q is 0 to 2;
w is 0 or 1;

X is O, S(O)m, , -CH=CH-;
m is 0 to 2;

R1, R2, R1a, R2a, R1b, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(O)mR7a, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;

R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl; phenyl and v is 0 to 2;
R3a and R3b are independently hydrogen, R9, C1-C6 alkyl substituted with R9 phenyl substituted with R9, or phenoxy substituted with R9;

R9 is as defined in Claim 1.

R12a, R12b and R12c are independently R5a, OR5a or COR5a; R12a and R12b, or R12b and R12C, or R13 and R12b or R12a and R4b can be taken together to form -(CH2)r-B-(CH2)s-where B is CHR', O, S(O)m or NR10, m is 0, 1 or 2, r and s are independently 0 to 3, R1 is as defined above and R10 is hydrogen, C1-C6 alkyl, phenyl C1-C6 alkyl or C1-C5 alkanoyl -C1-C6 alkyl.

R13 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are hydroxy, NR10R11, 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;

R14 and R15 are as defined in Claim 1;

R4, R4a, R4b, R5 and R5a are independently hydrogen, phenyl, substituted phenyl, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents on the alkyl or phenyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, R1 substituted or R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1 substituted or R1, R2 independently disubstituted phenyl, C1-C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy or formyl;

R4 and R5 can be taken together to form -(CH2)rB(CH2)s- where B is CHR1, O, S(O)m or N-R10, r and s are independently 1 to 3 and R1 and R10 are as defined above;

R6 is hydrogen, C1-C10 alkyl or phenyl C1-C10 alkyl;

A is where x and y are independently 0-2;

R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, -NR10R11 where R10 and R11 are independently hydrogen, C1-C6 alkyl, or C1-C5 alkanoyl-C1-C6 alkyl; or R8 and R8a can be taken together to form -(CH2)t- where t is 2 to 4; and R8 and R8a can independently be joined to one or both of R4 and R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

3. A compound of Claim 2 wherein:

n is 0 or 1;
p is 0 to 3;
q is 0 to 2;
w is 0 or 1;
x is O, S(O)m, -CH=CH-;
m is 0 or 1;

R1, R2, R1a, R2a, R1b, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(O)mR7a, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;

R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is 0 to 2:

R3a and R3b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9 or phenoxy substituted with R9;

R12a, R12b and R12c are independently R5a or OR5a. R12a and R12b, or R12b and R12C, or R13 and R12b or R12a and R4b can be taken together to form -(CH2)r-B-(CH2)s- where B is CHR1, O, S(O)m or NR10, m is 0, 1 or 2, r and s are independently 0 to 2, R1 is as defined above, and R10 is hydrogen, C1-C6 alkyl or C1-C5 alkanoyl-C1-C6 alkyl;

R13 is C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents arephenyl 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;

R4, R4a, R4b, R5 and R5a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents on the alkyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, fluoro, R1 substituted or R1, R2 independently disubstituted phenyl, C1-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy;

R6 is hydrogen or C1-C10 alkyl;

A is where x and y are independently 0-2;

R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, R1 substituted or R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; or R8 and R8a can independently be joined to one or both of R4 and R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

4. A compound of Claim 3 wherein:

n is 0 or 1;
p is 0 to 2;
q is 1;
w is 1;
X is O, S(O)m or -CH=CH-;
m is 0 or 1;

R1, R2, R1a, R2a, R1b, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(O)mR7a, R7bO(CH2)v-, R7bCOO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;

R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is 0 or 1;

R3a and R3b are independently hydrogen, R9, or C1-C6 alkyl substituted with R9;

R12a, R12b and R12c are independently R5a. R12a and R12b, or R12b and R12c, or R13 and R12b or R12a and R4b can be taken together to form -(CH2)r-B-(CH2)s- where B is CHR1, O, S(O)m or NR10, m is 0, 1 or 2, r and s are independently 0 to 2, R1 is as defined above and R10 is hydrogen, C1-C6 alkyl or C1-C5 alkanoyl-C1-C6 alkyl, R13 is C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents arephenyl 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;

R4, R4a, R4b, R5, and R5a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents on the alkyl are from 1 to 3 of hydroxy, C1-C3 alkoxy, fluoro, R1 substituted or R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy;

R6 is hydrogen;

A is where x and y are independently 0-1;

R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, R1 substituted or R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; and R8 and R8a can independently be joined to one or both of R4 and R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms;
and pharmaceutically acceptable salts thereof.

5. A stereospecific compound of Claim 1 having the following structural formula:

where X, n, p, q, L, w, R1a, R2a, R3a, R4, R5, R6, R14, R15, and A
are as defined in Claim 1

6. A compound of Claim 1 which is:

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]benzenebutanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-benzenebutanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]benzenepentanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-benzenepentanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-3-[(phenylmethyl)-oxy]propanamide;

(R-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-3-[(phenylmethyl)-oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1 -oxobutyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-(1H-tetra-zol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-3-[[(2,6-difluoro-phenyl)methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]propanamide;

(R)-4'-[[[2-[(3-Amino-3-methyl-1-oxobutyl)amino]-1-oxo-4-phenylbutyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxa-mide;

(R)-4'-[[[2-[(2-Amino-2-methyl-1-oxopropyl)-amino]-1-oxo-4-phenylbutyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxa-mide;

(R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-4-phenylbutyl]-amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-4-phenylbutyl]-amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(3-Amino-3-methyl-1-oxobutyl)amino]-1-oxo-5-phenylpentyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxa-mide;

(R)-4'-[[[2-[(2-Amino-2-methyl-1-oxopropyl)-amino]-1-oxo-5-phenylpentyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxa-mide;

(R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-5-phenylpentyl]-amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-1-oxo-5-phenylpentyl]-amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(3-Amino-3-methyl-1-oxobutyl)amino]-1-oxo-3-(1H-indole-3-yl)propyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(2-Amino-2-methyl-1-oxopropyl)-amino]-1-oxo-3-(1H-indole-3-yl)propyl]amino]-methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-3-(1H-indole-3-yl)propyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-3-(1H-indole-3-yl)propyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(3-Amino-3-methyl-1-oxobutyl)amino]-1oxo-3-[(phenylmethyl)oxy]propyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(2-Amino-2-methyl-1-oxopropyl)-amino]-1-oxo-3-[(phenylmethyl)oxy]propyl]amino]-methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-3-[(phenylmethyl)-oxy]propyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-1-oxo-3-[(phenylmethyl)-oxy]propyl]-amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(3-Amino-3-methyl-1-oxobutyl)amino]-1-oxo-3-[[(2,6-difluorophenyl)methyl]oxy]propyl]-amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[(2-Amino-2-methyl-1-oxopropyl)-amino]-1-oxo-3-[[(2,6-difluorophenyl)methyl]oxy]-propyl]amino]methyl]-N-ethyl[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-1-oxo-3-[[(2,6-difluoro-phenyl)methyl]oxy]-propyl]amino]methyl]-N-ethyl-[1,1'-biphenyl]-2-carboxamide;

(R)-4'-[[[2-[[3-2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-1-oxo-3-[[(2,6-difluoro-phenyl)methyl]oxy]-propyl]amino]methyl]-N-ethyl-[1,1'-biphenyl]-2-carboxamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]benzene-butanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]benzene-butanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]benzene-pentanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]benzene-pentanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxo-butyl]amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][l,l'-biphenyl]-4-yl]methyl]-1H-indole-3 -propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl] -amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]-3-[(phenyl-methyl)oxy]propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide (R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[(methyl-amino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[(methylamino)carbonyl]-amino][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-benzenebutanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-benzenebutanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-benzenepentanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-benzenepentanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]-propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy] -propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-hydroxy-methyl[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-hydroxymethyl[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methyl-amino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-benzenebutanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]benzenebutanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methyl-amino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-benzenepentanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[[3-[2R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]benzenepentanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methyl-amino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]4-yl]methyl]-1H-indole-3-propananide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]-1H-indole-3-propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methyl-amino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)-oxy]propanamide;

(R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)-oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide;

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]-3-[(phenylmethyl)oxy]propanamide;

(R)-.alpha.-[(3-Amino-3-methyl-1-oxobutyl)amino]-N-[[2'-[[[(methyl-amino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)-methyl]oxy]propanamide, (R)-.alpha.-[(2-Amino-2-methyl-1-oxopropyl)amino]-N-[[2'-[[[(methylamino)carbonyl]amino]methyl]-[1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluoro-phenyl)methyl]oxy]propanamide;

(R)-.alpha.-[[3-[2(R)-Hydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]-propanamide; or ?

(R)-.alpha.-[[3-[2(S),3-Dihydroxypropyl]amino-3-methyl-1-oxobutyl]-amino]-N-[[2'-[[[(methylamino)carbonyl]-amino]methyl][1,1'-biphenyl]-4-yl]methyl]-3-[[(2,6-difluorophenyl)methyl]oxy]-propanamide.

7. A process for the preparation of a compound of Claim 1 which comprises reacting a compound having a formula:

II

where R6, R15, X, n and p are as defined in Claim 1 with a compound having the formula:

III
where R4 and A are defined in Claim 1 and G is a protecting group;
which step is either followed by or preceded by the treatment of the compound with V

where R1a, R2a, R3a, R14, L, q and w are as defined in Claim 1, followed by replacement of the protecting group G with R5.

8. The process of Claim 7 where compound II is first reacted with compound III followed by reaction with compound V.

9. A process for the preparation of a compound of Claim 1 which comprises reacting a compound having a formula:

IV

where R4, R6, R15, A, X, n and p are as defined in Claim 1 and G is a protecting group, with a compound having the formula:

V
where R1a, R2a, R3a, R14, L, q and w are as defined in Claim 1, followed by replacement of the protecting group G with R5.

10. The process of Claim 9 where the protecting group G is t-butoxycarbonyl or benzyloxycarbonyl.

11. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of a compound of Claim 1.

12. A composition useful for increasing the endogenous production or release of growth hormone in a human or an animal which comprises an inert carrier and an effective amount of a compound of Claim 1.

13. A composition useful for increasing the endogenous production or release of growth hormone in a human or an animal which comprises: an inert carrier; an effective amount of a compound of Claim 1; and another growth hormone secretagogue selected from the group consisting of: GHRP-6, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2, and B-HT920.

14. A method for the treatment of obesity which comprises administering to an obese patient an effective amount of a compound of Claim 1 in combination with an .alpha.2-adrenergic agonist or .beta.3-adrenergic agonist.

15. A composition for the treatment of obesity which comprises an inert carrier and an effective amount of a compound of Claim 1 in combination with an .alpha.2-adrenergic agonist or .beta.3-adrenergicagonist.

16. A method for the treatment of osteoporosis which comprises administering to a patient with osteoporosis an effective amount of a compound of Claim 1 in combination with parathyroid hormone or a bisphosphonate.

17. A composition for the treatment of osteoporosis which comprises an inert carrier and an effective amount of a compound of Claim 1 in combination with parathyroid hormone or a bisphosphonate.