I1J\( N\AJ\ D/Kn, B “p

42 Pages·2013·2.34 MB·English

‘ US005717097A ‘
United States Patent [191 [11] Patent Number: 5,717,097
Vacca et a]. [45] Date of Patent: Feb. 10, 1998
[54] HIV PROTEASE INHIBITORS USEFUL FOR Primary Examiner—loseph McKane
THE TREATMENT OF AIDS
Attorney Agent, or Firm—Mary A. Appollina; Melvin
[75] Inventors: Joseph P. Vacca. Telford; Bruce D. Winokur
Dorsey. Harleysville; James P. Gnare,
Quakertown; M. Katharine Holloway; [57] ABSTRACT
Randall W. Hungate. both of Lansdale;
Rhonda B. Levin, Lafayette Hill; Joel Compounds of formula
R. Huff. Gwynedd Valley, all of Pa.
Z ‘fl x R3
[73] Assignee: Merck & Co., Inc. Rahway. NJ.
I1J\( N\AJ\ D/Kn, B “p
[21] Appl. No.: 759,203
[22] Filed: Dec. 4, 1996
where A is usually carbonyl or —CH;——. D is usually
Related US. Application Data
—CH2—-; R1 and R2 are independently hydrogen or
[63] Continuation of Ser. No. 533,142, Sep. 25, 1995, abandoned, optionally-substituted C1 4alkyl or aryl. or R1 and R2 are
which is a continuation of Ser. No. 235,576, Apr. 29, 1994,
abandoned, which is a continuation-impart of Ser. No. joined together to fonn a monocyclic or bicyclic ring
59,038, May 7, 1993, Pat. No. 5,413,999, which is a
system, are HIV protease inhibitors. These compounds are
continuation-impart of Ser, No. 40,729, Mar. 31, 1993,
abandoned, which is a continuation-in-part of Ser. No. useful in the prevention or treatment of infection by HIV and
883,825, May 15, 1992, abandoned, which is a continuation
in the treatment of AIDS, either as compounds. pharmaceu
in-part of Ser. No. 789,508, Nov, 8, 1991, abandoned.
tically acceptable salts, pharmaceutical composition
[5 1] Int. Cl.6 ..................... .. C07D 241/04; C07D 401/06
[52] US. Cl. ........................................... .. 544/360; 544/390 ingredients. whether or not in combination with other
[53] Field of Search ....................... .. 544/360, 390 antivirals, immunomodulators. antibiotics or vaccines.
Methods of treating AIDS and methods of preventing or
[5 6] References Cited
treating infection by HIV are also described.
U.S. PATENT DOCUMENTS
5,413,999 5/1995 Vacca etal. .......................... .. 544/360 6 Claims, No Drawings
5,717,097
1 2
HIV PROTEASE INHIBITORS USEFUL FOR Some abbreviations that may appear in this application
THE TREATMENT OF AIDS are as follows.
This application is a continuation of application Ser. No.
08/533.142. ?led Sep. 25. 1995. now abandoned which is a ABBREVIATIONS
continuation of Ser. No. 08/235676. ?led Apr. 29. 1994.
Designation
now abandoned. which is a continuation-in-part of Ser. No.
08/059,038. ?led May 7. 1993. now issued as US. Pat. No. Protecting Group
5.413.999. which is a continuation-impart of Ser. No.
BOC (Boc) t-butyloxycarbony]
08/040.729. ?led Mar. 31. 1993. now abandoned. which is a
CBZ (Cbz) benzyloxycarbonyl(carbobenzoxy)
continuation-in-part of Ser. No. 071883.825. ?led May 15. TBS ('I'BDMS) t-butyLdimethyls?yl
1992. now abandoned. which is a continuation-in-part of Activating Group
Ser. No. 07/7 89.508. ?led Nov. 8. 1991. now abandoned; the
contents of all previous applications are hereby incorporated HBT (HOBT or HOB!) l-hydroxybenzotriamle hydrate
Coupling Reagent
by reference.
The present invention is concerned with compounds BOP reagent benzotriazol-l-yloxyn-is
which inhibit the protease encoded by hmnan immunode? (dimetbylarnino)phosphonilnn
hexa?uorophosphate
ciency virus (HIV) or pharrnaceutically acceptable salts
BOP-C1 bis(2-oxo-3-oxazolidinyl)phosphinic
thereof and are of value in the prevention of infection by
chloride
HIV. the treatment of infection by HIV and the treatment of 20 EDC 1-ethyl-3-(3-dimethylaminopmpyl)
the resulting acquired immune de?ciency syndrome (AJDS). carbodiimide hydrochloride
It also relates to pharmaceutical compositions containing the Other
compounds and to a method of use of the present compounds (BOC)20 (BOCZO) di-t-buty] dicarbonate
and other agents for the treatment of AIDS and vital infec
tion by HIV. 25 nBuLi (n-Buli) n-butyllithium
DMF dimethylformamide
Et3N triethylamine
BACKGROUND OF THE INVENTION
EtOAc ethyl acetate
A retrovirus designated human immunode?ciency virus IPA tri?uoroacetic acid
DMAP dimethylaminopyridine
(HIV) is the etiological agent of the complex disease that DME dimethoxyethane
includes progressive destruction of the immune system 30 LDA lithium diisopropylamide
(acquired immune de?ciency syndrome; AIDS) and degen THF ten'ahydrofman
eration of the central and peripheral nervous system. This
virus was previously known as LAV. HTLV-III. or ARV. A 11¢ L-isoleucine
common feature of retrovirus replication is the extensive Val L-valine
post-translational processing of precursor polyproteins by a
virally encoded protease to generate mature viral proteins
required for virus assembly and function. Inhibition of this DETAILED DESCRIPTION OF THE
processing prevents the production of normally infectious INVENTION AND PREFERRED
virus. For example. Kohl. N. E. et al.. Proc. Nat’lAcad., Sci. EMBODIMENTS
85. 4686 (1988) demonstrated that genetic inactivation of
This invention is concerned with compounds of Formula
the HIV encoded protease resulted in the production of
I. combinations thereof. or pharmaceutically acceptable salts
immature. non-infectious virus particles. These results indi
thereof. in the inhibition of HIV protease. the prevention or
cate that inhibition of the HIV protease represents a viable
treatment of infection by HIV and in the treatment of the
method for the treatment of AIDS and the prevention or
resulting acquired immune de?ciency syndrome (AIDS).
treatment of infection by HIV.
Compounds of Formula I are de?ned as follows:
The nucleotide sequence of HIV shows the presence of a
pol gene in one open reading frame [Ratner. L. et aL. Nature, Z If I X R3 I
313. 277(1985)]. Amino acid sequence homology provides
evidence that the pol sequence encodes reverse
transcriptase. an endonuclease and an HIV protease ['I‘oh. H.
et al.. EMBO J., 4. 1267 (1985); Power. M. D. et al.. Science,
B1. 1567 (1986); Pearl. L. H. et al.. Nature, 329. 351 wherein:
(1987)]. Applicants demonstrate that the compounds of this
A is
invention are inhibitors of HIV protease.
55
BRIEF DESCRIPTION OF THE INVENTION
Compounds of Formula I. as herein de?ned. are disclosed.
These compounds are useful in the inhibition of HIV
protease. the prevention of infection by HIV. the treatment X is independently —-0H. —NI-I2. F. or =0;
of infection by HIV and in the treatment of AIDS. either as Z is independently =0. =S. or =NH;
compounds. pharmaceutically acceptable salts. pharmaceu D is —(CRG2)_;
tical composition ingredients. whether or not in combination wherein:
with other antivirals. immunomodulators. antibiotics or vac R‘ is each independent of the other.
cines. Methods of treating AIDS. methods of preventing 65 1) —-H.
infection by HIV. and methods of treating infection by HIV 2) -—0H.
are also disclosed. 3) —NH;.
5,717,097
3 4
4) -—F. i)
5) ——C 14aJkoxy~
6) —SH. h)
7) -arylthi0-. or —CI-IZNHCR,
8) clialkylz 5
Rishdro enorC 1; '—CN.
R1 y 28 I l-4alky ‘ .2) _CF3.
and R are independently. I)
1) hydrogen.
2) —-CH alkyl unsubstituted or substituted with one or 10 0
more of _N_H2R1
a) halo.
b) hydmxy‘ m) aryl c1_3 alkoxy.
0) C1-3 alkoxy~ 15 I1) aryl.
d) aryl unsubstituted or substituted with one or more 0) _NRS02R_
of C1_4alky1. amino. hydroxy or aryl. P) __0p(O)(ORx)2‘ or
e) -—W-aryl or —W-benzyl. q) —R5. as de?ned below; or
wherein W is _O-, -S-, or _NH__ 4) heterocycle unsubstituted or substituted with one or
f) a 5-7 membered cycloalkyl group unsubstituted or 20 2f EmISJXwSEXbZt-igatIZd Cd;3 31F332; 0C5?
sPbsmumd with one or more of 5) carbocgclic unzubstituted or substiilnted Zuith one or
halo‘ more of halo. amino, hydroxy or CH alkoxy;
hydroxy‘ R1 and R2 can be joined together to form with the nitrogen
1“) CH alkoxy‘ or 25 to which R1 is attached a 3 to 10 membered monocyclic
iv) 31')’ L or bicyclic saturated ring system which consists of the
g) heterocycle unsubstituted or substituted with one nitrogen to which R1 is attached and from 2 to 9 carbon
or more of hydroxy. 0x0. halo. C1 4 alkoxy. atoms. and is unsubstituted or substituted with
C‘ 4a1kyl optionally substituted with hydroxy; 1) hydroxy.
30 2) CH alkyl unsubstituted or substituted with one 01'
‘(l1 ‘('1 more of
—C—O-—C1_;a1kyl, —N‘H—C—O—C [.3 alkyl; 3 gzllgr‘oxyq
c) C1_3 alkoxy.
or Boct 35 d) 3131
h) e) a 5-7 membered cycloalkyl group unsubstituted or
substituted with one or more of
h) i) halo.
_ NH _ cocwaikyl' 40 iiii)i ) hg dmro axl jl.l soxy. or
_ iv) aryl.
1) f) heterocycle. or
0 g) —NR2~
" 3) C1_3 alkoxy.
—NH—C—C1_a=1kyL 4s 4)
0
.i) —NH—<$02C1_3a1kYl~ ll
k) —NR2. —N'H—COC|_3 alkyl,
1) —COOR. or 50
m) —((CH,)mO)nR wherein m is 2. 3. 4 or 5 and n 5)
is zero. 1. 2 or 3. or
0
3) aryl. unsubstituted or substituted with one or more of
a) halo.
b) hydroxy. 55
c) —N02 or —NR2. 6) —NH—SO2C1_3alkyl.
d) CHalkyL 7) heterocycle,
e) C H alkoxy. unsubstituted or substituted with one 8) —W-aryl, or
or more of —-OH or Cb3 alkoxy, 9)
f) -COOR. 60
g) -w—cIf "y 1,
o
65 wherein W is as de?ned above; or
R1 and R2 can bejoined together to form with the nitrogen
to which R1 is attached a 3 to 10 membered monocyclic
5,717,097
5
or bicyclic saturated ring system which consists of the a) halo.
nitrogen to which R1 is attached. from 1 to 8 carbon b) hydroxy.
atoms and one or more unsubstituted or substituted
heteroatom selected from d) C 1 Jfalkyl.
1) e) C1_3 alkoxy. unsubstituted or substituted with one
or more of —OH or C1_3 alkoxy.
wherein V is absent or 10
0
ll
or —SO2—Q—-. R1 is de?ned as above for when R1
is independent from and not joined to R2. and
wherein Q is absent or —O—. —NR—. or hetero
cycle optionally substituted with —C14alkyl.
2)
_N _
l
heterocycle,
3) 25
I11) aryl CH alkoxy.
n) aryl.
o) —NRSO2R.
30
P) ——0P(0)(0R. 2- or
unsubstituted or substituted with aryl. q) —R’. as de?ned below. or
4)
5) monocyclic or bicyclic heterocyle containing from 1
to 3 heteroatoms chosen from the group consisting of
N. O~ and S and which is unsubstituted or substituted
35 with R5 and optionally with one or more of
a) halo.
b) C 1 4 alkyl. or
unsubstituted or substituted with aryl.
c) C ,_3 alkoxy;
5) —S(O),,—.
Rx is H or aryl;
wherein p is zero. 1 or 2. or
R5 is
6) -—O—; or
1) W—(CH2)m-NR6R7
R1 and R2 can bejoined together to form with the nitrogen
wherein W is as de?ned above.
to which R1 is attached a 3 to 10 member-ed monocyclic
In is 2, 3, 4 or 5. and
or bicyclic saturated ring system. which consists of the
R6 and R7 are independently
nitrogen to which R1 is attached and from 2 to 9 carbon
a) hydrogen.
atoms. in which the saturated ring system is fused to a
b) C1_6 alkyl. unsubstituted or substituted with one or
phenyl ring and the phenyl ring is unsubstituted or
more of
substituted with one or more of i) C1_3 alkoxy.
1) halo.
ii) —OH. or
2) C13 alkoxy.
iii) —-NR2.
3) hydroxy.
50
c) the same or di?°erent and joined together to form
4) C14 1»
a 5-7 member heterocycle~ such as morpholino.
5) —NHR .
containing up to two additional heteroatoms
wherein R1 is de?ned as above for when R1 is
selected from
independent from and not joined to R2. or
6) —NH-heterocycle;
55
R3 is R 0
II
1) —(CH2),——R‘ —o—, -s-,
wherein r is zero. 1. 2. 3. 4 or 5.
2) C1 italkenyl-R‘. or
——S—. or —SO2—. the heterocycle optionally
3) C1-4a1kyny1'R4;
substituted with CH alkyl. or
R‘ is
d) aromatic heterocycle unsubstituted or substituted
1) hydrogen.
with one or more of
2) CM alkyl. i) C14 aJkyL or
3) C5—C,0 cycloalkyl. optionally substituted with ii) _NR2~
hydroxy.
65 2) _(cn2) —NR6R" wherein q is 1. 2. 3. 4. or 5. and
4) C6—Cl0 aryl. unsubstituted or substituted with one or R‘5 and R‘1 are as de?ned above. except that Rt",l or R7
more of is not H or unsubstituted C1_6 alkyl. or
5,717,097
7 ‘ 8
3) benzofuryl. indolyl, amcycloalkyl. azabicyclo C7_n containing up to one additional heteroatom
cycloalkyl. or benzopiperidinyl. unsubstituted or selected from -—O—, —S—. or —NR—.
substituted with C14 alkyl; xiii) aryl.
B is absent. or xiv) —-CHO.
Xv) —0P(0)(0R,)2.
xvi)
10
wherein R8 is
substituted with one or more of amine or
1) —CH(CH3)2.
quaternary amine. or —O—((CH2)mO),,—R.
2) —CH(CH3)(CH2CH3). or
3) -phenyl; or -—OP(O)(ORx 2.
xvii)
J1 and J2 are independently
1) —YR9 wherein
0
ll
R9 is —OC—R. or
a) hydrogen.
b) C H, alkyl. unsubstituted or substituted with one or xviii)
more of
i) ——NR2. 0
ii) —OR. ll
iii) -—NHSO2C1_4 alkyl. 25
iv) -—NHSO2 aryl. or --NHSO2
(dialkylaminoaryl).
or
v) —CH2OR. c) —((CHZ),,IO),,CH3 or —((CH2),,,O),, H. wherein
vi) —C1_4 alkyl.
m and n are as de?ned above.
vii) 2) —N(R'’);.
3) —NR‘°R11 wherein R10 and R11 are as de?ned
above. or
4)
35
viii)
RIZ
I
_Y ('3 R12
R9
II
wherein Y. R9 and n are de?ned above; and
R12 is
1) hydrogen.
NH N-CN 45 2) aryl. unsubstituted or substituted with one or more of
a) R“. wherein R14 is
X) i) halo.
ii) —OR.
0
ll iii)
—N'HCR13,
0
ll
wherein R13 is
A) —H.
B) —CH alkyl. 55
iv) —CH2NR2,
C) -aryl.
v) —SO2NR2.
D) -heterocycle. or
vi) —NR2,
E) —NH—. —0-— or —(CH2)n-—
wherein n is zero. 1. 2 0r 3. substituted with vii)
I) —C,_4 alkyl. unsubstituted or substituted with one
or more of aryl or heterocycle. or 0
ll
II) aryl. unsubstituted or substituted with
-NHCR,
heterocycle.
xi) —-NR3‘BA' wherein A‘ is a eounterion.
viii) CH alkyl,
xii) —NR‘°R11 wherein R10 and R11 are the same 65
ix) phenyl
or different and are C ,_5 alkyl joined together
directly to form a 5-7 membered heterocycle x) —CF .
5,717,097
10
Xi) d)
R 0
l
—N-sozk,
xii) —OP(O)(OR,)2. or substituted with one or more of amine or quater
xiii) nary amine. —OP(O)(ORx)2. or
—O—((CH2),,,O),,—R.
—coR, 6)
II
0
15 or
f) —€1_4a1kyl-Phenyl;
or a pharmaceutically acceptable salt thereof.
In one embodiment of this invention. both A and D are
—CH2—.
substituted with one or more of amine or quater In a preferred embodiment of this invention. both A and
D are —CH2— and R1 and R2 are joined together to fonn
nary amine or —OP(O)(OR, 2.
with the nitrogen to which R1 is attached a 3 to 10 membered
3) heterocycle. such as isochroman. chroman.
monocyclic or bicyclic saturated ring system which consists
isothiochroman. thiochrornan. benzimidazole.
of the nitrogen to which R1 is attached and from 2 to 9
benzothiopyran. oxobenzothiopyran. benzopyran.
benzothiopyranylsulfone. 25 carbon atoms. and is unsubstituted or substituted with
1) hydroxy.
benzothiopyranylsu?’oxide. the ring or rings being
2) CM alkyl unsubstituted or substituted with one or more
unsubstituted or substituted with one or more of of
a) R“, as de?ned above. a) hydroxy.
b) —OCH alkenyl. 3D b) C H alkoxy.
c) phenyl-CM alkyl. c) aryl.
d) d) a 5-7 membered cycloalkyl group unsubstituted or
substituted with one or more of
0 i) halo.
ll 35 ii) hydroxy.
iii) C1,3 alkoxy. or
iv) aryl.
substituted with one or more of amine or quater e) heterocycle. or
nary amine. or —OP(O)(OR,,)2. f) —NR,.
3) Cl_3 alkoxy.
or
e) 4)
0
45
4) A 5 to 7 membered carbocyclic or 7-10 membered
bicyclic carbocyclic ring. such as cyclopentane.
cyclohexane. indane. norbornane. naphthalene,
thiopyran. isothiopyl'an. or benzopyran. ?1e carbocy
clic ring being unsubstituted or substituted with one
or more of
a) R“. as de?ned above.
55
b) —CH2OR.
c) —(CH2),,—NR2. C5_1?alkyl, pyridine.
—W-C-aryl.
ll
0
wherein W is —O—. —S—. 1' —NH—; or
R1 and R2 are joined together to form with the nitrogen to
which R1 is attached a 3 to 10 membered monocyclic or
—((CH,),,,O),.—R. quinuclidiniumyl substituted
bicyclic saturated ring system which consists of the nitrogen
with R. piperazine-Clntalkyl-benzyl substituted
65 to which R1 is attached. from 1 to 8 carbon atoms and one
once or more with R. or morpholino-CMalkyl
or more unsubstituted or substituted heteroatom selected
benzyl.
from
5 ,717,097
11
l)
wherein V is absent or
0
0
ll
0r —SO2—Q-. R1 is de?ned as above for when R1 is
independent from and not joined to R2. and wherein Q
is absent or —O—. --NR---~ or heterocycle optionally
substituted with —CMalkyl.
2)
_.IN _ 20
C14 alkenyl, wherein W is —O——. —S——. or —NH——; or
R1 and R2 are joined together to form with the nitrogen to
which R1 is attached a 3 to 10 membered monocyclic or
unsubstituted or substituted with aryl. bicyclic saturated ring system which consists of the nitrogen
3) —S(O)p—. wherein p is zero. 1 or 2. or 25 to which R1 is attached. from 1 to 8 carbon atoms and one
or more unsubstituted or substituted heteroatorn selected
4) —O—; or
from
R1 and R2 are joined together to form with the nitrogen to
which R1 is attached a 3 to 10 membered monocyclic or
bicyclic saturated ring system which consists of the nitro
gen to which R1 is attached and from 2 to 9 carbon atoms.
in which the saturated ring system is fused to a phenyl ring
and the phenyl ring is unsubstituted or substituted with one
wherein V is absent or
or more of 35
1) CL3 alkoxy. 0
ll
2) hydroxy.
3) CH alkyl. or
or —SO2-Q—. R1 is de?ned as above for when Rl is
independent from and not joined to R2, and wherein Q
wherein R1 is de?ned as above for when R1 is inde is absent or ——O-—. —NR-—. or heterocycle optionally
pendent from and not joined to R2. substituted with —CMalkyl.
A second. more preferred embodiment of this invention is
2) —S(O)p—. wherein p is zero. 1 or 2. or
further limited to compounds wherein A and D are both 45 3) —O—;
—CH2--- and R1 and R2 are joined together to form with the
R3 is benzyl. unsubstituted or substituted with one or more
nitrogen to which R1 is attached a 3 to 10 membered
of
monocyclic or bicyclic saturated ring system which consists
a) hydroxy.
of the nitrogen to which R1 is attached and from 2 to 9
b) —NO,. or —NR2.
carbon atoms. and is unsubstituted or substituted with
c) Cl 4a1kyl.
1) hydroxy.
d) C1_3 alkoxy. unsubstituted or substituted with one or
2) C1_4 alkyl unsubstituted or substituted with one or more more of —OH or Cb3 alkoxy.
of
8)
a) hydroxy.
55
b) C1_3 alkoxy,
—Cu NR’ ,
c) aryL
O
d) a 5-7 membered cycloalkyl group unsubstituted or
substituted with one or more of
f) —CH2NR2
i) halo.
ii) hydroxy. S)
iii) C1_3 alkoxy, or
O
iv) aryl. n
e) heterocycle. or —CHINHCR,
65
3) C,_3 alkoxy. h) -c1=3.
5,717,097
13 14
i)
0
0 II II
N —C—O—C|_3alkyl, —NH—C—0—C1_3a]kyl;
—N'HC& 5
or Bee.
1) —NRSO2R. h)
k) —OP(O)(ORX)2. or
1) —R5; 10 II
and B is absent. _Nn_coc"’alkyl’
A third. most preferred embodiment of this invention is ,
further limited to compounds wherein A and D are both 1)
—CH2—- and 0
x is —0H' ‘5 "
Q -—NH—C—C _ alkyl,
Z is —O; l 3
R l and R 2 _- ]0l- l'l6d together to form wi.t h the ni. trogen J‘ ) _NH__sO2C1_3alkyL
WhlCh R is attached a 3 to 10 membered monocychc k) _NR _
or bicyclic saturated ring system which consists of the 20 l) __C0(2)R or
nitrogen to which R1 is attached and from 2 to 9 carbon m) _((CH ') O) R whcrcin m is 2 3 4 or 5 and H
atoms. and is unsubstituted or substituted with is 2cm 12 "i 0:3 or “ *
_w'aryl or 3) aryl. unsubstituted or substituted with one or more of
-w-c 1; a) halo.
"my 25 b) hydroxy.
0 0) —N02 or —NR2,
d) CMalkyl.
or e) C1‘3 alkoxy. unsubstituted or substituted with one
R1 and R2 are joined together to form with the nitrogen to 30 or more of _OH or C1-3 alkoxy
which R1 is attached a 3 to 10 membered monocyclic f) _COOR~
or bicyclic saturated ring system which consists of the g)
nitrogen to which R1 is attached. from 1 to 8 carbon
atoms and one of fl)
35 _CNR2,
_}lI_ ,
V—R‘ h) —CH2NR2.
i)
wherein V is absent or 40
II
I‘; —CH¢NHCR,
_..C_Q._
3') ---CN.
“5 k —CF
or _so,-Q_. 1) ~
R1 is de?ned as above for when R1 is independent from )
and not joined to R2, that is. R1 is 0
1) hydrogen. ||
2) —CM alkyl unsubstituted or substituted with one or 50 —NT1NR,
more of
a) h31°~ m) 1C _ alkox .
b) hydroxy, n) ‘ 3 y
3)) C113 alkogy‘ a b a m 0) "'NRSO’R'
ary unsu stitute or su stitute wi one or more 55 P 0 OR
of CHalkyl. amino. hydroxy or aryl, :35 (01.x * 2‘ or
e) —W-aryl or —W-benzy1,
4) heterocycle unsubstituted or substituted with one or
wherein W is —0—. --S—. or —NH—,
more of hydroxy, 0x0. halo. amino‘ C1 4 alkoxy. CM
f) a 5-7 membered cycloalkyl group unsubstituted or
alkyl optionally substituted with hydroxy; or Boc;
Silbsumted Wlth mm or mom of 60 5) carbocyclic unsubstituted or substituted with one or
lilalod’r more of halo, amino. hydroxy or C1_4 alkoxy;
21?) g ogéoxy or and wherein Q is absent or --O—. -—-NR—- or hetm'ocycle
iv) optionally substituted with —C14alky1;
g) heterocycle unsubstituted or substituted with one 65 R3 is benzyl, unsubstituted or substituted with one or
or more of hydroxy. 0x0, halo, C H alkoxy. more of (1) hydroxy, (2) C1,3 alkoxy substituted with
C1 4alkyl optionally substituted with hydroxy;
one or more of —-OH or (3)
5,717,097
15 16
Colnpound B
—O
N 0;
butylcarbamoyl)-piperazinyl))-pentancamidc_
20
The most prefcned compounds of this invention are
compounds A through H and J. shown below. Compound C
Compound A 25
H
H N
CH 01-1 30 H
H :
N N,’
H
o
CONT-1+ 35
N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-((4-(2-(4
40 morpholinyl)ethoxy)phenyl)mcthyl)-4(S)-hydroxy-5
N-(2(R)-hyd.roxy-1(S)-indanyl)-2(R)-phcnylmethyl-4(S)- (2-(3(S)—N'-(t-butylcarbamoyl)4488-838 )
hydroxy-5-(2-(3(S)-N‘-(t-butylcarbamoyl)-(4aS,8aS)- dccahydroisoquinolinoyb-penwneamide.
dccahydroisoquinoline)yl)-pentaneamide.
45 Compound D
-I \ _\—
K