U.S. patent application number 11/783814 was filed with the patent office on 2007-08-23 for antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds.
This patent application is currently assigned to Anadys Pharmaceuticals, Inc.. Invention is credited to Benjamin Ayida, Vlad E. Gregor, Thomas Hermann, Douglas Murphy, Klaus B. Simonsen, Zhongxiang Sun, Dionisios Vourloumis, Geoffrey C. Winters, Yuefen Zhou.
Application Number | 20070197533 11/783814 |
Document ID | / |
Family ID | 34381051 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070197533 |
Kind Code |
A1 |
Zhou; Yuefen ; et
al. |
August 23, 2007 |
Antibacterial 3,5-diaminopiperidine-substituted aromatic and
heteroaromatic compounds
Abstract
The invention relates to antibacterial
3,5-diaminopiperidine-substituted aromatic and heteroaromatic
compounds and pharmaceutical compositions thereof. This invention
also relates to a method of using such compounds in the treatment
of bacterial infections in mammals, especially humans.
Inventors: |
Zhou; Yuefen; (San Diego,
CA) ; Vourloumis; Dionisios; (San Diego, CA) ;
Gregor; Vlad E.; (Del Mar, CA) ; Winters; Geoffrey
C.; (Coquitlam, CA) ; Hermann; Thomas;
(Cardiff By The Sea, CA) ; Ayida; Benjamin; (Chula
Vista, CA) ; Sun; Zhongxiang; (San Diego, CA)
; Murphy; Douglas; (San Diego, CA) ; Simonsen;
Klaus B.; (Frederiksberg, DK) |
Correspondence
Address: |
CONNOLLY BOVE LODGE & HUTZ LLP
1875 EYE STREET, N.W.
SUITE 1100
WASHINGTON
DC
20036
US
|
Assignee: |
Anadys Pharmaceuticals,
Inc.
San Diego
CA
|
Family ID: |
34381051 |
Appl. No.: |
11/783814 |
Filed: |
April 12, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10940615 |
Sep 15, 2004 |
7223759 |
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11783814 |
Apr 12, 2007 |
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60502612 |
Sep 15, 2003 |
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60548852 |
Mar 2, 2004 |
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Current U.S.
Class: |
514/241 ;
514/242; 514/248; 514/249; 514/252.03; 514/255.05; 514/263.22;
514/275; 514/313; 514/317; 514/318; 544/183; 544/209; 544/237;
544/238; 544/277; 544/330; 544/353; 544/405; 546/194; 546/226 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 401/04 20130101 |
Class at
Publication: |
514/241 ;
514/242; 514/252.03; 514/248; 514/249; 514/255.05; 514/263.22;
514/313; 514/317; 514/318; 544/183; 544/209; 544/238; 544/237;
514/275; 544/330; 544/277; 544/353; 544/405; 546/194; 546/226 |
International
Class: |
A61K 31/53 20060101
A61K031/53; A61K 31/52 20060101 A61K031/52; A61K 31/506 20060101
A61K031/506; A61K 31/502 20060101 A61K031/502; A61K 31/501 20060101
A61K031/501; A61K 31/4545 20060101 A61K031/4545; A61K 31/497
20060101 A61K031/497; C07D 473/10 20060101 C07D473/10; C07D 403/02
20060101 C07D403/02; C07D 401/02 20060101 C07D401/02 |
Goverment Interests
[0002] This invention was made possible by Grant Number 1R43
AI151104-01 from the National Institute of Allergy and Infectious
Diseases. The United States Government may have certain rights in
the invention.
Claims
1-14. (canceled)
15. A method of inhibiting a microorganism comprising administering
to the microorganism an effective amount of a composition
comprising the compound of formula I ##STR1002## wherein: Ring A is
a 5- or 6-membered mono- or bicyclic aryl or heteroaryl; M.sup.1
and M.sup.2 are independently --H, halo, --CF.sub.3, --CN,
--NO.sub.2, --CONH.sub.2, --COOH, --OH, or --NHNH.sub.2, or an
unsubstituted or substituted --(C.sub.1-C.sub.6)alkyl, aryl,
heteroaryl, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heteroaryl,
--(CH.sub.2).sub.n-heterocycloalkyl, --(CH.dbd.CH).sub.n-aryl,
--(CH.dbd.CH).sub.n-heteroaryl, --(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl, --(C.ident.C).sub.n-aryl,
--(C.ident.C).sub.n-heteroaryl, --O--(C.sub.1-C.sub.6)alkyl,
--O-aryl, --O-heteroaryl, --O-cycloalkyl, --O-heterocycloalkyl,
--S--(C.sub.1-C.sub.6)alkyl, --S-aryl, --S-heteroaryl,
--S-cycloalkyl, --S-heterocycloalkyl,
--(C.dbd.O)(C.sub.1-C.sub.6)alkyl, --(C.dbd.O)aryl,
--(C.dbd.O)heterocycloalkyl, --O(C.dbd.O)--(C.sub.1-C.sub.6)alkyl,
--(C.dbd.O)O--(C.sub.1-C.sub.6)alkyl, --(S.dbd.O)aryl,
--(S.dbd.O)heterocycloalkyl, --S(O).sub.2aryl,
--S(O).sub.2heterocycloalkyl, --NHC(NH)-aryl, --NHNH-aryl,
--NHNHC(O)-aryl, --NHNH-cycloheteroalkyl, --NHNHS(O).sub.2-aryl,
--NHOH, --NHO--(C.sub.1-C.sub.6)alkyl,
--N(OH)--(C.sub.1-C.sub.6)alkyl,
--N((C.sub.1-C.sub.6)alkyl)O--(C.sub.1-C.sub.6)alkyl,
--NHNHC(S)NH--(C.sub.1-C.sub.6)alkyl, --NHNH-heteroaryl, or
--N(R.sup.1)R.sup.2, wherein R.sup.1 and R.sup.2 are independently
selected from --H, a substituted or unsubstituted alkyl, aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl, or R.sup.1 and R.sup.2
together with the N atom form a 4-, 5-, or 6-membered substituted
or unsubstituted heterocycloalkyl, wherein n is an integer from
1-4; X.sub.n is independently selected from --H, halo, --CF.sub.3,
--CN, --COOH, --OH, --NH.sub.2, --NO.sub.2, --C(O)N(R.sup.3)R.sup.4
wherein R.sup.3 and R.sup.4 are independently
--(C.sub.1-C.sub.6)alkyl or --H, and optionally substituted
--O--(C.sub.1-C.sub.6)alkyl or --(C.sub.1-C.sub.6)alkyl; or a
pharmaceutically acceptable salt, hydrate, or solvate thereof.
16. The method of claim 15 wherein the compound is wherein Ring A
is selected from the group consisting of: ##STR1003## ##STR1004##
##STR1005##
17. The method of claim 15 wherein the compound is wherein Ring A
is selected from the group consisting of: ##STR1006##
##STR1007##
18. The method of claim 15 wherein the compound is wherein Ring A
is Formula Ia.
19. The method of claim 15 wherein the compound is wherein M.sup.1
and M.sup.2 are each --N(R.sup.1)R.sup.2.
20. The method of claim 15 wherein the compound is wherein the
compound is M.sup.1 and M.sup.2 are independently selected from the
group consisting of: ##STR1008## ##STR1009## ##STR1010##
##STR1011## ##STR1012## ##STR1013## ##STR1014##
21. The method of claim 15 wherein the compound is wherein M.sup.2
is selected from the group consisting of: ##STR1015##
22. The method of claim 15 wherein the compound is wherein Ring A
is selected from the group consisting of: ##STR1016##
##STR1017##
23. The method of claim 15 wherein the compound is wherein Ring A
is Formula Ia.
24. A method of treating a bacterial infection in a mammal
comprising administering to the mammal in need thereof an effective
amount of a composition comprising the compound of formula I
##STR1018## wherein: Ring A is a 5- or 6-membered mono- or bicyclic
aryl or heteroaryl; M.sup.1 and M.sup.2 are independently --H,
halo, --CF.sub.3, --CN, --NO.sub.2, --CONH.sub.2, --COOH, --OH, or
--NHNH.sub.2, or an unsubstituted or substituted
--(C.sub.1-C.sub.6)alkyl, aryl, heteroaryl,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heteroaryl,
--(CH.sub.2).sub.n-heterocycloalkyl, --(CH.dbd.CH).sub.n-aryl,
--(CH.dbd.CH).sub.n-heteroaryl, --(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl, --(C.ident.C).sub.n-aryl,
--(C.ident.C).sub.n-heteroaryl, --O--(C.sub.1-C.sub.6)alkyl,
--O-aryl, --O-heteroaryl, --O-cycloalkyl, --O-heterocycloalkyl,
--S--(C.sub.1-C.sub.6)alkyl, --S-aryl, --S-heteroaryl,
--S-cycloalkyl, --S-heterocycloalkyl,
--(C.dbd.O)(C.sub.1-C.sub.6)alkyl, --(C.dbd.O)aryl,
--(C.dbd.O)heterocycloalkyl, --O(C.dbd.O)--(C.sub.1-C.sub.6)alkyl,
--(C.dbd.O)O--(C.sub.1-C.sub.6)alkyl, --(S.dbd.O)aryl,
--(S.dbd.O)heterocycloalkyl, --S(O).sub.2aryl,
--S(O).sub.2heterocycloalkyl, --NHC(NH)-aryl, --NHNH-aryl,
--NHNHC(O)-aryl, --NHNH-cycloheteroalkyl, --NHNHS(O).sub.2-aryl,
--NHOH, --NHO--(C.sub.1-C.sub.6)alkyl,
--N(OH)--(C.sub.1-C.sub.6)alkyl,
--N((C.sub.1-C.sub.6)alkyl)O--(C.sub.1-C.sub.6)alkyl,
--NHNHC(S)NH--(C.sub.1-C.sub.6)alkyl, --NHNH-heteroaryl, or
--N(R.sup.1)R.sup.2, wherein R.sup.1 and R.sup.2 are independently
selected from --H, a substituted or unsubstituted alkyl, aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl, or R.sup.1 and R.sup.2
together with the N atom form a 4-, 5-, or 6-membered substituted
or unsubstituted heterocycloalkyl, wherein n is an integer from
1-4; X.sub.n is independently selected from --H, halo, --CF.sub.3,
--CN, --COOH, --OH, --NH.sub.2, --NO.sub.2, --C(O)N(R.sup.3)R.sup.4
wherein R.sup.3 and R.sup.4 are independently
--(C.sub.1-C.sub.6)alkyl or --H, and optionally substituted
--O--(C.sub.1-C.sub.6)alkyl or --(C.sub.1-C.sub.6)alkyl; or a
pharmaceutically acceptable salt, hydrate, or solvate thereof.
25. The method of claim 24 wherein the mammal is a human.
26. The method of claim 24 wherein the compound is wherein Ring A
is selected from the group consisting of: ##STR1019## ##STR1020##
##STR1021##
27. The method of claim 24 wherein the compound is wherein Ring A
is selected from the group consisting of: ##STR1022##
##STR1023##
28. The method of claim 24 wherein the compound is wherein Ring A
is Formula Ia.
29. The method of claim 24 wherein the compound is wherein M.sup.1
and M.sup.2 are each --N(R.sup.1)R.sup.2.
30. The method of claim 24 wherein the compound is wherein the
compound is M.sup.1 and M.sup.2 are independently selected from the
group consisting of: ##STR1024## ##STR1025## ##STR1026##
##STR1027## ##STR1028## ##STR1029## ##STR1030##
31. The method of claim 24 wherein the compound is wherein M.sup.2
is selected from the group consisting of: ##STR1031##
32. The method of claim 24 wherein the compound is wherein Ring A
is selected from the group consisting of: ##STR1032##
##STR1033##
33. The method of claim 24 wherein the compound is wherein Ring A
is Formula Ia.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional
Application No. 60/502,612 filed Sep. 15, 2003 and U.S. Provisional
Application No. 60/548,852 filed Mar. 2, 2004 the contents of each
are incorporated herein by reference in their entireties.
1. FIELD OF THE INVENTION
[0003] The invention relates to 3,5-diaminopiperidine-substituted
aromatic and heteroaromatic compounds and pharmaceutical
compositions thereof. The compounds of the invention are useful as
antibacterial agents. This invention also relates to a method of
using such compounds in the treatment of bacterial infections in
mammals, especially humans.
2. BACKGROUND OF THE INVENTION
[0004] An "antibiotic" is broadly defined as a chemical compound
that inhibits the growth of microorganism. Antibiotics can act on
organisms by inhibiting cell wall synthesis, increasing cell
membrane permeability, interfering with protein synthesis, or
interfering with nucleic acid metabolism. In general, bacterial
pathogens may be classified as either Gram-positive or
Gram-negative. Antibiotic compounds with activity against both
Gram-positive and Gram-negative pathogens are generally regarded as
having broad spectrum activity.
[0005] When the first therapeutic antibiotic, penicillin, was
introduced in the early 1940's, many believed that the threat from
infectious diseases was over. However, in the past 25 years,
through the abuse and misuse of antibiotics, many bacteria have
developed resistance to these antibiotics. The most frequent misuse
is probably in the treatment of fevers that are not caused by
bacterial infections. Other common misuses and errors include
choosing an ineffective antibiotic, giving inadequate or excessive
doses, treating non-bacterial infections such as uncomplicated
viral disease, using an improper route of administration,
continuing use after bacterial resistance has developed, continuing
in the presence of a serious toxic or allergic reaction,
prematurely stopping therapy, using improper combinations of
chemotherapeutic drugs, and relying on chemotherapy or prophylaxis
to the exclusion of surgical intervention (e.g., drainage of
localized infection and removal of a foreign body).
[0006] Today, there are strains of virtually every major bacterial
human pathogen that are resistant to some of the most effective
antibiotics. These strains include pathogens that can cause
diarrhea, urinary tract infections, otitis media, meningitis,
tuberculosis, gonorrhea, pneumonia, dysentery, wound infections,
septicemia, bacteremia and surgical infections.
[0007] Whereas in the first decades of antibiotics discovery,
development of novel antibacterial therapeutics has kept pace with
the occurrence of drug-resistant bacterial strains, the widespread
and sometimes indiscriminate use of antibiotics has accelerated the
emergence of resistance, often against multiple drugs
simultaneously and in pathogenic bacteria that cause
life-threatening infections. Not only is antibiotic resistance
escalating in agents of infectious diseases, but also normally
nonpathogenic bacteria are acquiring resistance, and acting as
opportunistic pathogens, increasingly threatening patients with
weakened immune defense.
[0008] The problem of antibiotic resistance is particularly severe
because examples of most antibacterial drug classes used today have
been in the clinic for more than 30 years. The initial broad stream
of novel antibiotics discovered from both natural and synthetic
sources, has narrowed down to a trickle. Novel and potent
antibiotics are required to replace the currently used drugs, which
are increasingly compromised by development of resistance. Thus,
there is a crucial need for novel antibacterial agents that work by
novel mechanisms and effectively inhibit the growth of
bacteria.
3. SUMMARY OF THE INVENTION
[0009] The present invention has addressed this need by the
discovery of 3,5-diaminopiperidine-substituted aromatic and
heteroaromatic compounds and pharmaceutically acceptable salts
thereof, which have antibacterial activity against Gram-positive
and Gram-negative bacteria.
[0010] In a general aspect, the invention relates to compounds of
Formula I ##STR1## wherein:
[0011] Ring A is a 5 or 6-membered mono- or bicyclic aryl or
heteroaryl;
[0012] M.sup.1 and M.sup.2 are independently --H, halo, CF.sub.3,
--CN, --NO.sub.2, --CONH.sub.2, --COOH, --OH, or NHNH.sub.2, or an
unsubstituted or substituted --(C.sub.1-C.sub.6)alkyl, aryl,
heteroaryl, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heteroaryl,
--(CH.sub.2).sub.n-heterocycloalkyl, --(CH.dbd.CH).sub.n-aryl,
--(CH.dbd.CH).sub.n-heteroaryl, --(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl, --(C.ident.C).sub.n-aryl,
--(C.ident.C).sub.n-heteroaryl, --O--(C.sub.1-C.sub.6)alkyl,
--O-aryl, --O-heteroaryl, --O-cycloalkyl, --O-heterocycloalkyl,
--S--(C.sub.1-C.sub.6)alkyl, --S-aryl, S-heteroaryl, S-cycloalkyl,
S-heterocycloalkyl, --(C.dbd.O)(C.sub.1-C.sub.6)alkyl,
--(C.dbd.O)aryl, --(C.dbd.O)heterocycloalkyl,
--O(C.dbd.O)--(C.sub.1-C.sub.6)alkyl,
--(C.dbd.O)O--(C.sub.1-C.sub.6)alkyl, --(S.dbd.O)aryl,
--(S.dbd.O)heterocycloalkyl, --S(O).sub.2aryl,
--S(O).sub.2heterocycloalkyl, NHC(NH)-aryl, NHNH-aryl,
--NHNHC(O)-aryl, --NHNH-cycloheteroalkyl, --NHNHS(O).sub.2-aryl,
--NHOH, --NHO--(C.sub.1-C.sub.6)alkyl,
--N(OH)--(C.sub.1-C.sub.6)alkyl,
--N((C.sub.1-C.sub.6)alkyl)O--(C.sub.1-C.sub.6)alkyl,
--NHNHC(S)NH--(C.sub.1-C.sub.6)alkyl, NHNH-heteroaryl, or
N(R.sup.1)R.sup.2, wherein R.sup.1 and R.sup.2 are independently
selected from --H, a substituted or unsubstituted alkyl, aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl, or R.sup.1 and R.sup.2
together with the N atom form a 4-, 5-, or 6-membered substituted
or unsubstituted heterocycloalkyl, wherein n is 1-4; and
[0013] In one embodiment, X.sub.n is independently selected from
--H, halo, --CF.sub.3, --CN, --COOH, --OH, --NH.sub.2, --NO.sub.2,
--C(O)N(R.sup.3)R.sup.4 wherein R.sup.3 and R.sup.4 are
independently --(C.sub.1-C.sub.6)alkyl or --H, and optionally
substituted --O--(C.sub.1-C.sub.6)alkyl or
--(C.sub.1-C.sub.6)alkyl, wherein n is 1-3.
[0014] In one embodiment of the invention, ring A is selected from:
##STR2## ##STR3## ##STR4##
[0015] In another embodiment, the invention relates to compounds of
Formula I wherein M.sup.1 and M.sup.2 are selected from
N(R.sup.1)R.sup.2, wherein R.sup.1 and R.sup.2 are independently
selected from --H, a substituted or unsubstituted alkyl, aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl, or R.sup.1 and R.sup.2
together with the N atom form a 4-, 5-, or 6-membered substituted
or unsubstituted heterocycloalkyl.
[0016] In another preferred embodiment, the invention relates to
compounds of Formula I wherein M.sup.1 and M.sup.2 are
independently selected from N(R.sup.1)R.sup.2, wherein R.sup.1 and
R.sup.2 are independently selected from --H, a substituted or
unsubstituted aryl or heteroaryl, or R.sup.1 and R.sup.2 together
with the N atom form a 4-, 5-, or 6-membered heterocycloalkyl or
bis-amino alkyl amino group selected from the following: ##STR5##
##STR6##
[0017] In another preferred embodiment, the invention relates to
compounds of Formula Iu: ##STR7## wherein M.sup.1 is H or halo, or
an unsubstituted or substituted --(C.sub.1-C.sub.6)alkyl,
--O--(C.sub.1-C.sub.6)alkyl, --O-heterocycloalkyl, aryl,
heteroaryl, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heteroaryl,
--(CH.sub.2).sub.n-heterocycloalkyl, --(CH.dbd.CH).sub.n-aryl,
--(CH.dbd.CH).sub.n-heteroaryl, --(C.ident.C).sub.n-aryl,
--(C.ident.C).sub.n-heteroaryl, or N(R.sup.1)R.sup.2, wherein
R.sup.1 and R.sup.2 are independently selected from --H, a
substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl,
or heterocycloalkyl, or R.sup.1 and R.sup.2 together with the N
atom form a 4-, 5-, or 6-membered substituted or unsubstituted
heterocycloalkyl, and wherein n is 1-4.
[0018] In another preferred embodiment of the invention, X.sub.n if
present is independently selected from --H, --OH, halo, and
optionally substituted --(C.sub.1-C.sub.6)alkyl and
--O--(C.sub.1-C.sub.6)alkyl, wherein n is 1 or 2.
[0019] In a more preferred embodiment, the invention relates to
compounds of Formula I wherein ring A is selected from:
##STR8##
[0020] In another more preferred embodiment, M.sup.1 and M.sup.2
are independently selected from: ##STR9## ##STR10## ##STR11##
##STR12## ##STR13## ##STR14## ##STR15##
[0021] In a most preferred embodiment, the invention relates to
compounds of Formula I wherein ring A is selected from Formulas Ia,
Ib, Id, Ie, If, Ih, Ii, Ir, and It; X is --H or
--(C.sub.1-C.sub.6)alkyl; and M.sup.1 and M.sup.2 are independently
selected from: ##STR16## ##STR17## ##STR18##
[0022] In another embodiment, the invention relates to compounds or
salts thereof individually selected from Table 1. For example the
compound can be selected from the group consisting of a compound
selected from the group consisting of: [0023]
N-[4-(2,2-difluoro-benzo[1,3]dioxol-5-ylcarbamoyl)-3-hydroxy-phenyl]-4,6--
Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0024]
N-[4-(4-chloro-2,5-dimethoxy-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-(-
(3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0025]
N-[4-(2,4-dichloro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,-
5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0026]
N-[4-(3-chloro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0027]
N-[4-(4-fluoro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0028]
N-[4-(2,5-dimethoxy-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3-
,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0029]
N-[4-(3-chloro-4-fluoro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5-
S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0030]
N-[3-hydroxy-4-(3-trifluoromethoxy-phenylcarbamoyl)-phenyl]-4,6-Bis-((3R,-
5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0031]
N-[4-(3,4-difluoro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,-
5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0032]
N-[4-(4-chloro-2-fluoro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5-
S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0033]
N-[4-(benzo[1,3]dioxol-5-ylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0034]
N-[3-hydroxy-4-(3-trifluoromethylsulfanyl-phenylcarbamoyl)-phenyl]-4,6-Bi-
s-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0035]
N-[3-hydroxy-4-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-4,6-Bis-((3R,5-
S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0036]
N-[4-(3,4-dichloro-phenylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,-
5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0037]
N-[3-hydroxy-4-(4-hydroxy-phenylcarbamoyl)-phenyl]-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0038]
N-[4-(1H-benzoimidazol-5-ylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0039]
1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-[bis-(2-amino-ethyl)-amino]-6-((3R,5S)-3,5-diamino-piperidin-1-yl)--
[1,3,5]triazin-2-ylamino]-phenyl}-amide; [0040]
N-{4-[2-(2-chloro-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0041]
3-{4-[4-((3S,5R)-3-Amino-5-hydroxy-piperidin-1-yl)-6-((3S,5R)-3,5-diamino-
-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-N-(2-chloro-phenyl)-3-o-
xo-propionamide; [0042] 1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((3S,5R)-3-amino-5-hydroxy-piperidin-1-yl)-6-((3S,5R)-3,5-diamino-p-
iperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide; [0043]
3-[4-((3S,5R)-3-Amino-5-hydroxy-piperidin-1-yl)-6-((3S,5R)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazin-2-ylamino]-fluoren-9-one; [0044]
4-[4-((3S,5R)-3-Amino-5-hydroxy-piperidin-1-yl)-6-((3S,5R)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-benzoic acid
phenyl ester; [0045]
N-{4-[4-((3S,5R)-3-Amino-5-hydroxy-piperidin-1-yl)-6-((3S,5R)-3,5-diamino-
-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-chloro-benz-
amide; [0046]
N-Benzyl-N-{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-((3R,4S)-3,4-diam-
ino-pyrrolidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-methyl--
benzenesulfonamide; [0047] 1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-((3R,4S)-3,4-diamino-pyrroli-
din-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide; [0048]
N-[4-(3,5-dichloro-2-hydroxy-benzenesulfonylamino)-3-hydroxy-phenyl]-4,6--
Bis((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0049]
N-[4-(4-ethoxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0050]
N-{4-[4-((3R,5S)-3,5-Bis-(aminomethyl)-piperidin-1-yl)-6-((3R,5S)-3,5-dia-
mino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-chloro--
benzamide; [0051] 1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((3R,5S)-3,5-bis-(aminomethyl)piperidin-1-yl)-6-((3R,5S)-3,5-diamin-
o-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide; [0052]
N-{4-[2-(3,4-difluoro-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3-
,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0053]
N-{4-[2-(2,2-difluoro-benzo[1,3]dioxol-5-ylcarbamoyl)-acetyl]-phenyl}-4,6-
-Bis((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0054]
N-[4-(3-bromo-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-diamin-
o-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0055]
N-[3-hydroxy-4-(3-phenyl-acryloylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0056]
1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((2S,4S)-4-amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide; [0057]
3-{4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-3-oxo-N-(4-trifluo-
romethylsulfanyl-phenyl)-propionamide; [0058]
4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-benzoic acid
phenyl ester; [0059]
N-{4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-chloro-
-benzamide; [0060]
3-{4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-N-(2,2-difluoro-be-
nzo[1,3]dioxol-5-yl)-3-oxo-propionamide; [0061]
1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((2S,4S)-4-amino-2-hydroxymethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide;
[0062]
3-{4-[4-((2S,4S)-4-Amino-2-hydroxymethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-3-oxo-N-(4-trifl-
uoromethylsulfanyl-phenyl)-propionamide; [0063]
3-{4-[4-((2S,4S)-4-Amino-2-hydroxymethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-N-(2,2-difluoro--
benzo[1,3]dioxol-5-yl)-3-oxo-propionamide; [0064]
N-(2-Chloro-phenyl)-3-{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-methox-
y-[1,3,5]triazin-2-ylamino]-phenyl}-3-oxo-propionamide; [0065]
N-Benzyl-N-{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-methoxy-[1,3,5]tr-
iazin-2-ylamino]-2-hydroxy-phenyl}-4-methyl-benzenesulfonamide;
[0066] 1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-methoxy-[1,3,5]triazin-2-yla-
mino]-phenyl}-amide; [0067]
3-{4-[4-((3R,5S)-3,5-Diamino-piperidin-1-yl)-6-methoxy-[1,3,5]triazin-2-y-
lamino]-phenyl}-3-oxo-N-(4-trifluoromethylsulfanyl-phenyl)-propionamide;
[0068]
4-[4-((3R,5S)-3,5-Diamino-piperidin-1-yl)-6-methoxy-[1,3,5]triazi-
n-2-ylamino]-2-hydroxy-benzoic acid phenyl ester; [0069]
4-Chloro-N-{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-methoxy-[1,3,5]tr-
iazin-2-ylamino]-2-hydroxy-phenyl}-benzamide; [0070]
3-{4-[4-((3R,5S)-3,5-Diamino-piperidin-1-yl)-6-methoxy-[1,3,5]triazin-2-y-
lamino]-phenyl}-N-(3,4-difluoro-phenyl)-3-oxo-propionamide; [0071]
3-{4-[4-((3R,5S)-3,5-Diamino-piperidin-1-yl)-6-methoxy-[1,3,5]triazin-2-y-
lamino]-phenyl}-N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-3-oxo-propionamide;
[0072]
N-{4-[(adamantane-1-carbonyl)-amino]-3-hydroxy-phenyl}-4,6-Bis-(-
(3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0073]
N-[4-(3-chloro-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0074]
1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((3R,4S)-3-aminomethyl-4-hydroxy-piperidin-1-yl)-6-((3R,5S)-3,5-dia-
mino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide;
[0075] 1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-((2S,3S)-2-aminomethyl-3-hydroxy-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide;
[0076]
N-{4-[4-((2S,3S)-2-Aminomethyl-3-hydroxy-pyrrolidin-1-yl)-6-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-meth-
yl-benzamide; [0077]
N-{3-hydroxy-4-[2-(1H-indol-3-yl)-2-oxo-acetylamino]-phenyl}-4,6-Bis-((3R-
,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0078]
N-{3-hydroxy-4-[3-phenyl-2-(toluene-4-sulfonylamino)-propionylamino]-phen-
yl}-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0079]
N-[4-(3-oxo-3-phenyl-propionylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-
-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0080]
N-[3-hydroxy-4-(4-methoxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0081]
N-[4-(2,4-dimethoxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0082]
N-[3-hydroxy-4-(2-methoxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0083]
N-Benzyl-N-{4-[4-((3R,5S)-3,5-diamino-piperidin-1-yl)-6-(4-pyridin-4-yl-p-
iperazin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-methyl-benzen-
esulfonamide; [0084]
4-Chloro-N-{4-[4-((3S,5R)-3,5-diamino-piperidin-1-yl)-6-piperazin-1-yl-[1-
,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-benzamide; [0085]
N-{4-[4-((3R,5S)-3,5-Diamino-piperidin-1-yl)-6-(piperidin-4-ylamino)-[1,3-
,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-methyl-benzamide; [0086]
4-Chloro-N-{4-[4-((3S,5R)-3,5-diamino-piperidin-1-yl)-6-(piperidin-4-ylam-
ino)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-benzamide; [0087]
4-Chloro-N-{4-[4-((3S,5R)-3,5-diamino-piperidin-1-yl)-6-(piperidin-3-ylam-
ino)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-benzamide; [0088]
N-{4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-phenyl}-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0089]
N-[3-hydroxy-4-(4-methyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0090]
4-[4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-
-2-hydroxy-benzoic acid phenyl ester; [0091]
N-(9H-fluoren-2-yl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]t-
riazine-2-amine; [0092]
N-{4-[4-(3-Amino-azetidin-1-yl)-6-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1-
,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-chloro-benzamide;
[0093]
N-pyrene-1-yl-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-
e-2-amine; [0094]
N-(4-methyl-2-oxo-2H-chromen-7-yl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-
-1-yl)-[1,3,5]triazine-2-amine; [0095]
N-(9-oxo-9H-fluoren-3-yl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1-
,3,5]triazine-2-amine; [0096]
N-(4-phenylazo-phenyl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,-
5]triazine-2-amine; [0097]
N-[4-(6-methyl-benzothiazol-2-yl)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazine-2-amine; [0098]
3-{4-[4-((2S,4R)-2-Aminomethyl-4-hydroxy-pyrrolidin-1-yl)-6-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-3-oxo-N-(4-trifl-
uoromethylsulfanyl-phenyl)-propionamide; [0099]
3-{4-[4-((2S,4R)-2-Aminomethyl-4-hydroxy-pyrrolidin-1-yl)-6-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-N-(2,2-difluoro--
benzo[1,3]dioxol-5-yl)-3-oxo-propionamide; [0100]
1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4-(2-amino-ethylamino)-6-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]-
triazin-2-ylamino]-phenyl}-amide; [0101]
N-[3-(2-hydroxy-3-methyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0102]
N-[3-hydroxy-4-(2-hydroxy-3-methyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-
-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0103]
N-[4-(2,3-dihydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazine-2-amine; [0104]
N-[3-(2,3-dihydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazine-2-amine; [0105]
N-[4-(2,3-dihydroxy-benzoylamino)-3-methyl-phenyl]-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0106]
N-[4-(2,3-dihydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0107]
N-[4-(2-hydroxy-4-methyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0108]
N-[3-hydroxy-4-(2-hydroxy-4-methyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-
-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0109]
N-{4-[2-(3-chloro-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0110]
N-[4-(2-phenylcarbamoyl-acetyl)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamino-pipe-
ridin-1-yl)-[1,3,5]triazine-2-amine; [0111]
N-{4-[2-(4-trifluoromethylsulfanyl-phenylcarbamoyl)-acetyl]-phenyl}-4,6-B-
is((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0112]
N-{4-[2-(3-trifluoromethylsulfanyl-phenylcarbamoyl)-acetyl]-phenyl}-4,6-B-
is((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0113]
N-{4-[2-(4-chloro-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0114]
N-[4-(4-chloro-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0115]
N-[3-(2-hydroxy-3-nitro-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamin-
o-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0116]
N-[4-(2,4-dihydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazine-2-amine; [0117]
N-[4-(2,4-dihydroxy-benzoylamino)-3-methyl-phenyl]-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0118]
1-Hydroxy-naphthalene-2-carboxylicacid{4-[3-((3R,5S)-3,5-diamino-piperidi-
n-1-yl)-5-((3S,5R)-3,5-diamino-piperidin-1-yl)-phenylamino]-phenyl}-amide;
[0119]
N-{4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5-
S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-
-2-(1H-indol-3-yl)-2-oxo-acetamide; [0120]
1-Benzyloxy-naphthalene-2-carboxylicacid{4-[3-((3R,5S)-3,5-diamino-piperi-
din-1-yl)-5-((3S,5R)-3,5-diamino-piperidin-1-yl)-phenylamino]-phenyl}-amid-
e; [0121] 1-Hydroxy-naphthalene-2-carboxylic acid
{4-[4,6-bis-((2S,4S)-4-amino-2-aminomethyl-pyrrolidin-1-yl)-[1,3,5]triazi-
n-2-ylamino]-phenyl}-amide; [0122]
N-(4-hexanoylamino-3-hydroxy-phenyl)-4,6-Bis-((3R,5S)-3,5-diamino-piperid-
in-1-yl)-[1,3,5]triazine-2-amine; [0123]
N-[3-hydroxy-4-(7-methyl-octanoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0124]
N-[4-(2-ethyl-heptanoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0125]
N-(4-decanoylamino-3-hydroxy-phenyl)-4,6-Bis-((3R,5S)-3,5-diamino-piperid-
in-1-yl)-[1,3,5]triazine-2-amine;
[0126]
N-(4-benzoylamino-3-hydroxy-phenyl)-4,6-Bis-((3R,5S)-3,5-diamino--
piperidin-1-yl)-[1,3,5]triazine-2-amine; [0127]
N-{4-[4-(2-ethyl-heptanoylamino)-benzenesulfonylamino]-3-hydroxy-phenyl}--
4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0128]
N-[4-(4-decanoylamino-benzenesulfonylamino)-3-hydroxy-phenyl]-4,6-
-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0129]
N-{3-hydroxy-4-[4-(3-methyl-butyrylamino)-benzenesulfonylamino]-phenyl}--
4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0130]
1-Hydroxy-naphthalene-2-carboxylicacid{4-[4-((3S,5R)-3,5-diamino--
piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-amide; [0131]
N-{4-[4-[Bis-(2-amino-ethyl)-amino]-6-((3R,5S)-3,5-diamino-piperidin-1-yl-
)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-2-(1H-indol-3-yl)-2-oxo-acet-
amide; [0132]
N-{4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-phenyl}-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0133]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0134]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-methyl-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0135]
N-[3-chloro-4-(4-chloro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0136]
N-[3,5-dichloro-4-(4-chloro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,-
5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0137]
N-[3-bromo-4-(4-chloro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3-
,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0138]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-fluoro-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0139]
N-(8-hydroxy-quinolin-5-yl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)--
[1,3,5]triazine-2-amine; [0140]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-trifluoromethyl-phenyl]-4,6-Bis(-
(3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0141]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-phenylcarbamoyl-phenyl]-4,6-Bis(-
(3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0142]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-methoxy-phenyl]-4,6-Bis-((3R,5S)-
-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0143]
N-{4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-phenyl}-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0144]
N-[3-chloro-4-(4-chloro-2-hydroxy-benzoylamino)-5-methyl-phenyl]-4,6-Bis--
((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0145]
N-[4-(4-fluoro-2-hydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-
-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0146]
N-[3-hydroxy-4-(2-hydroxy-5-trifluoromethoxy-benzoylamino)-phenyl]-4,6-Bi-
s((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0147]
N-[3-chloro-4-(3,4-difluoro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,-
5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0148]
N-{3-chloro-4-[4-(1,3-dihydro-isoindol-2-yl)-2-hydroxy-benzoylamino]-phen-
yl}-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0149]
N-{3-chloro-4-[(2-hydroxy-naphthalene-1-carbonyl)-amino]-phenyl}--
4,6-Bis((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0150]
N-{3-chloro-4-[(2-hydroxy-6-trifluoromethyl-pyridine-3-carbonyl)--
amino]-phenyl}-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-
e-2-amine; [0151]
N-{3-hydroxy-4-[4-(7-methyl-octanoylamino)-benzenesulfonylamino]-phenyl}--
4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0152]
N-[4-(4-fluoro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3-
,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0153]
N-(3-chloro-4-nitro-phenyl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)--
[1,3,5]triazine-2-amine; [0154]
N-{4-[4-(1,3-dihydro-isoindol-2-yl)-2-hydroxy-benzoylamino]-phenyl}-4,6-B-
is((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0155]
N-{4-[(2-hydroxy-6-trifluoromethyl-pyridine-3-carbonyl)-amino]-phenyl}-4,-
6-Bis((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0156]
N-(6-nitro-benzothiazol-2-yl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-y-
l)-[1,3,5]triazine-2-amine; [0157]
N-[4-(2-hydroxy-3,5-diisopropyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,-
5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0158]
N-[4-(4-dimethylamino-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,-
5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0159]
N-[4-(5-bromo-2-hydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0160]
N-[3-hydroxy-4-(2-hydroxy-3,5-diisopropyl-benzoylamino)-phenyl]-4,6-Bis((-
3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0161]
N-[4-(4-dimethylamino-2-hydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis((-
3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0162]
N-[4-(5-chloro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0163]
N-[4-(5-bromo-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamin-
o-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0164]
N-(4-hydroxy-naphthalen-1-yl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl-
)-[1,3,5]triazine-2-amine; [0165]
N-[3-hydroxy-4-(2-hydroxy-4-methoxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S-
)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0166]
N-[3-hydroxy-4-(2-hydroxy-5-methoxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S-
)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0167]
N-[3-hydroxy-4-(2-hydroxy-4-methyl-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-
-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0168]
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-
-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0169]
N-{4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-4-chloro-
-2-hydroxy-benzamide; [0170]
N-[3-(4-chloro-2-hydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diami-
no-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0171]
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(3,5-dichloro-2,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-pyridin-4-y-
lamino)-phenyl]-amide; [0172]
N-[3-(2,4-dihydroxy-benzoylamino)-phenyl]-4,6-Bis-((3R,5S)-3,5-diamino-pi-
peridin-1-yl)-[1,3,5]triazine-2-amine; [0173]
N-[4-(2,4-dihydroxy-benzoylamino)-3-methyl-phenyl]-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0174]
N-[4-(2,4-dihydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0175]
1-Hydroxy-naphthalene-2-carboxylicacid{4-[6-((3R,5S)-3,5-diamino-piperidi-
n-1-yl)-8-((3S,5R)-3,5-diamino-piperidin-1-yl)-7H-purin-2-ylamino]-phenyl}-
-amide; [0176]
1-Hydroxy-naphthalene-2-carboxylicacid{4-[2-((3R,5S)-3,5-diamino-piperidi-
n-1-yl)-6-((3S,5R)-3,5-diamino-piperidin-1-yl)-pyrimidin-4-ylamino]-phenyl-
}-amide; [0177]
N-{3-hydroxy-4-[(2-hydroxy-naphthalene-1-carbonyl)-amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0178]
N-{4-[(2-hydroxy-naphthalene-1-carbonyl)-amino]-phenyl}-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0179]
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-pyridin-4-ylamino)-pheny-
l]-amide; [0180]
N-{4-[2-(4-methoxy-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5--
diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0181]
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-pyridin-2-ylamino)-pheny-
l]-amide; [0182]
N-{4-[2-(3-bromo-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0183]
N-{4-[2-(biphenyl-4-ylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5-dia-
mino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0184]
N-{4-[2-(2-chloro-5-trifluoromethyl-phenylcarbamoyl)-acetyl]-phenyl}-4,6--
Bis((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine;
[0185]
N-{4-[2-(4-chloro-2,5-dimethoxy-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis(-
(3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0186]
N-{4-[2-(4-fluoro-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,5S)-3,5-d-
iamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0187]
N-{4-[2-(3-trifluoromethyl-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,-
5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0188]
N-{4-[2-(4-chloro-2-fluoro-phenylcarbamoyl)-acetyl]-phenyl}-4,6-Bis-((3R,-
5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0189]
N-{3-hydroxy-4-[(2-hydroxy-pyridine-3-carbonyl)-amino]-phenyl}-4,6-Bis-((-
3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0190]
N-{4-[4-((2S,4S)-4-Amino-2-aminomethyl-pyrrolidin-1-yl)-6-((3R,5S)-3,5-di-
amino-piperidin-1-yl)-[1,3,5]triazin-2-ylamino]-2-hydroxy-phenyl}-2,4-dihy-
droxy-benzamide; [0191]
N-(4-{4-[benzyl-(toluene-4-sulfonyl)-amino]-3-hydroxy-phenylcarbamoyl}-3--
hydroxy-phenyl)-4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazi-
ne-2-amine; [0192]
N-[3-hydroxy-4-(4-methyl-2-oxo-2H-chromen-7-ylcarbamoyl)-phenyl]-4,6-Bis(-
(3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; [0193]
N-[4-(5-bromo-2,3-dihydro-indole-1-carbonyl)-3-hydroxy-phenyl]-4,6-Bis-((-
3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine; and
[0194]
N-[4-(biphenyl-4-ylcarbamoyl)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-3,5-diam-
ino-piperidin-1-yl)-[1,3,5]triazine-2-amine.
[0195] The invention is also directed to pharmaceutically
acceptable prodrugs, pharmaceutically active metabolites,
pharmaceutically acceptable solvates, and pharmaceutically
acceptable salts of the compounds, prodrugs, metabolites or
solvates of Formula I. Advantageous methods of making the compounds
of Formula I are also described.
[0196] In another aspect, the invention relates to a method for the
treatment of bacterial infection in a mammal, including a human,
comprising administering to said mammal an amount of a compound of
the Formula I as defined above, or a pharmaceutically acceptable
prodrug, pharmaceutically active metabolite, pharmaceutically
acceptable solvate, or pharmaceutically acceptable salt, that is
effective in reducing the bacterial infection. The compounds of the
present invention inhibit the bacterial growth of both
Gram-positive and Gram-negative strains.
[0197] In another aspect, Formula I compounds or pharmaceutically
acceptable compositions thereof are utilized in a method for
inhibiting the bacterial growth of both Gram-positive and
Gram-negative strains at MIC (minimum inhibitory concentrations) of
better than 32 .mu.g/ml. The compounds are bactericidal at these
concentrations and they retain potency in common
antibiotics-resistant strains.
[0198] In another aspect, the invention comprises a process of
synthesizing compounds of formula I. In one embodiment, the process
comprises selectively synthesizing a cis isomer of the Formula I
compound.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Definitions
[0199] Where the following terms are used in this specification,
they are used as defined below:
[0200] The terms "comprising" and "including" are used herein in
their open, non-limiting sense.
[0201] The term "alkyl" as used herein refers to a straight- or
branched-chain alkyl group having one to twelve carbon atoms.
Exemplary alkyl groups include methyl (Me, which also may be
structurally depicted by "/"), ethyl (Et), n-propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl,
tert-pentyl, hexyl, isohexyl, and the like. The term "lower alkyl"
designates an alkyl having from 1 to 6 carbon atoms (a
(C.sub.1-C.sub.6)alkyl).
[0202] The term "alkoxy" refers to --O-alkyl. Illustrative examples
include methoxy, ethoxy, propoxy, and the like.
[0203] The term "alkenyl" represents alkyl moieties having at least
one carbon-carbon double bond wherein alkyl is as defined above and
including E and Z isomers of said alkenyl moiety.
[0204] The term "alkynyl" represents alkyl moieties having at least
one carbon-carbon triple bond wherein alkyl is as defined
above.
[0205] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halo" represents chloro, fluoro, bromo or
iodo.
[0206] The term "cycloalkyl" refers to a saturated or partially
saturated, monocyclic or fused or spiro polycyclic, carbocycle
having from three to twelve ring atoms per ring and up to twenty
ring atoms in total. Illustrative examples of cycloalkyl groups
include the following moieties: ##STR19## and the like.
[0207] A "heterocycloalkyl" refers to a monocyclic, or fused or
spiro polycyclic, ring structure that is saturated or partially
saturated and has from three to twelve ring atoms per ring selected
from C atoms and N, O, and S heteroatoms and up to twenty ring
atoms in total. A heterocycloalkyl has at least one ring
heteroatom. Illustrative examples of heterocycloalkyl groups
include: ##STR20## and the like.
[0208] The term "aryl" (Ar) refers to a monocyclic, or fused or
Spiro polycyclic, aromatic carbocycle (ring structure having ring
atoms that are all carbon) having from three to twelve ring atoms
per ring and up to twenty total ring atoms. Illustrative examples
of aryl groups include the following moieties: ##STR21## and the
like.
[0209] The term "heteroaryl" (heteroAr) refers to a monocyclic, or
fused or spiro polycyclic, aromatic heterocycle (ring structure
having ring atoms selected from carbon atoms as well as nitrogen,
oxygen, and sulfur heteroatoms) having from three to twelve ring
atoms per ring and up to twenty total ring atoms. In a heteroaryl,
at least one ring atom is a heteroatom. Illustrative examples of
heteroaryl groups include the following moieties: ##STR22## and the
like.
[0210] The term "substituted" means that the specified group or
moiety bears one or more substitutents. The term "unsubstituted"
means that the specified group bears no substitutents.
"Substituted" can mean that the specified group or moiety bears
substitutents that differ from each other.
[0211] Thus, the terms "substituted alkyl," "substituted alkoxy,"
"substituted alkenyl," "substituted alkynl," "substituted
cycloalkyl," "substituted heterocycloalkyl," "substituted aryl," or
"substituted heteroaryl" refer to that particular group, which is
substituted with one or more substitutents independently selected
from the group consisting of: halogens; .dbd.O; .dbd.S; --CN; and
--NO.sub.2; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl,
aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
--(CH.sub.2).sub.zCN where z is an integer from 0 to 4, .dbd.NH,
--NHOH, --OH, --C(O)H, --OC(O)H, --C(O)OH, --OC(O)OH,
--OC(O)OC(O)H, --OOH, --C(NH)NH.sub.2, --NHC(NH)NH.sub.2,
--C(S)NH.sub.2, --NHC(S)NH.sub.2, --NHC(O)NH.sub.2, --S(O.sub.2)H,
--S(O)H, --NH.sub.2, --C(O)NH.sub.2, --OC(O)NH.sub.2, --NHC(O)H,
--NHC(O)OH, --C(O)NHC(O)H, --OS(O.sub.2)H, --OS(O)H, --OSH,
--SC(O)H, --S(O)C(O)OH, --SO.sub.2C(O)OH, --NHSH, --NHS(O)H,
--NHSO.sub.2H, --C(O)SH, --C(O)S(O)H, --C(O)S(O.sub.2)H, --C(S)H,
--C(S)OH, --C(SO)OH, --C(SO.sub.2)OH, --NHC(S)H, --OC(S)H,
--OC(S)OH, --OC(SO.sub.2)H, --S(O.sub.2)NH.sub.2, --S(O)NH.sub.2,
--SNH.sub.2, --NHCS(O.sub.2)H, --NHC(SO)H, --NHC(S)H, and --SH
groups unsubstituted or substituted with one or more substitutents
independently selected from the group consisting of halogens,
.dbd.O, --NO.sub.2, --CN, --(CH.sub.2), --CN where z is an integer
from 0 to 4, --OR.sup.c, --NR.sup.cOR.sup.c, --N(R.sup.c)R.sup.c,
--C(O)NR.sup.c, --C(O)OR.sup.c, --C(O)R.sup.c,
--N(R.sup.c)C(O)N(R.sup.c)R.sup.c, --NR.sup.cC(O)R.sup.c,
--OC(O)OR.sup.c, --OC(O)N(R.sup.c)R.sup.c, --SR.sup.c,
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted
alkynyls, unsubstituted aryls, unsubstituted cycloalkyls,
unsubstituted heterocycloalkyls, and unsubstituted heteroaryls,
where R.sup.c is hydrogen, unsubstituted alkyl, unsubstituted
alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted
heteroaryl, or two or more R.sup.c groups together cyclize to form
part of a heteroaryl or heterocycloalkyl group unsubstituted or
substituted with an unsubstituted alkyl group.
[0212] In accordance with a convention used in the art, ##STR23##
are used in structural formulae herein to depict the bond that is
the point of attachment of the moiety or substitutent to the core
or backbone structure. Moreover, ##STR24## are used in structural
formulae herein to depict that the point of attachment of the
moiety or substitutent to the core of the backbone aryl structure
is unspecified.
[0213] The term "preventing" refers to the ability of a compound or
composition of the invention to prevent a disease identified herein
in patients diagnosed as having the disease or who are at risk of
developing such disease. The term also encompasses preventing
further progression of the disease in patients who are already
suffering from or have symptoms of such disease.
[0214] The term "treating" refers to:
[0215] (i) preventing a disease, disorder, or condition from
occurring in an animal or human that may be predisposed to the
disease, disorder and/or condition, but has not yet been diagnosed
as having it;
[0216] (ii) inhibiting the disease, disorder, or condition, i.e.,
arresting its development; and
[0217] (iii) relieving the disease, disorder, or condition, i.e.,
causing regression of the disease, disorder, and/or condition.
[0218] The term "treatment" refers to the act of treating as
"treating" is defined immediately above.
[0219] One of the compounds of the invention is
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine, which is a
meso compound that is identical to
(3S,5R)-3,5-bis(tert-butoxycarbonylamino)-piperidine. This compound
can also be termed
cis-3,5-bis(tert-butoxycarbonylamino)-piperidine. For purposes of
this application, all these terms are understood to refer to the
same compound.
[0220] The 3,5-bis(tert-butoxycarbonylamino)-piperidine compound
can also exist in the trans configuration. The trans compound, and
derivatives thereof, are also within the scope of the
invention.
[0221] The compounds of the invention may also exhibit the
phenomenon of tautomerism. While Formula I (including Formulas Ia
through Iu and M.sup.1, M.sup.2, and X substitutents) cannot
expressly depict all possible tautomeric forms, it is to be
understood that Formula I is intended to represent any tautomeric
form of the depicted compound and are not to be limited merely to a
specific compound form depicted by the formula drawings.
[0222] The present invention also includes isotopically-labelled
compounds, which are identical to those recited in Formula I but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, .sup.125I, and .sup.131I, respectively. Compounds of the
present invention, prodrugs thereof, and pharmaceutically
acceptable salts of said compounds or of said prodrugs which
contain the aforementioned isotopes and/or other isotopes of other
atoms are within the scope of this invention. Certain
isotopically-labelled compounds of the present invention, for
example those into which radioactive isotopes such as .sup.3H and
.sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labelled compounds of Formula I of this
invention and prodrugs thereof can generally be prepared by
carrying out the procedures disclosed in the Schemes and/or in the
Examples and Preparations below, by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
[0223] The inventive compounds of Formula I may exist as single
stereoisomers (i.e., essentially free of other stereoisomers),
racemates, and/or mixtures of enantiomers and/or diastereomers. All
such single stereoisomers, racemates and mixtures thereof are
intended to be within the scope of the present invention.
Preferably, the inventive compounds that are optically active are
used in optically pure form. The structures as depicted in the
application include both cis and trans configurations, unless a
specific configuration is depicted. The compounds of the invention
may also exist as particular configurations. Preferably, the
compounds of the invention exist in a cis configuration.
[0224] As generally understood by those skilled in the art, an
optically pure compound having one chiral center (i.e., one
asymmetric carbon atom) is one that consists essentially of one of
the two possible enantiomers (i.e., is enantiomerically pure), and
an optically pure compound having more than one chiral center is
one that is both diastereomerically pure and enantiomerically pure.
Preferably, the compounds of the present invention are used in a
form that is at least 90% optically pure, that is, a form that
contains at least 90% of a single isomer (80% enantiomeric excess
("e.e.") or diastereomeric excess ("d.e.")), more preferably at
least 95% (90% e.e. or d.e.), even more preferably at least 97.5%
(95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or
d.e.).
[0225] Additionally, Formula I are intended to cover solvated as
well as unsolvated forms of the identified structures. For example,
Formula I includes compounds of the indicated structure in both
hydrated and non-hydrated forms. Other examples of solvates include
the structures in combination with isopropanol, ethanol, methanol,
DMSO, ethyl acetate, acetic acid, or ethanolamine.
[0226] In addition to compounds of Formula I, the invention
includes pharmaceutically acceptable prodrugs, pharmaceutically
active metabolites, and pharmaceutically acceptable salts of such
compounds and metabolites.
[0227] The compounds of the Formula I may be administered in the
form of a prodrug which is broken down in the human or animal body
to give a compound of the Formula I. A prodrug may be used to alter
or improve the physical and/or pharmacokinetic profile of the
parent compound and can be formed when the parent compound contains
a suitable group or substitutent which can be derivatised to form a
prodrug. Examples of pro-drugs include in-vivo hydrolysable esters
of a compound of the Formula I or a pharmaceutically-acceptable
salt thereof. Various forms of prodrugs are known in the art, for
examples see: a) Design of Prodrugs, edited by H. Bundgaard,
(Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396,
edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook
of Drug Design and Development, edited by Krogsgaard-Larsen and H.
Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H.
Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug
Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal
of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et
al., Chem Pharm Bull, 32,692 (1984).
[0228] An in vivo hydrolysable ester of a compound of the Formula I
or a pharmaceutically-acceptable salt thereof containing carboxy or
hydroxy group is, for example, a pharmaceutically-acceptable ester
which is hydrolyzed in the human or animal body to produce the
parent acid or alcohol. Suitable pharmaceutically-acceptable esters
for carboxy include (C.sub.1-C.sub.6)alkoxymethyl esters for
example methoxymethyl, (C.sub.1-C.sub.6)alkanoyloxymethyl esters
for example pivaloyloxymethyl, phthalidyl esters,
(C.sub.3-C.sub.6)cycloalkoxycarbonyloxy(C.sub.1-C.sub.6)alkyl
esters for example 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolan-2-onylmethyl esters for example
5-methyl-1,3-dioxolan-2-ylmethyl; and
(C.sub.1-C.sub.6)alkoxycarbonyloxyethyl esters for example
1-methoxycarbonyloxyethyl and may be formed at any carboxy group in
the compounds of this invention.
[0229] "A pharmaceutically active metabolite" is intended to mean a
pharmacologically active product produced through metabolism in the
body of a specified compound or salt thereof. After entry into the
body, most drugs are substrates for chemical reactions that may
change their physical properties and biologic effects. These
metabolic conversions, which usually affect the polarity of the
Formula I compounds, alter the way in which drugs are distributed
in and excreted from the body. However, in some cases, metabolism
of a drug is required for therapeutic effect. For example,
anticancer drugs of the anti-metabolite class must be converted to
their active forms after they have been transported into a cancer
cell.
[0230] Since most drugs undergo metabolic transformation of some
kind, the biochemical reactions that play a role in drug metabolism
may be numerous and diverse. The main site of drug metabolism is
the liver, although other tissues may also participate.
[0231] A feature characteristic of many of these transformations is
that the metabolic products, or "metabolites," are more polar than
the parent drugs, although a polar drug does sometime yield a less
polar product. Substances with high lipid/water partition
coefficients, which pass easily across membranes, also diffuse back
readily from tubular urine through the renal tubular cells into the
plasma. Thus, such substances tend to have a low renal clearance
and a long persistence in the body. If a drug is metabolized to a
more polar compound, one with a lower partition coefficient, its
tubular reabsorption will be greatly reduced. Moreover, the
specific secretory mechanisms for anions and cations in the
proximal renal tubules and in the parenchymal liver cells operate
upon highly polar substances.
[0232] As a specific example, phenacetin (acetophenetidin) and
acetanilide are both mild analgesic and antipyretic agents, but are
transformed within the body to a more polar and more effective
metabolite, p-hydroxyacetanilid (acetaminophen), which is widely
used today. When a dose of acetanilide is given to a person, the
levels of successive metabolites reach a peak and then decay in the
plasma sequentially. During the first hour, acetanilide is the
principal plasma component. In the second hour, as the acetanilide
level falls, the metabolite acetaminophen concentration reaches a
peak. Finally, after a few hours, the principal plasma component is
a further metabolite that is inert and can be excreted from the
body. Thus, the plasma concentrations of one or more metabolites,
as well as the drug itself, can be pharmacologically important.
[0233] "A pharmaceutically acceptable salt" is intended to mean a
salt that retains the biological effectiveness of the free acids
and bases of the specified compound and that is not biologically or
otherwise undesirable. A compound of the invention may possess a
sufficiently acidic, a sufficiently basic, or both functional
groups, and accordingly react with any of a number of inorganic or
organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt. Exemplary pharmaceutically
acceptable salts include those salts prepared by reaction of the
compounds of the present invention with a mineral or organic acid
or an inorganic base, such as salts including sulfates,
pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,
monohydrogenphosphates, dihydrogenphosphates, metaphosphates,
pyrophosphates, chlorides, bromides, iodides, acetates,
propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, flumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycolates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0234] If the inventive compound is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, or
with an organic acid, such as acetic acid, maleic acid, succinic
acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,
oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid,
such as glucuronic acid or galacturonic acid, an alpha-hydroxy
acid, such as citric acid or tartaric acid, an amino acid, such as
aspartic acid or glutamic acid, an aromatic acid, such as benzoic
acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic
acid or ethanesulfonic acid, or the like.
[0235] If the inventive compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include organic salts
derived from amino acids, such as glycine and arginine, ammonia,
primary, secondary, and tertiary amines, and cyclic amines, such as
piperidine, morpholine and piperazine, and inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron,
copper, zinc, aluminum and lithium.
[0236] In the case of agents that are solids, it is understood by
those skilled in the art that the inventive compounds and salts may
exist in different crystal or polymorphic forms, all of which are
intended to be within the scope of the present invention and
specified formulas.
[0237] A further aspect of the present invention is directed to a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier or a diluent and a therapeutically effective amount of a
Formula I compound, a pharmaceutically acceptable salt, hydrate,
ester, solvate, prodrug, metabolite, or stereoisomer.
[0238] Formula I compounds are useful in the manufacture of
pharmaceutical formulations comprising an effective amount thereof
in conjunction with or as an admixture with excipients or carriers
suitable for either enteral or parenteral application. As such,
formulations of the present invention suitable for oral
administration may be in the form of discrete units such as
capsules, cachets, tablets, troche or lozenges, each containing a
predetermined amount of the active ingredient; in the form of a
powder or granules; in the form of a solution or a suspension in an
aqueous liquid or nonaqueous liquid; or in the form of an
oil-in-water emulsion or a water-in-oil emulsion. The active
ingredient may also be in the form of a bolus, electuary, or
paste.
[0239] The composition will usually be formulated into a unit
dosage form, such as a tablet, capsule, aqueous suspension or
solution. Such formulations typically include a solid, semisolid,
or liquid carrier. Exemplary carriers include lactose, dextrose,
sucrose, sorbitol, mannitol, starches, gum acacia, calcium
phosphate, mineral oil, cocoa butter, oil of theobroma, alginates,
tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene
sorbitan monolaurate, methyl hydroxybenzoate, propyl
hydroxybenzoate, talc, magnesium stearate, and the like.
[0240] Particularly preferred formulations include tablets and
gelatin capsules comprising the active ingredient together with (a)
diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol,
cellulose, dried corn starch, and glycine; and/or (b) lubricants,
such as silica, talcum, stearic acid, its magnesium or calcium
salt, and polyethylene glycol.
[0241] Tablets may also contain binders, such as magnesium aluminum
silicate, starch paste, gelatin, tragacanth, methylcellulose,
sodium carbosymethylcellulose and polyvinylpyrrolidone; carriers,
such as lactose and corn starch; disintegrants, such as starches,
agar, alginic acid or its sodium salt, and effervescent mixtures;
and/or absorbents, colorants, flavors, and sweeteners. The
compositions of the invention may be sterilized and/or contain
adjuvants, such as preserving, stabilizing, swelling or emulsifying
agents, solution promoters, salts for regulating osmotic pressure,
and/or buffers. In addition, the composition may also contain other
therapeutically valuable substances. Aqueous suspensions may
contain emulsifying and suspending agents combined with the active
ingredient. All oral dosage forms may further contain sweetening
and/or flavoring and/or coloring agents.
[0242] These compositions are prepared according to conventional
mixing, granulating, or coating methods, respectively, and contain
about 0.1 to 75% of the active ingredient, preferably about 1 to
50% of the same. A tablet may be made by compressing or molding the
active ingredient optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing, in
a suitable machine, the active ingredient in a free-flowing form
such as a powder or granules, optionally mixed with a binder,
lubricant, inert diluent, surface active, or dispersing agent.
Molded tablets may be made by molding, in a suitable machine, a
mixture of the powdered active ingredient and a suitable carrier
moistened with an inert liquid diluent.
[0243] When administered parenterally, the composition will
normally be in a unit dosage, sterile injectable form (aqueous
isotonic solution, suspension, or emulsion) with a pharmaceutically
acceptable carrier. Such carriers are preferably non-toxic,
parenterally-acceptable and contain non-therapeutic diluents or
solvents. Examples of such carriers include water; aqueous
solutions, such as saline (isotonic sodium chloride solution),
Ringer's solution, dextrose solution, and Hanks' solution; and
nonaqueous carriers, such as 1,3-butanediol, fixed oils (e.g.,
corn, cottonseed, peanut, sesame oil, and synthetic mono- or
di-glyceride), ethyl oleate, and isopropyl myristate.
[0244] Oleaginous suspensions can be formulated according to
techniques known in the art using suitable dispersing or wetting
agents and suspending agents. Among the acceptable solvents or
suspending mediums are sterile fixed oils. For this purpose, any
bland fixed oil may be used. Fatty acids, such as oleic acid and
its glyceride derivatives, including olive oil and castor oil,
especially in their polyoxyethylated forms, are also useful in the
preparation of injectables. These oil solutions or suspensions may
also contain long-chain alcohol diluents or dispersants.
[0245] Sterile saline is a preferred carrier, and the compounds are
often sufficiently water soluble to be made up as a solution for
all foreseeable needs. The carrier may contain minor amounts of
additives, such as substances that enhance solubility, isotonicity,
and chemical stability, e.g., anti-oxidants, buffers and
preservatives.
[0246] When administered rectally, the composition will usually be
formulated into a unit dosage form such as a suppository or cachet.
These compositions can be prepared by mixing the compound with
suitable non-irritating excipients that are solid at room
temperature, but liquid at rectal temperature, such that they will
melt in the rectum to release the compound. Common excipients
include cocoa butter, beeswax and polyethylene glycols or other
fatty emulsions or suspensions.
[0247] Formulations suitable for nasal or buccal administration
(such as self-propelling powder dispensing formulations), may
comprise about 0.1% to about 5% w/w of the active ingredient or,
for example, about 1% w/w of the same. In addition, some
formulations can be compounded into a sublingual troche or
lozenge.
[0248] Moreover, the compounds may be administered topically,
especially when the conditions addressed for treatment involve
areas or organs readily accessible by topical application,
including disorders of the eye, the skin or the lower intestinal
tract.
[0249] For topical application to the eye, or ophthalmic use, the
compounds can be formulated as micronized suspensions in isotonic,
pH-adjusted sterile saline or, preferably, as a solution in
isotonic, pH-adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, the
compounds may be formulated into ointments, such as petrolatum.
[0250] For topical application to the skin, the compounds can be
formulated into suitable ointments containing the compounds
suspended or dissolved, for example, mixtures with one or more of
the following: mineral oil, liquid petrolatum, white petrolatum,
propylene glycol, polyoxyethylene compound, polyoxypropylene
compound, emulsifying wax and water. Alternatively, the compounds
can be formulated into suitable lotions or creams containing the
active compound suspended or dissolved in, for example, a mixture
of one or more of the following: mineral oil, sorbitan
monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0251] Topical application to the lower intestinal tract can be
effected in rectal suppository formulations (see above) or in
suitable enema formulations.
[0252] The formulations may conveniently be presented in unit
dosage form and may be prepared by any of the methods well known in
the art of pharmacy. All methods include the step of bringing the
active ingredient into association with the carrier, which
constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing the
active ingredient into association with a liquid carrier or a
finely divided solid carrier or both, and then, if necessary,
shaping the product into the desired formulation.
[0253] The pharmaceutical composition of the present invention is
used in amount that are therapeutically effective and the amounts
used may depend upon the desire release profile, the concentration
of the pharmaceutical composition required for the sensitizing
effect, and the length of time that the pharmaceutical composition
has to be released for treatment.
[0254] Formula I compounds of the invention are preferably
administered as a capsule or tablet containing a single or divided
dose of the compound, or as a sterile solution, suspension, or
emulsion, for parenteral administration in a single or divided
dose.
[0255] The compounds of the invention are used in the composition
in amounts that are therapeutically effective. While the effective
amount of the Formula I compounds will depend upon the particular
compound being used, amounts of these compounds varying from about
1% to about 65% have been easily incorporated into liquid or solid
carrier delivery systems.
[0256] For medical use, the amount required of a Formula I compound
to achieve a therapeutic effect will vary according to the
particular compound administered, the route of administration, the
mammal under treatment, and the particular disorder in disease
concerned. A suitable systemic dose of a Formula I compound for a
mammal suffering from, or likely to suffer from, any condition as
described herein is typically in the range of about 0.1 to about
100 mg of base per kilogram of body weight. It is understood that
the ordinarily skilled physician or veterinarian will readily be
able to determine and prescribe the amount of the compound
effective for the desired prophylactic or therapeutic
treatment.
[0257] In so proceeding, the physician or veterinarian may employ
an intravenous bolus followed by an intravenous infusion and
repeated administrations, as considered appropriate. In the methods
of the present invention, the compounds may be administered, for
example, orally, parentally, in inhalation spray, topically,
rectally, nasally, buccally, sublingually, vaginally,
intraventricularly, or via an implanted reservoir in dosage
formulations containing conventional non-toxic
pharmaceutically-acceptable carriers, adjuvants and vehicles.
[0258] Parenteral includes, but is not limited to, the following
examples of administration: intravenous, subcutaneous,
intramuscular, intraspinal, intraosseous, intraperitoneal,
intrathecal, intraventricular, intrasternal or intracranial
injection and infusion techniques, such as by subdural pump.
Invasive techniques are preferred, particularly direct
administration to damaged neuronal tissue. While it is possible for
the Formula I compounds to be administered alone, it is preferable
to provide it as part of a pharmaceutical formulation.
[0259] To be effective therapeutically as central nervous system
targets, the compounds used in the methods of the present invention
should readily penetrate the blood-brain barrier when peripherally
administered. Compounds that cannot penetrate the blood-brain
barrier, however, can still be effectively administered by an
intraventricular route.
[0260] The compounds used in the methods of the present invention
may be administered by a single dose, multiple discrete doses or
continuous infusion. Since the compounds are small, easily
diffusible and relatively stable, they are well suited to
continuous infusion. Pump means, particularly subcutaneous or
subdural pump means, are preferred for continuous infusion.
[0261] For the methods of the present invention, any effective
administration regimen regulating the timing and sequence of doses
may be used. Doses of the compounds preferably include
pharmaceutical dosage units comprising an efficacious quantity of
active compound. By an efficacious quantity is meant a quantity
sufficient to provide immune enhancing response and/or derive the
desired beneficial effects through administration of one or more of
the pharmaceutical dosage units.
[0262] An exemplary daily dosage unit for a vertebrate host
comprises an amount of from about 0.001 mg/kg to about 50 mg/kg.
Typically, dosage levels on the order of about 0.1 mg to about
10,000 mg of the active ingredient compound are useful in the
treatment of the above conditions, with preferred levels being
about 0.5 mg to about 2,000 mg. The specific dose level for any
particular patient will vary depending upon a variety of factors,
including the activity of the specific compound employed; the age,
body weight, general health, sex, and diet of the patient; the time
of administration; the rate of excretion, any combination of the
compound with other drugs; the severity of the particular disease
being treated; and the form and route of administration. Typically,
in vitro dosage-effect results provide useful guidance on the
proper doses for patient administration. Studies in animal models
can also be helpful. The considerations for determining the proper
dose levels are well known in the art.
[0263] The compounds and compositions can be co-administered with
one or more therapeutic agents either (i) together in a single
formation, or (ii) separately in individual formulations designed
for optimal release rates of their respective active agent. Each
formulation may contain from about 0.01% to about 99.99% by weight,
preferably from about 3.5% to about 60% by weight, of the compound
of the invention, as well as one or more pharmaceutical excipients,
such as wetting, emulsifying and pH buffering agents. When the
compounds used in the methods of the invention are administered in
combination with one or more other therapeutic agents, specific
dose levels for those agents will depend upon considerations such
as those identified above for compositions and methods of the
invention in general.
[0264] For the methods of the present invention, any administration
regimen regulating the timing and sequence of delivery of the
compound can be used and repeated as necessary to effect treatment.
Such regimen may include pretreatment and/or co-administration with
additional therapeutic agents.
[0265] The inventive agents may be prepared using the reaction
routes and synthesis schemes as described below, employing the
general techniques known in the art using starting materials that
are readily available. A particularly useful compilation of
synthetic methods which may be applicable to the synthesis of
compounds of the present invention may be found in Comprehensive
Organic Transformations, Larock, R. C., VCH: New York, 1989. The
synthesis of non-exemplified compounds according to the invention
may be successfully performed by modifications apparent to those
skilled in the art, e.g., by appropriately protecting interfering
groups, by changing to other suitable reagents known in the art, or
by making routine modifications of reaction conditions. A
compendium of protecting groups which may be useful, together with
reaction conditions for their introduction and removal may be found
in Protective Groups in Organic Synthesis, Second Edition; Greene,
T. W.; Wuts, P. G. M., Wiley: New York 1991. Alternatively, other
reactions disclosed herein or generally known in the art will be
recognized as having applicability for preparing other compounds of
the invention.
4.2 Preparation of Compounds
[0266] In the synthetic schemes described below, unless otherwise
indicated all temperatures are set forth in degrees Celsius.
Reagents were purchased from commercial suppliers such as Aldrich
Chemical Company or Lancaster Synthesis Ltd. and were used without
further purification unless otherwise indicated. Tetrahydrofuran
(THF) and N,N-dimethylformamide (DMF) were purchased from Aldrich
in Sure Seal bottles and used as received. THF, Et.sub.2O,
CH.sub.2Cl.sub.2, MeCN, MeOH, PhMe, EtOAc, diisopropylethylamine,
pyridine and Et.sub.3N were used as received.
[0267] The reactions set forth below were done in anhydrous
solvents generally either in flasks or vials. Glassware was oven
dried and/or heat dried and vials (8 mL and 40 mL) were used as
received. The reactions were monitored by thin layer chromatography
(TLC) and/or LC-MS and terminated as judged by the consumption of
starting material. Analytical TLC was performed on silica gel 60
F.sub.254 0.25 mm plates (Merck), and visualized with UV light (254
nm). Preparative TLC was performed on Merck 1.0 mm silica gel 60
F.sub.254 plates and visualized with UV light (254 nm).
[0268] Work-ups were typically done by evaporation of the solvents
under reduced pressure on a rotary evaporator or in a Savant
SpeedVac followed by liquid-liquid extraction between CHCl.sub.3 or
EtOAc and H.sub.2O layers. The product solution was then
concentrated in vacuo. Column chromatography was completed under
positive pressure using 230-400 mesh silica gel. Hydrogenation was
done at the pressure indicated in the examples.
[0269] Both .sup.1H-NMR and .sup.13C-NMR spectra were recorded on a
Varian Mercury-VX400 instrument operating at 400 MHz. NMR spectra
were reported in ppm using reference standard such as CDCl.sub.3
(7.27 ppm and 77.00 ppm), CD.sub.3OD (3.4 and 4.8 ppm and 49.3
ppm), DMSO-d.sub.6, or internally tetramethylsilane (0.0 ppm) when
appropriate. Other NMR solvents were used as needed. When peak
multiplicities are reported, the following abbreviations are used:
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
br (broadened), dd (doublet of doublets), dt (doublet of triplets).
Coupling constants, when given, are reported in Hertz (Hz).
[0270] Mass spectra reported are ES or APCI LC/MS conducted by the
Analytical Chemistry Department of Anadys Pharmaceuticals, Inc.
Elemental analyses were conducted by the Atlantic Microlab, Inc. in
Norcross, Ga. or by Numega, Inc., in San Diego, Calif.
[0271] The described synthetic pathways and experimental procedures
utilize many common chemical abbreviations, THF (tetrahydrofuran),
DMF (N,N-dimethylformamide), EtOAc (ethyl acetate), DMSO (di-methyl
sulfoxide), DMAP (4-dimethylaminopyridine), DBU
(1,8-diazacyclo[5.4.0]undec-7-ene), TFA (trifluoroacetic acid),
.sup.iPr.sub.2NEt (diisopropylethylamine), HOBt
(1-hydroxybenzotriazole hydrate), EDCl
(1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride),
NMP (N-methylpyrrolidinone), DME (ethylene glycol dimethyl ether),
DMA (N,N-dimethylacetamide), HMPA (hexamethylphosphoramide), ELSD
(evaporative light scattering detector), ESI (electrospray
ionization), APCI (atmospheric pressure chemical ionization),
Pd.sub.2(dba).sub.3 (tris(dibenzylideneacetone)dipalladium(0)),
Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene), BINAP
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Boc
(N-tert-butoxycarbonyl), DBN (1,5-diazobicyclo[4,3,0]non-5-ene),
DABCO (1,4-diazabicyclo[2,2,2]octane), ACN (acetonitrile) and the
like.
4.3 General Method of Synthesis of Formula Ia Compounds
[0272] Scheme 1 describes a general synthetic procedure for
preparing compound (4) and (7) of Formula Ia. ##STR25##
[0273] R.sup.1a and R.sup.2a are independently defined as R.sup.1
and R.sup.2.
[0274] In this general method of producing compounds of Formula Ia,
the 2-chloro-3,5-dinitropyridine 1 was hydrogenated to
3,5-diaminopyridine 2, followed by protecting the amino-groups as
the di-BOC derivative 3. This was subsequently hydrogenated to the
piperidine derivative 4.
[0275] Cyanuric chloride (5) was treated sequentially by three
different amines at increasing temperatures. Preferably the less
reactive amines, such as aromatic or heteroaromatic amines were
used first to displace the most reactive Cl, followed by reactive
amines to displace the second Cl and finally
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) was used
to displace the third Cl to give compound 6. Deprotection of the
BOC of compound 6 with HCl in dioxane furnished the targets of
compound 7.
[0276] This methodology is useful for the production of various
derivatives represented by Formula Ia. Other variations of this
methodology would be apparent to those skilled in the art. This
methodology and variants thereof are collectively termed triazine
chemistry.
4.3.1 Synthesis of 3,5-diaminopyridine hydrochloride (2)
[0277] 2-chloro-3,5-dinitro-pyridine (27.36 g, 1) was divided into
two equal portions and added into two 2 L round bottomed flasks.
Methanol (700 mL) was then added to each flask. Nitrogen gas was
bubbled through the solution while stirring and 7.15 g of 10%
palladium on carbon was divided into two equal portions and added
to each flask portion-wise under nitrogen. The solutions were
cooled down under N.sub.2 to 0.degree. C. using an ice-water bath.
The N.sub.2 inlets were then replaced by hydrogen balloons. After
evacuation, the solutions were exposed to H.sub.2 gas at slightly
positive pressure. This vacuum-hydrogen exchange was done at least
5 times. The reactions were stirred under slight positive pressure
of H.sub.2 for 2 days. Then the solutions were filtered with
suction through Celite to remove the catalyst. The filtrate was
concentrated down in vacuo. The crude product (24.27 g, >100%
crude yield) was obtained as a dark green solid that was
immediately used directly in the next step without further
purification. The identity of the product (2) was confirmed by
LC-MS.
4.3.2 Synthesis of di-BOC-protected 3,5-diamino-pyridine (3)
[0278] The crude 3,5-diaminopyridine hydrochloride (19.56 g, 0.1344
mol, 2) was dissolved in 150 mL of methanol in a 2 L reaction
vessel. Nitrogen was used to purge the flask. The reaction solution
was then cooled to 0.degree. C. A solution of 58.67 g (0.2688 mol)
of di-tert-butyldicarbonate in 85 mL of methanol was added
dropwise. 18.9 mL of triethylamine (0.1344 mol) was diluted with 20
ml of methanol and added dropwise. Then another 58.67 g of
di-tert-butyldicarbonate dissolved in 85 mL of methanol was added
dropwise. After that another 29.34 g of di-tert-butyldicarbonate,
dissolved in 40 mL of methanol was added dropwise.
[0279] The reaction mixture was allowed to warm up to room
temperature (r.t.) and was stirred overnight. TLC analysis showed
that no starting material and very little mono-BOC-protected
diaminopyridine remained. The methanol was removed in vacuo. The
resulting solid was dissolved in ethyl acetate and was extracted
with brine. The aqueous layer was extracted three times with ethyl
acetate. The organic layers were combined and washed with brine.
The organic layer was dried with MgSO.sub.4 and passed through a
layer of silica gel (135 cm.times.3 cm) constructed in a fritted
funnel. The silica was thoroughly washed with ethyl acetate. The
ethyl acetate solution was concentrated in vacuo and the resulting
solid was dissolved in a minimal amount of refluxing methylene
chloride. It was allowed to cool down to room temperature
naturally.
[0280] The crystallized solid was filtered with suction and washed
with a very small amount of CH.sub.2Cl.sub.2 and hexane and was
dried in a vacuum oven at 50-60.degree. C. The first crop of
crystals weighed 18.12 g. Using the same method a second crop of
crystals was obtained, which weighed 5.02 g, a third crop of the
crystals weighed 3.85 g and the fourth crop of crystals (from
methanol) weighed 3.59 g. Total 30.58 g of the desired product (3)
was obtained (73.6% isolated yield). .sup.1H NMR (CDCl.sub.3):
.delta. 8.23 ppm (s, 2H), 8.18 (s, 2H), 6.68 (s, 2H, NH), 1.54 (s,
18H, BOC).
4.3.3 Synthesis of
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4)
[0281] The 3,5-di-BOC diamino-pyridine (3) (10 g, 32.34 mmol) was
dissolved in 350 mL of methanol. Glacial acetic acid (1.85 mL,
32.34 mmol) was added, followed by 5% Rh--C (wet, 6.66 g, 5 mol %),
purged with N.sub.2 and transferred to a high-pressure
hydrogenator. The vessel was flushed with H.sub.2 twice at 500 psi
of H.sub.2 gas, the H.sub.2 pressure was increased to 1000 psi and
heated to 110.degree. C. Then the H.sub.2 pressure was increased to
2200 psi and the mixture was stirred for 28 hours. The reaction
mixture was cooled to room temperature.
[0282] The catalyst was filtered off through Celite with suction.
The filtrate was then concentrated in vacuo to remove methanol.
Na.sub.2CO.sub.3 (3.43 g, 32.34 mmol) in 100 mL of H.sub.2O was
added followed by 100 mL of EtOAc. After stirring for 90 minutes, a
thick white precipitate formed. The mixture was then suction
filtered and the solid washed with EtOAc, dried in a vacuum oven at
60.degree. C. overnight. The desired product
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (5.6 g)
was obtained as an off-white solid that was confirmed by LC-MS and
.sup.1H NMR. MS m/e 316 [M+1] (exact MS: 315). .sup.1H NMR
(DMSO-d.sub.6): .delta. 6.71 (br, 2H, NH), 3.16-3.30 (br, 2H),
2.78-2.81 (m, 2H), 1.99 (t, 2H, J=11.2 Hz), 1.855 (br, 1H), 1.59
(s, 1H), 1.09 (q, 1H, J=11.6 Hz). The above process produces the
cis isomer in high purity.
[0283] This compound
[(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine] is
identical to
(3S,5R)-3,5-bis-(tert-butoxycarbonylamino)-piperidine.
[0284] The trans-3,5-bis-(tert-butoxycarbonylamino)-piperidine can
be made in a way similar to that described in WO 00/056729
(Published Sep. 28, 2000). In the WO 00/056729 patent application,
the synthesis of a mixture of the cis- and
trans-3,5-bis(ethoxycarbonylamino)piperidine was described with a
trans/cis ratio of 80/20.
3.3.4 EXAMPLE 1
Synthesis of Formula Ia Compound 8
[0285] ##STR26##
[0286] Cyanuric chloride (400 .mu.L of 0.25 M, 5) in anhydrous THF
was cooled to -25.degree. C. for about 0.5 hours.
N-(4-Amino-2-hydroxy-phenyl)-4-chloro-benzamide (400 .mu.L of 0.25
M) in anhydrous THF containing 100 .mu.mol of .sup.iPr.sub.2NEt was
then injected into the above cooled cyanuric chloride solution. The
reaction mixture was vortexed and immediately put back in a freezer
at -25.degree. C. overnight.
[0287] The reaction mixture was then warmed up to room temperature
with shaking. A solution of 4-N-BOC protected piperazine (400 .mu.L
of 0.25 M) in anhydrous THF containing 100 .mu.mol of iPr.sub.2NEt
was then added into the above solution. The resulting reaction
mixture was shaken at room temperature for 24 hours. A slurry of
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (100
.mu.mol) in THF (0.125 M) was added, followed by 100 .mu.L of 1.0 M
.sup.iPr.sub.2NEt in THF. The reaction mixture was shaken at
80.degree. C. for 48 h. Then the reaction mixture was dried under
vacuum with slight heating. The product was first pre-purified by
liquid-liquid extraction using CHCl.sub.3 and H.sub.2O. The organic
layer washed with H.sub.2O three times and was then analyzed by
LC-MS (after further dilution by CH.sub.3CN) to confirm the
identity of the desired product. The organic layer was then
concentrated under vacuum. The crude product was further purified
by reverse-phase HPLC purification using a mixture of ACN and water
to give a
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine-substituted-3-hydro-
xy-4-(4'-chlorobenzeneamide)aniline substituted triazine
intermediate.
[0288] The resulting above purified tri-BOC-intermediate was then
dissolved in MeOH (2 mL) and treated with 2 mL of 4.0 M HCl in
1,4-dioxane. After shaking at room temperature overnight, the
solvent and excess HCl was evaporated under vacuum with heating
(40-60.degree. C.). 2 mL of MeOH was added to dissolve the crude
product and the resulting solution was concentrated under vacuum to
small volume. The solid was then filtered under vacuum and washed
with small amount of MeOH, dried in vacuo for 2 hours. LC-MS, NMR
and elemental analysis were used to confirm the identity of the
desired product (8) as an HCl salt. LC-MS (exact MS: 538.23): MS
m/e 539.3 [M+1]; .sup.1H NMR (DMSO-d.sub.6): .delta. 9.80 (br, 1H),
9.47 (s, 1H), 9.38 (br, 2H, CNH.sub.2.sup.+), 9.21 (s, 1H), 8.59
(br, 6H, 2NH.sub.3.sup.+), 7.95 (d, 2H, J=8.4 Hz), 7.56 (d, 2H
J=8.4 Hz), 7.5 (d, 1H), 7.41 (s, 1H), 7.06 (d, 1H), 5.05 (br, 2H),
4.0 (br, 4H), 3.12 ((br, 6H), 2.78 (m, 3H), 1.76 (q, 1H).
4.3.5 EXAMPLE 2
Synthesis of Compound 11 of Formula Ia (Scheme 2)
[0289] In this example, a modification of the 3,5-diaminopiperidine
was made on the final product instead of making the
3,5-diaminopiperadine derivative first and then attaching the
triazine. ##STR27##
[0290] Into 40 mg of compound 9 (made in the same way as compound 6
using the procedure described in Scheme 1), 2 mL of BH.sub.3.THF
(1.0 M) was added and the mixture was stirred at room temperature
for 15 hours. The LC-MS result indicated that the reaction was
incomplete. An additional amount of BH.sub.3.THF (1.0 M, 1 mL) in
THF was added and the mixture was shaken at room temperature
overnight. LC-MS indicated no further improvement in the reaction
progress. The reaction mixture was then concentrated under reduced
pressure and the crude product (10) was purified by MS-triggered
HPLC. Compound 10 was dissolved in 2 mL of MeOH and 2 mL of 4.0 M
HCl in dioxane was then added and the mixture was shaken at room
temperature overnight. The mixture was concentrated under reduced
pressure and the residue was purified by reverse-phase HPLC to give
2.8 mg of final product (11) with HPLC purity of 100% by ELSD.
LC-MS: m/e 481.1 [M+1].sup.+.
[0291] Each of the Formula Ia compounds shown in Table 1 were
prepared in a manner similar to one of the protocols exemplified
above.
4.4 General Method of Synthesis of Compounds of Formula Ia Having a
Second 3,5-diaminopiperidine Group
[0292] Scheme 3 describes a general synthetic procedure for
preparing compound (10) of Formula Ia. ##STR28##
[0293] R* refers to the substitutents defined above for a
"substituted aryl" group.
[0294] In this general method of producing Formula Ia compounds,
cyanuric chloride (5) was treated with an aromatic amine at a low
temperature, followed by treatment with 4 to give the
trisubstituted 1,3,5-triazine derivative 13. Deprotection (removal
of the BOC protecting groups by HCl in dioxane) gave the target
compound 14. In a specific example the aromatic amine was
3,4-dichloroaniline, which gave the triazine derivative 15. In the
case of the 3,4-dichlorophenylamino substitution, the target
compound was 16. This methodology is useful for the production of
various derivatives represented by Formula Ia having a second
3,5-diamino piperidine moiety. Other variations of this methodology
would be apparent to those skilled in the art.
4.4.1 General procedure for the synthesis of 1,3,5-triazine
compounds substituted with two
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine groups
(13)
[0295] Cyanuric chloride (5) (400 .mu.L of 0.25 M) in anhydrous THF
was cooled to -25.degree. C. for about 0.5 hours. 400 .mu.L of 0.25
M of an aniline in anhydrous THF (or DMF) containing 100 .mu.mol of
.sup.iPr.sub.2NEt was then injected into the above cooled cyanuric
chloride solution. The reaction mixture was briefly vortexed and
immediately put back in freezer at -25.degree. C. overnight.
[0296] The reaction mixture was then warmed up to room temperature
with shaking.
[0297] A slurry of
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (100
.mu.mol) in THF (0.125M) was added, followed by 100 .mu.L of 1 M
iPr.sub.2NEt in THF. The reaction mixture was shaken at 80.degree.
C. for 48 h. The reaction mixture was dried under vacuum with
slight heating. The product was first pre-purified by liquid-liquid
extraction using CHCl.sub.3 and H.sub.2O. The organic layer washed
with H.sub.2O twice and was then analyzed by LC-MS (after further
dilution by CH.sub.3CN) to confirm the identity of the desired
product. The organic layer was then concentrated under vacuum. The
crude product was further purified by flash column chromatography
or HPLC to get the desired product (13).
4.4.2 General procedure for the synthesis of 1,3,5-triazine
compounds substituted with two 3,5-diaminopiperidine groups
(14)
[0298] The resulting above purified intermediate (13) was then
dissolved in a mixture of MeOH and dioxane (1:1, 2 mL) and treated
with 2 mL of 4 M HCl in dioxane. After shaking at room temperature
overnight, the solvent and excess HCl was evaporated under vacuum
with heating (40-60.degree. C.). NMR, LC-MS, or both, were used to
confirm the identity of the desired product (14).
4.4.3 EXAMPLE 3
2-(3,4-dichlorophenylamino)-4,6-bis(3,5-diaminopiperidinyl)-1,3,5-triazine
(16)
[0299] ##STR29##
[0300] Cyanuric chloride (400 .mu.L of 0.25 M, 5) in anhydrous THF
was cooled to -25.degree. C. for about 0.5 hours.
3,4-dichloroaniline (400 .mu.L of 0.25 M) in anhydrous THF
containing 100 .mu.mol of .sup.iPr.sub.2NEt was then injected into
the above cooled cyanuric chloride solution. The reaction mixture
was vortexed and immediately put back in freezer at -25.degree. C.
overnight.
[0301] The reaction mixture was then warmed up to room temperature
with shaking. A slurry of 3,5-di-BOC-protected diaminopiperidine
(200 .mu.mol) in THF (0.125 M) was added, followed by 200 .mu.L of
1.0 M .sup.iPr.sub.2NEt in THF. The reaction mixture was shaken at
80.degree. C. for 48 h. Then the reaction mixture was dried under
vacuum with slight heating. The product was first pre-purified by
liquid-liquid extraction using CHCl.sub.3 and H.sub.2O. The organic
layer washed with H.sub.2O three times and was then analyzed by
LC-MS (after further dilution by CH.sub.3CN) to confirm the
identity of the desired product. The organic layer was then
concentrated under vacuum. The crude product was further purified
by flash chromatography using a mixture of solvents of hexane,
ethyl acetate and methylene chloride to give two
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine substituted
and 3,4-di-chloroaniline substituted triazine (15). This product
was confirmed by LC-MS. LC-MS (exact MS: 866.4; MW: 867.86): a
single HPLC peak (both ELSD and UV-254) with MS (m/e) of 867.5
[M+1] and 869.5 [M+3] was found as expected.
[0302] The intermediate (15), purified as above, was dissolved in
MeOH (2 mL) and treated with 2 mL of 4.0 M HCl in 1,4-dioxane.
After shaking at room temperature overnight, the solvent and excess
HCl was evaporated under vacuum with heating (40-60.degree. C.). 2
mL of MeOH was added to dissolve the crude product and the
resulting solution was concentrated under vacuum to a small volume.
The solid was then filtered under vacuum and washed with small
amount of MeOH, dried over oil vacuum pump for 2 hours. LC-MS, NMR
and elementary analysis were used to confirm the identity of the
desired product (16) as an HCl salt. LC-MS (exact MS: 466.19; MW:
467.4): MS m/e 467.1 [M+1] and 469.1 [M+3] were found; .sup.1H NMR
(DMSO-d.sub.6): .delta. 9.46 (br, 1H), 8.66 and 8.61 (12H, 4
NH.sub.3.sup.+), 8.03 (br, 1H), 7.64-7.69 (m, 2H), 5.36 (d, 2H),
4.70-4.90 (m, 2H), 3.05-3.30 (m, 4H), 2.87 (t, 2H, J=12 Hz), 2.71
(t, 2H, J=11.6 Hz), 1.77 (q, 2H, J=11.6 Hz); Elemental analysis
calculated (calcd) (%) for
C.sub.19H.sub.28Cl.sub.2N.sub.10.4.5HCl.1.8H.sub.2O: C, 34.36; H,
5.44; N, 21.10; C, 134.77; and O, 4.34; found C, 34.53; H, 5.59; N,
20.82; Cl, 34.90; and O, 4.28.
4.5 Synthesis of Salicylic Acid Derivative 17 of Formula Ia and
Related Compounds
[0303] ##STR30##
[0304] R, R.sup.5 and R.sup.6 refer to substitutents as defined for
substituted aryls.
[0305] Two methods (Method A and Method B) were used for synthesis
of the compounds represented by 17.
[0306] R.sup.1 and R.sup.2 refer to the substitutents as defined on
p. 3.
4.5.1 Method A: Synthesis of Salicylic Amide Substituted Aniline
Followed by Attachment of the Triazine Ring
[0307] Scheme 4 describes the general procedure for preparing
salicylic acid derivative of Formula Ia using method A.
Scheme 4
[0308] ##STR31##
[0309] R.sup.1 and R.sup.2 refer to substitutents as defined on p.
3.
[0310] R.sup.5 and R.sup.6 refer to substitutents as defined for
substituted aryls. In this general method, salicylic acid (18) was
first coupled with nitro-substituted or Fmoc-substituted aniline
(19) followed by the reduction of the nitro-group or deprotection
of the Fmoc group to give the salicylic amide substituted aniline
21. The key intermediate 21 was allowed to react with cyanuric
chloride 5 first, followed by treating with amine 22, and then 4 at
different temperatures in the presence of base to give the desired
product 17.
4.5.2 General Methods of Deprotection
[0311] (1) Simultaneous Removal of Boc and Benzyl-Ether Protecting
Groups (Scheme 5): ##STR32##
[0312] R refers to substitutents defined for substituted aryls.
[0313] The Boc/benzyl protected compound (23) was dissolved in a
mixture of thioanisole and TFA (1:4, 0.1 M) and shaken in a Teflon
septum capped vial for 3 h. LC-MS typically indicated complete
reaction at this point. The mixture was concentrated to an oil,
dissolved in aqueous 1.0 M HCl and washed with a mixture of
hexanes/EtOAc (4:1, 5 times). The aqueous phase was concentrated to
dryness under reduced pressure. Purification by reverse phase HPLC
followed by lyophilization twice from aqueous 0.25 M HCl gave the
desired product (24) as the HCl salt in moderate to high yield. (2)
Removal of Boc Protecting Groups (Scheme 6): ##STR33##
[0314] R.sup.6 and R.sup.7 refer to substitutents as defined for
substituted aryls with the proviso that R.sup.7 is not
--O-benzyl.
[0315] The Boc protected compound (25) was dissolved in a mixture
of MeOH (0.1 M) and 4 M HCl in dioxane (0.1 M). The mixture was
shaken in a Teflon septum capped vial for 16 h at room temperature.
A white precipitate was typically observed. LC-MS typically
indicated complete reaction at this point. The mixture was
concentrated to dryness under reduced pressure. Purification by
reverse phase HPLC followed by lyophilization twice from aqueous
0.25 M HCl gave the desired product (26) as the HCl salt in
moderate to high yield.
4.5.3 Method A-1: Amide Coupling of Salicylic Acid Chloride with
Nitroaniline in the Presence of K.sub.2CO.sub.3 or NaHCO.sub.3
(Scheme 7)
[0316] Scheme 7 describes the general procedure for preparing
salicylic acid derivative 34 of Formula Ia using method A-1.
##STR34## ##STR35##
[0317] R.sup.1 and R.sup.2 refer to substitutents as defined on p.
3.
[0318] R.sup.5 and R.sup.6 refer to substitutents as defined for
substituted aryls.
[0319] Into a salicylic acid (27) is added THF followed by cesium
carbonate (3 equiv.) and benzyl bromide (2 equiv.). The reaction
mixture is heated to reflux for 2-16 h. After cooling to room
temperature, cesium carbonate is filtered off through Celite and
the filtrate is dried under vacuum. The crude product is dissolved
in CHCl.sub.3 and washed twice with H.sub.2O via extraction. The
organic layer is dried over MgSO.sub.4, filtered and dried under
reduced pressure to give product 28. In some cases, flash
chromatography purification might be needed.
[0320] Compound 28 is dissolved in MeOH. NaOH (1.0 M) is added into
the reaction mixture. The reaction mixture was then heated to
65.degree. C. with stirring for 4 h. After the reaction was
complete, the mixture was cooled to room temperature and 1.0 N HCl
was added to neutralize the reaction mixture. The reaction mixture
is dried under vacuum and dissolved in CHCl.sub.3 and washed with
H.sub.2O via extraction. The organic layer is dried over
MgSO.sub.4, filtered and dried under vacuum again to give product
29.
[0321] Compound 29 is put into a round-bottom flask. Thionyl
chloride (20 equiv.) is added into the flask as a solvent followed
by 3 drops of DMF. The reaction mixture is heated to reflux for 3 h
under N.sub.2 atmosphere. The reaction mixture is concentrated
under reduced pressure. Toluene is added into the reaction vessel
and the solution is concentrated down again to help remove residual
thionyl chloride. This process is repeated once more. The crude
product is further dried on oil pump vacuum for half an hour to
give product 30. Compound 30 is immediately used in the next
step.
[0322] Compound 30 is dissolved in THF. K.sub.2CO.sub.3 (10 equiv.)
is added followed by nitroaniline 31 (1.5 equiv). The reaction
mixture is stirred at room temperature for 2 h. K.sub.2CO.sub.3 is
filtered off through Celite and the filtrate is concentrated under
vacuum. The residue is dissolved in CHCl.sub.3, and then washed
with H.sub.2O for extraction of salts. The organic layer is dried
and purified by flash chromatography to give product 32.
[0323] Compound 32 is dissolved in ethanol and is shaken at
80.degree. C. for 5-15 minutes (if not soluble, DMF is added) in an
opened vial. In the meantime the heating plate is heated to
55.degree. C. The sample vial is then placed on the heating plate
at 55.degree. C. without cap. NH.sub.2NH.sub.2 (excess) is added
and immediately followed by Raney Nickel (a catalytic amount, 50%
slurry in water). The vial is let sit on the heating plate at
55.degree. C. for 15-20 minutes until bubbling stops. After
filtering off the solid through a plug of Celite and washing with
MeOH, the filtrate is dried under vacuum until very dry to give the
product 33. Compound 33 is immediately used in the next step in
triazine chemistry as shown in step 3 of scheme 4. In some cases,
purification by flash chromatography is needed.
[0324] At the end of synthesis of the final product and prior to
biological testing, the benzyl group is removed by the treatment
with thioanisole (10 equiv), methanesulfonic acid (16 equiv) and
TFA (as a solvent) in an ice-water bath for 1 h to give compound
34. After completion of the reaction, the solvent is evaporated in
vacuo and the resulting residue is purified by HPLC to give the
final product for biological testing. The Boc groups are also
removed under this condition.
4.5.4 EXAMPLE 4
Synthesis of Salicylic Acid Derivative 44 Using Method A-1 where
K.sub.2CO.sub.3 was Used During the Salicylic Amide Formation
(Scheme 8)
[0325] ##STR36## ##STR37##
Step 1: 2,4-Bis-benzyloxy-benzoic acid benzyl ester (36)
[0326] 2,4-dihydroxy-benzoic acid (35) (2 g, 13 mmol) in THF (250
mL) was mixed with cesium carbonate (16.9 g, 52 mmol) and benzyl
bromide (6.2 mL, 52 mmol). The reaction mixture was refluxed
overnight and then cooled down to room temperature. Cesium
carbonate was filtered off through filter paper. The solvent was
removed under reduced pressure. Liquid-liquid extraction was
performed using 200 mL of CHCl.sub.3 and H.sub.2O (100 mL.times.3).
The organic layer was dried over MgSO.sub.4. After filtering off
the MgSO.sub.4, the organic layer was concentrated to give compound
36 (4.3 g) as a solid. LC-MS (ESI): m/e=425.2 [M+1].sup.+
Step 2: 2,4-Bis-benzyloxy-benzoic acid (37)
[0327] NaOH (1 N) (150 mL) was added to compound 36 (4.3 g) in MeOH
(50 mL). The reaction mixture was heated to 65.degree. C. with
stirring for 48 h. After the reaction mixture was cooled down to
room temperature, 1.0 M HCl (200 mL) was added to neutralize the
reaction mixture. The solvent was concentrated under reduced
pressure. The residue was extracted with CHCl.sub.3 and H.sub.2O.
The combined organic layer was dried over MgSO.sub.4. After the
MgSO.sub.4 was filtered off, the solvent was removed under reduced
pressure. The residue was purified by flash chromatography to give
the compound 37 (1.3 g) as a solid with total yield of 38.92% for 2
steps. LC-MS (ESI): m/e=335.2 [M+1].sup.+
Step 3: 2,4-Bis-benzyloxy-benzoyl chloride (38)
[0328] Compound 37 (1 g, 3 mmol) was mixed with thionyl chloride
(7.2 g, 60 mmol) and 3 drops of DMF. The reaction mixture was
refluxed for 3 h under nitrogen. After cooling down to room
temperature, thionyl chloride was removed under reduced pressure.
Toluene (5 mL) was then added, and the mixture was dried under
reduced pressure again. This process was repeated twice to ensure
all the excess of thionyl chloride was removed. The compound 38 was
further dried under high vacuum for half an hour and was used
directly in the next step without purification.
Step 4: 2,4-Bis-benzyloxy-N-(2-hydroxy-4-nitro-phenyl)-benzamide
(39)
[0329] Compound 37 (1 g, 3 mmol) was dissolved in THF (100 mL).
K.sub.2CO.sub.3 (2 g, 15 mmol) was added followed by
2-amino-5-nitro-phenol (693 mg, 4.5 mmol). The reaction mixture was
allowed to stir at room temperature overnight. K.sub.2CO.sub.3 was
filtered off though filter paper. The solvent was removed under
reduced pressure. Liquid-liquid extraction was performed using
CHCl.sub.3 (100 mL) and H.sub.2O (50 mL). The organic layer was
dried over MgSO.sub.4. After MgSO.sub.4 was filtered off, the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography to give compound 39 (786 mg, 55.7%
isolated yield). LC-MS (ESI): m/e=471.1 [M+1].sup.+
Step 5: N-(4-Amino-2-hydroxy-phenyl)-2,4-bis-benzyloxy-benzamide
(40)
[0330] Compound 39 (470 mg, 1 mmol) was dissolved in MeOH (15 mL)
and THF (15 mL). Raney Nickel (50% slurry in water) (2 mL) was
added to the reaction mixture followed by anhydrous hydrazine (1
mL). The reaction mixture was stirred at room temperature for 30
minutes until the bubbling was stopped. The solid was filtered off
through Celite under reduced pressure and washed with MeOH. The
solvent was removed under reduced pressure. Liquid-liquid
extraction was performed using CHCl.sub.3 (15 mL) and H.sub.2O (8
mL.times.2). The organic layer was dried over MgSO.sub.4, filtered
and concentrated to give the compound 40 (263.8 mg, 59.9% crude
yield) LC-MS (ESI): m/e=441.1 [M+1].sup.+
Step 6:
2,4-Bis-benzyloxy-N-[4-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-2-h-
ydroxy-phenyl]-benzamide (41)
[0331] NaHCO.sub.3 (300 mg, 3.58 mmol) was added to a solution of
compound 40 (263.8 mg, 598 .mu.mol) in THF (5 mL). Cyanuric
chloride (110 mg, 598 .mu.mol) in THF (3 mL) was added to the
reaction mixture in an ice water bath. The reaction mixture was
stirred from 0.degree. C. to room temperature for 30 minutes. The
reaction progress was monitored by TLC and LC-MS. The reaction
mixture was directly used in the next step. LC-MS (ESI): m/e=588.2
[M+H].sup.+
Step 7:
(1-{4-[4-(2,4-Bis-benzyloxy-benzoylamino)-3-hydroxy-phenylamino]-6-
-chloro-[1,3,5]triazin-2-yl}-5-tert-butoxycarbonylamino-piperidin-3-yl)-ca-
rbamic acid tert-butyl ester (42)
[0332] (3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (190
mg, 598 .mu.mol) was added into the above reaction mixture. The
reaction mixture was stirred at room temperature for about five
hours. The reaction progress was monitored by TLC and LC-MS. The
reaction mixture was used directly in the next step without workup.
LC-MS (ESI): m/e=867.5 [M+H].sup.+
[0333] Step 8:
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (190 mg,
598/mol) was added into the reaction mixture from the previous
step. The mixture was heated at 80.degree. C. overnight. The
solvent was removed under reduced pressure. Liquid-liquid
extraction was performed using CHCl.sub.3 and H.sub.2O. The organic
layer was dried over MgSO.sub.4. After filtration, the solvent was
removed under reduced pressure. The resulting solid was purified by
flash chromatography to give the intermediate 43 (263.6 mg, 33.6%
isolated yield for 3 steps) as a solid. LC-MS (ESI): m/e=1146.7
[M+H].sup.+
Step 9:
N-{4-[4,6-Bis-(3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamin-
o]-2-hydroxy-phenyl}-2,4-dihydroxy-benzamide (44)
[0334] Compound 43 (263.6 mg, 230 .mu.mol) was dissolved in TFA (2
mL). Thioanisole (291 mg, 2.3 mmol) was then added. The mixture was
shaken at room temperature for 2 h. The solvent was removed under
reduced pressure. The crude was then purified by HPLC purification
to give the desired compound 44 (40.6 mg, 18.7% isolated yield).
LC-MS (ESI): m/e=566.5 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta.=1.82 (q, 2H, J=11.2 Hz), 2.74 (t, 2H, J=10.8
Hz), 2.88 (s, br, 2H), 3.26 (m, 4H), 4.96 (s, br, 2H), 5.40 (s,
2H), 6.41 (m, 2H), 7.04 (d, 1H, J=8.8 Hz), 7.57 (d, 1H, J=2.4),
7.87 (d, 1H, J=8.4 Hz), 8.15 (d, 1H, J=8.4 Hz), 8.71 (d, 10H,
J=43.2 Hz), 9.08 (s, 1H), 10.04 (s, 2H), 10.36 (s, 1H);
[0335] Elemental analysis calculated (%) for
C.sub.26H.sub.35N.sub.11O.sub.4.7H.sub.2O.7HCl: C, 32.98; H, 5.96;
N, 16.27. found: C, 33.36; H, 5.95; N, 16.11.
4.5.5 EXAMPLE 5
Synthesis of Keto Acid Derivative 49 Using Method A-1 where
NaHCO.sub.3 was Used in the Amide Formation
[0336] ##STR38##
[0337] The .alpha.-keto acid chloride (45) (673.5 mg, 3.24 mmol),
2-hydroxy-4-nitro-aniline (46) (0.5 g, 3.24 mmol), NaHCO.sub.3
(1.36 g, 16.22 mmol) and 10 mL of THF were mixed and the mixture
was stirred at room temperature for 2 hours. The additional
.alpha.-keto acid chloride (45) (100 mg, 0.48 mmol) was added.
After stirring for 1 hour at room temperature, the TLC result
confirmed the completion of the reaction. EtOAc (30 mL) and
H.sub.2O (20 mL) were added. After liquid-liquid extraction, the
two layers were separated. HCl (1.0 M, 13 mL) was then added into
the aqueous layer to neutralize it. The product in the aqueous
layer was extracted out by EtOAc (50 mL.times.3) via liquid-liquid
extraction. The organic layers were combined, dried over anhydrous
Na.sub.2SO.sub.4 overnight. After filtration, the solvent was
concentrated under reduced pressure to give a yellow solid. After
recrystallization in MeOH, 957 mg of the pure desired product (47)
was obtained in 91.1% isolated yield. Multiple batches of this
reaction had been run. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta.=12.40 (s, 1H), 11.50 (1, s, br, 1H), 10.08 (s, 1H), 8.97
(d, J=3.2 Hz, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.22-8.28 (m, 1H), 7.83
(dd, J=8.8 Hz, J.sub.2=2.6 Hz, 1H), 7.73 (d, J=2.8 Hz, 1H),
7.53-7.58 (m, 1H), 7.26-7.31 (m, 2H).
[0338] Compound 47 (1.36 g, 4.18 mmol), Fe powder (702.2 mg, 12.54
mmol), 25 mL of EtOH and saturated NH.sub.4Cl (15 mL) were mixed.
The mixture was refluxed for 3.5 hours. TLC result confirmed the
completion of the reaction. The reaction mixture was concentrated
on a rotary evaporator without filtering off the iron powder. The
residue was directly added on a silica gel column and was purified
by flash chromatography using 100% EtOAc as eluting solvent to give
1.065 g (86.6% isolated yield) desired product (48) as a yellow
solid with HPLC purity of 100% by ELSD. LC-MS: m/e 296.3
[M+1].sup.+ (expect ms: 295.1). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta.=12.26 (s, br, 1H), 9.77 (s, br, 1H), 9.57
(s, 1H), 8.98 (s, 1H), 8.22-8.27 (m, 1H), 7.80 (d, J=8.8 Hz, 1H),
7.50-7.56 (m, 1H), 7.22-7.29 (m, 2H), 6.20 (d, J=2.4 Hz, 1H), 6.05
(dd, J=8.6 Hz, J.sub.2=2.2 Hz, 1H), 4.98 (s, 2H).
[0339] Aniline 48 underwent the triazine chemistry using the same
method as described in step 3 in Scheme 800, where
NH(R.sup.3)R.sup.4 is
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine, with
.sup.iPr.sub.2NEt as the base. The final product (49) was obtained
as the HCl salt in 41.9% yield (from compound 48 to compound 49,
calculated based on the molecular weight of the HCl salt obtained
by elemental analysis). Elemental analysis calculated (%) for
C.sub.29H.sub.36N.sub.12O.sub.3.5HCl 4H.sub.2O: C, 40.74; H, 5.78;
N, 19.66. found: C, 41.08; H, 5.40; N, 19.57. LC-MS: m/e 601.4
[M+1].sup.+ (expect ms: 600.30). .sup.13C NMR (500 MHz, D.sub.2O):
.delta.=177.652, 157.063, 144.909, 138.602, 134.505, 134.215,
125.041, 122.906, 122.055, 120.294, 118.989, 118.641, 111.240,
110.694, 109.491, 104.716, 44.006, 43.504 and 31.446. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta.=12.39 (d, J=2.8 Hz, 1H), 10.35 (s,
br, 1H), 9.74 (s, 1H), 9.15 (s, br, 1H), 8.98 (d, J=3.2 Hz, 1H),
8.44-8.74 (m, 12H), 8.22-8.28 (m, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.60
(d, J=2 Hz, 1H), 7.52-7.57 (m, 1H), 7.24-7.30 (m, 2H), 7.07 (d, J=8
Hz, 1H). 5.30-5.43 (m, 2H), 4.90 (s, br, 2H), 3.06-3.30 (m, 4H),
2.78-2.92 (m, 2H), 2.62-2.78 (m, 2H), 2.40-2.54 (m, 2H), 1.76 (q,
J=11.6 Hz, 2H).
4.5.6 Method A-2: Amide Coupling of Salicylic Acid with
Nitroaniline Using PBr.sub.3 Reagent
[0340] Scheme 10 describes the general procedure of synthesis of
compound 53 of Formula Ia using method A-2. ##STR39##
[0341] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0342] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0343] The following reactions were run in either direct fashion or
parallel fashion. In case of the parallel synthesis, some reactions
were run on the MiniBlock.TM. XT system (supplied from
Mettler-Toledo AutoChem, Inc) and some reactions were run in a
silicon oil bath.
[0344] Equivalent amounts of compound 49 and compound 50 in 0.1 M
xylene or a mixture of xylene and NMP were mixed and placed in test
tubes that were placed on the MiniBlock.TM. XT system and were
heated to 130.degree. C. A fresh made solution of PBr.sub.3 (0.4
equivalent) was added at 130.degree. C. and the mixture was
continued to heat at 130.degree. C. for 0.5-4 hours. After cooling,
the reaction mixture was dried under reduced pressure. The residue
was purified by liquid-liquid extraction (CHCl.sub.3/aqueous
saturated NaHCO.sub.3, brine). The LC-MS result confirmed that the
organic layer contained the desired product. The organic layer was
then dried under reduced pressure to give the desired product
51.
[0345] Compound 51 was dissolved in THF and MeOH and the mixture
was heated to 50.degree. C. Excess of 98% NH.sub.2NH.sub.2 (120
.mu.L for 600 .mu.mol reaction scale) and excess of Raney Nickel
(50% slurry in H.sub.2O) (400 .mu.L for 600 .mu.mol reaction scale)
was added and the mixture was let sit at 50.degree. C. for 15-30
minutes. Upon the completion of the nitro-reduction reaction
confirmed by LC-MS, the reaction mixture was cooled and the
inorganic solid was filtered off through a plug of silica gel and
Celite. The filtrate was concentrated under reduced pressure and
was further purified by flash chromatography on silica gel using a
gradient of hexane and EtOAc to give the pure desired aniline
52.
[0346] Aniline (52) was used in the triazine chemistry as shown in
the step 3 of Scheme 4 to give the desired product 53.
4.5.7 EXAMPLE 6
Synthesis of Salicylic Acid Derivative 61 Using Method A-2 (Scheme
11)
[0347] ##STR40## ##STR41##
[0348] 4-Dimethylamino-2-hydroxy-benzoic acid (54) (55 mg, 300
.mu.mol) and 2-chloro-4-nitro-aniline (55) in xylene (4 mL) were
heated to reflux. PBr.sub.3 (12 .mu.L, 120 .mu.mol) was added drop
wise. The reaction mixture was refluxed for another 3 h and then
cooled down to room temperature. The solvent was removed under
reduced pressure. Liquid-liquid extraction with CHCl.sub.3 (4 mL)
and H.sub.2O (2 mL.times.3) followed by flash chromatography
purification gave the compound 56 (71 mg, 70.6%) as a solid. LC-MS
(ESI): m/z=336.2 [M+1].sup.+
[0349] Compound 56 (71 mg, 212 .mu.mol) was dissolved in MeOH (2
mL) and THF (2 mL). Raney Nickel (50% slurry in water) (500 .mu.L)
was added to the reaction mixture followed by anhydrous hydrazine
(30 .mu.L, 848 .mu.mol). The reaction mixture was stirred for 15-20
minutes until the bubbling stopped. The solid was filtered off
celite under nitrogen and washed with MeOH. The solvent was removed
under reduced pressure. The solid was extracted with CHCl.sub.3 (3
mL) and H.sub.2O (1.5 mL.times.2). The organic layer was dried over
MgSO.sub.4. After filtration, the solvent was evaporated under
vacuum to give 57 (24 mg, 37%) as a solid. LC-MS (ESI): m/z=306.2
[M+1].sup.+
[0350] NaHCO.sub.3 (40 mg, 468 .mu.mol) was added into a solution
of compound 57 (24 mg, 78 .mu.mol) in THF (3 mL). Cyanuric chloride
(5) (16 mg, 78 .mu.mol) in THF (1 ml) was added into the reaction
mixture under water-ice bath. The reaction mixture was stirred from
0.degree. C. to room temperature for 40 minutes. The reaction was
monitored by TLC and LC-MS. The reaction mixture containing 58 was
directly used in next step.
[0351] (3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4)
(25 mg, 78 .mu.mol) was added into the above reaction mixture. The
reaction mixture was stirred at room temperature for 5 hours. The
reaction was monitored by TLC and LC-MS and the desired product 59
was confirmed by LC-MS. The reaction mixture was directly used in
next step.
[0352] The reaction mixture from the previous step was treated with
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (25 mg,
78 .mu.mol) and heated at 80.degree. C. overnight. The solvent was
removed under reduced pressure. Liquid-liquid extraction was
performed using CHCl.sub.3 (4 mL) and H.sub.2O (2 mL.times.2). The
organic layer was dried over MgSO.sub.4, filtered. The solvent was
removed under reduced pressure. The resulting solid was purified by
flash chromatography to give the compound 60 as a solid. LC-MS
(ESI): m/e=1011.4 [M+1].sup.+
[0353] A solution of compound 60 in MeOH (2 mL) was treated with 4
M HCl in dioxane (3 mL) to give the final product 61 (10.4 mg,
16.7%, 13 .mu.mol) (4 steps) that was purified by HPLC. LC-MS
(ESI): m/z=611.4 [M+1].sup.+; .sup.1H NMR (400 MHz, D.sub.2O): 1.72
(q, 2H, J=12.4 Hz), 2.50 (s, br, 2H), 2.83 (t, 4H, J=12 Hz), 3.05
(s, 6H), 3.34 (s, br, 4H), 4.89 (s, br, 4H), 6.69 (s, 1H), 6.80 (m,
1H), 7.465 (s, 2H), 7.65 (m, 1H), 7.81(m, 1H)
4.5.8 Method A-3: Amide Coupling of Salicylic Acid with
NHBoc-Substituted Aniline Using HOBt/EDCI (Scheme 12)
[0354] Scheme 12 describes a general procedure to synthesis of
salicylic acid derivative 5 of Formula Ia using method A-3.
##STR42##
[0355] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0356] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0357] In this general method, the salicylic acid (27) was coupled
with the NHFmoc-substituted aniline (62) using HOBt/EDCl in the
presence of base to form the salicylic amide 63. De-protecting the
Fmoc-group using piperidine gave the key salicylic amide
substituted aniline 52 that underwent the same triazine chemistry
as that described in step 3 of Scheme 4 to give the desired product
53.
4.5.9 EXAMPLE 7
Synthesis of Salicylic Acid Derivative 73 of Formula Ia Using
Method A-3 (Scheme 13)
[0358] ##STR43##
[0359] Compound 64 (101.6 mg, 304.2 .mu.mol), compound 65 (133 mg,
304.2 .mu.mol) and 1.0 M of .sup.iPr.sub.2NEt in THF were mixed.
HOBt (93.2 mg, 608.4 .mu.mol) in 1.2 mL of THF was added and the
resulting mixture was shaken at room temperature for 5 minutes.
EDCl (117 mg, 608.4 .mu.mol) in 2.4 mL of CH.sub.2Cl.sub.2 was then
added and the mixture was shaken at room temperature for 16 hours.
LC-MS result confirmed the completion of the reaction. The mixture
was concentrated on a rotary evaporator and the residue was
purified by liquid-liquid extraction using CHCl.sub.3 (6 mL), 15%
aqueous NaHCO.sub.3 (3 mL) and H.sub.2O (3 mL) to give 253.5 mg of
the desired product (66) as a brown puffy solid. LC-MS: m/e 753.4
[M+1].sup.+.
[0360] The compound 66 was dissolved in 2.5 mL of THF. Piperidine
(1 mL, 10.1 mmol), was added, and the mixture was shaken at room
temperature for 3.5 hours. LC-MS result confirmed the completion of
the reaction. The mixture was concentrated under reduced pressure
and the residue was purified by flash chromatography using a
gradient of hexane and EtOAc to give 95.4 mg (179.8 .mu.mol) of the
desired product 67 as a gray solid in 59.1% isolated yield for 2
steps. LC-MS: m/e 531.3 [M+1].sup.+.
[0361] Compound 67 (95.4 mg, 179.8 .mu.mol) was dissolved in 3 mL
of THF. NaHCO.sub.3 (91 mg, 1.08 mmol) was added followed by 4
drops of water. The mixture was cooled to -78.degree. C. using a
dry ice-acetone bath. A solution of cyanuric chloride (5) (33.2 mg,
180 .mu.mol) in 800 .mu.L of THF was added with stirring. The
reaction mixture was stirred at -78.degree. C. to room temperature
overnight. LC-MS result confirmed the completion of the reaction
and the identity of the desired product 68 with the HPLC purity of
100% by ELSD. LC-MS: m/e 678.2 [M+1].sup.+.
[0362] A slurry of amine 4 (57 mg, 180.7 .mu.L) in 800 .mu.L of THF
was added into the above reaction mixture containing compound 68.
The resulting mixture was stirred at room temperature for 4.5
hours. LC-MS confirmed the completion of the reaction and the
identity of the desired product 69. LC-MS: m/e 957.6 [M+1].sup.+
(expect ms: 956.4).
[0363] A mixture of amine 70 (85 mg, 269.5 .mu.mol) in 1.0 mL of
THF was added. The reaction mixture was heated at 80.degree. C.
with stirring overnight. The solvent was removed under reduced
pressure and the residue was purified by liquid-liquid extraction
using CH.sub.2Cl.sub.2 (4 mL) and H.sub.2O (2 mL.times.2). The
organic layer was concentrated under reduced pressure and the
residue was purified by flash column on silica gel using a gradient
of hexane and EtOAc to give 142.1 mg (115 .mu.mol) of the desired
product 71 as a pale pink solid in 90.4% isolated yield for 2 steps
(after considering 35.6 mg of the starting material 69 recovered
during the purification).
[0364] Compound 71 (142.1 mg, 115 .mu.mol) was dissolved in 12 mL
of methanol. The solution was degassed by alternately connecting
the system with vacuum, then N.sub.2 for three times. Pd/C (dry, 10
wt %, 300 mg) was added under N.sub.2 atmosphere. A balloon
containing H.sub.2 was then attached to the reaction system. The
reaction mixture was stirred at room temperature for 3 hours under
slightly positive pressure of H.sub.2. The LC-MS result of the
reaction mixture confirmed the identity of the desired product
(72). MeOH (10 mL) was added to dilute the reaction mixture, and
the inorganic solid was filtered off through Celite twice. The
solvent was evaporated under reduced pressure to give 75.9 mg (78.6
.mu.mol, 68.4% isolated yield) of the desired product 72 as a dark
gray solid with HPLC purity of 100% by ELSD.
[0365] Compound 72 (75.9 mg, 78.6 .mu.mol) was dissolved in 3 mL of
MeOH. HCl (4.0 M in dioxane, 3 mL) was added and the reaction
mixture was shaken at room temperature overnight. The solvent was
evaporated under reduced pressure to give 62.4 mg of crude product
73 as a pale gray solid. The crude product was purified by
reverse-phase HPLC using a gradient of CH.sub.3CN and H.sub.2O to
give 38.7 mg (44.3 .mu.mol, 56.3% yield based on the molecular
weight determined by elemental analysis) of the desired pure
product 73 as the HCl salt as a very pale yellow solid. LC-MS: m/e
566.3 [M+1].sup.+ (expect ms: 565.29). Elemental analysis
calculated (%) for C.sub.26H.sub.35N.sub.11O.sub.4.5.5HCl.6H.sub.2O
(874.25): C, 35.72; H, 6.05; N, 17.62. found: C, 35.93; H, 5.74;
17.39. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=10.39 (s, 1H),
10.00-10.28 (m, 3H), 8.48-8.80 (m, 12H, 4 NH.sub.3.sup.+),
8.10-8.22 (m, 1H), 7.85 (d, 1H), 7.20-7.50 (m, 1H), 7.00 (s, br,
1H), 6.40 (s, 1H), 6.36 (d, 1H), 5.20-5.40 (m, 1H), 4.85-5.05 (m,
1H), 3.20-3.60 (m, 8H), 2.70-2.95 (m, 2H), 2.40-2.65 (m, 1H),
1.70-2.00 (m, 3H).
4.5.10 Method A4: Amide Coupling of Salicylic Acid with
NHBoc-Substituted Aniline Using
2-(1H-Benzotriazol-1-yl)-1,1,3,3-Tetramethyl-uronium
Hexafluorophosphate (HBTU) (Scheme 13a)
[0366] Scheme 13a describes the general procedure for preparing
salicylic acid derivative 53 of Formula Ia using method A-4.
##STR44##
[0367] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0368] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0369] In this general method, HBTU was used as the coupling
reagent in the first step, whereas other steps are the same as that
in Scheme 12.
4.5.11 EXAMPLE 8
Synthesis of the Salicylic Acid Derivative (79) of Formula Ia Using
Method A4 (Scheme 14)
[0370] ##STR45## ##STR46##
[3-Benzyloxy-4-(4-fluoro-2-hydroxy-benzoylamino)-phenyl]-carbamic
acid 9H-fluoren-9-ylmethyl ester (75)
[0371] 4-Fluoro-2-hydroxy-benzoic acid (74) (0.15 g, 0.961 mmol)
was dissolved in DMF (6 mL),
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium
hexafluorophosphate (HBTU) (0.382 g, 1.01 mmol) was added followed
by .sup.iPr.sub.2EtN (0.167 mL, 0.961 mmol) and the mixture was
shaken in a Teflon septum capped 40 mL I-Chem vial at room
temperature for 25 minutes. (4-Amino-3-benzyloxyphenyl)-carbamic
acid 9H-fluoren-9-ylmethyl ester (0.419 g, 0.961 mmol) was added
and the mixture was shaken at room temperature for 16 h. LC-MS
indicated complete coupling at this point. The mixture was diluted
with EtOAc (50 mL), washed with water (25 mL), aqueous saturated
NaHCO.sub.3 (25 mL) and brine (25 mL) via extraction, dried over
MgSO.sub.4. The organic layer was concentrated to give a yellow
oil. Purification by flash chromatography using a gradient of
hexane and EtOAc (eluding with 15-100% EtOAc in hexane in 30
minutes) gave the desired product (75) upon concentration (0.192 g,
0.334 mmol, 35% yield). LC-MS (ESI): (exact mass: 574.19) m/e=575.2
[M+1].sup.+ (100%), 1149.5 [2M+1].sup.+ (25%).
N-(4-Amino-2-benzyloxy-phenyl)-4-fluoro-2-hydroxy-benzamide
(76)
[0372]
[3-Benzyloxy-4-(4-fluoro-2-hydroxy-benzoylamino)-phenyl]-carbamic
acid 9H-fluoren-9-yl-methyl ester (75) (0.192 g, 0.334 mmol) was
dissolved in a mixture of THF (3 mL) and DMF (1 mL). Piperidine
(0.57 g, 6.68 mmol) was added. The mixture was shaken at room
temperature in a Teflon septum capped vial for 20 minutes. TLC
indicated complete de-protection at this point. The mixture was
concentrated to give an oil. Purification by flash chromatography
using a gradient of hexane and EtOAc (5-100% EtOAc in hexane for 25
minutes followed by 100% EtOAc for 5 minutes) gave the desired
product (76) upon concentration (0.060 g, 0.170 mmol, 51% yield).
LC-MS (ESI): (exact mass: 352.12) m/e=353.3 [M+1].sup.+ (100%),
705.3 [2M+1].sup.+ (5%).
N-[2-Benzyloxy-4-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-phenyl]-4-fluoro--
2-hydroxy-benzamide (77)
[0373] N-(4-Amino-2-benzyloxy-phenyl)-4-fluoro-2-hydroxy-benzamide
(76) (0.060 g, 0.170 mmol) was dissolved in THF (3.4 mL),
NaHCO.sub.3 (0.086 g, 1.02 mmol) was added and the mixture was
chilled on a dry-ice/acetone bath. Cyanuric chloride (5) (0.032 g,
0.184 mmol) was dissolved in THF (2 mL) and added directly to the
chilled solution while stirring. The ice bath was removed and the
mixture continued to stir while warming to room temperature for 1
h. TLC (R.sub.f: 0.8 compared to R.sub.f: 0.35 for compound 76 in
1:1 hexane/EtOAc, single spot) indicated complete reaction at this
point. The reaction mixture was used immediately in the next step
without purification or characterization.
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-pipe-
ridin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-4-fluoro-2-hydroxy-benzamide
(78)
[0374] (3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidine (4)
(0.107 g, 0.34 mmol) was suspended in DMF (2 mL), sonicated for 2
minutes and added to the crude reaction mixture containing
N-[2-Benzyloxy-4-(4,6-dichloro-[1,3,5]-triazin-2-ylamino)-phenyl]-4-fluor-
o-2-hydroxy-benzamide (77). The mixture was heated to 80.degree. C.
for 16 h. LC-MS and TLC (R.sub.f: 0.4 compared to R.sub.f: 0.8 for
compound 77 in 1:1 hexane/EtOAc, single spot) indicated complete
reaction at this point. The mixture was diluted with EtOAc (50 mL),
washed with aqueous saturated NaHCO.sub.3 (25 mL), water (25 mL)
and brine (25 mL) via extraction, dried over MgSO.sub.4 and
concentrated to give a brown oil. Purification by flash
chromatography on silica gel using a gradient of hexane and EtOAc
(15-100% EtOAc in hexane) gave the desired product (78) upon
concentration (0.126 g, 0.119 mmol, 70% total yield for two steps).
LC-MS (ESI): (exact mass: 1057.54) m/e=1058.8 [M+1].sup.+
(100%).
N-[4-(4-fluoro-2-hydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine (79)
[0375]
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylami-
no)-piperidin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-4-fluoro-2-hydroxy-b-
enzamide (78) (0.126 g, 0.119 mmol) was dissolved in a mixture of
thioanisole and TFA (1:4, 5 mL) and shaken in a Teflon septum vial
for 2.5 h. LC-MS indicated complete reaction at this point. The
mixture was concentrated (to about 1 mL), dissolved in aqueous 1.0
M HCl (15 mL) and washed with a mixture of hexane/EtOAc (4:1,
5.times.5 mL). The aqueous phase was concentrated to give a beige
powder. Purification by reverse phase HPLC followed by
lyophilization twice from aqueous 0.25 M HCl gave the desired
product (79) as a white powder as the HCl salt [0.063 g, 075 mmol
(calculated based on the molecular weigh of the HCl salt determined
by elemental analysis), 63% yield, 7.8% total yield for 5 steps].
LC-MS (ESI): (exact mass: 567.28) m/e=568.3 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.78 (q, 2H, J=12 Hz), 2.71
(t, 2H, J=11.2 Hz), 2.86 (t, 2H, J=11.2 Hz), 3.18 (m, 4H), 4.91 (s,
br, 2H), 5.36 (s, br, 2H), 6.76-6.85 (m, 2H), 6.96 (d, 1H, J=8.4
Hz), 7.59 (s, 1H), 8.05 (t, 1H, J=8 Hz), 8.15 (d, 1H, J=9.2 Hz),
8.60 (s, br, 7H), 8.69 (s, br, 7H), 9.13 (s, 1H), 10.51 (s, 1H).
Elemental analysis calculated (%) for
C.sub.26H.sub.34FN.sub.11O.sub.3.7H.sub.2O.4HCl: C, 37.20; H, 6.24;
N, 18.35. found: C, 36.87; H, 6.36; N, 18.45.
4.5.12 Method B: To Make the Triazine Substituted Aniline
Intermediate First Followed by the Amide Coupling with Salicylic
Acid or Activated Salicylic Acid (Scheme 15)
[0376] Scheme 15 describes the general procedure for preparing
salicylic acid derivative 3 of Formula Ia using method B.
##STR47##
[0377] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0378] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0379] In this general method, the triazine-substituted aniline
(80) is coupled with the salicylic acid (27) or activated salicylic
acid (81) to give the desired compound 53. Removing the protecting
groups in compound 53 (as shown in Scheme 5 & 6) gives the
final products as the HCl salt.
4.5.13 Method B-1: Amide Coupling Using HOBt/EDCI (Scheme 16)
[0380] Scheme 16 describes the general procedure for preparing
salicylic acid derivative 82 of Formula Ia using method B-1.
##STR48## R.sup.1 and R.sup.2 refer to substitutents defined on p.
3. R.sup.5 and R.sup.8 refer to substitutents as defined for
substituted aryls with the proviso that R.sup.8 does not include
strong e-withdrawing groups such as the NO.sub.2 group.
[0381] In this general method, a solution of 4 equivalents of
.sup.iPr.sub.2NEt in THF was added to a mixture of 1 equivalent of
salicylic acid (27) and 1 equivalent of aniline (80) in THF
followed by 4 equivalent of HOBt in THF. After shaking 5 minutes, 4
equivalent of EDCl in CH.sub.2Cl.sub.2 was added. The reaction
mixture was shaken at room temperature for 4 h. Another equivalent
of salicylic acid was then added. The reaction mixture was allowed
to shake at room temperature overnight. The solvent was removed
under reduced pressure. The residue was dissolved in CHCl.sub.3.
The organic solvent washed with 10% NaHCO.sub.3 and H.sub.2O via
extraction, dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. After flash chromatography purification, compound
53 was obtained.
4.5.14 EXAMPLE 9
Synthesis of Salicylic Acid Derivative Using Method B-1 (Scheme
17)
[0382] ##STR49##
[0383] .sup.iPr.sub.2NEt (115 .mu.L, 652 .mu.mol) in THF (1 mL) was
added to a mixture of 4-methylsalicylic acid (84) (24.8 mg, 163
.mu.mol) and aniline (83) (150 mg, 163 .mu.mol) in THF (2 mL)
followed by HOBT (99.85 mg, 652/.mu.mol) in THF (2 mL). After
stirring for 5 minutes, EDCl (124.99 mg, 652 .mu.mol) in
CH.sub.2Cl.sub.2 (2 mL) was then added. The reaction mixture was
shaken at room temperature for 4 hours. Another 2 equivalents of
4-methylsalicylic acid (84) (49.6 mg, 326 .mu.mol) was added. The
reaction mixture was allowed to shake at room temperature
overnight. The solvent was removed under reduced pressure. The
solid was dissolved in CHCl.sub.3 (4 mL). The organic solvent
washed with 10% aqueous NaHCO.sub.3 (2 ml) and H.sub.2O (2
mL.times.2). The organic layer was dried over MgSO.sub.4, filtered
and the solvent was removed under reduced pressure. After flash
chromatography purification, compound 85 (140 mg, 81.5% isolated
yield) was obtained as a solid. LC-MS (ESI): m/e=1054.5
[M+1].sup.+
[0384]
N-(4-[4,6-Bis-(3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamin-
o]-2-hydroxy-phenyl)-2-hydroxy-4-methyl-benzamide (86): Compound 85
(140 mg, 132 .mu.mol) was dissolved in TFA (2 mL). Thioanisole (165
mg, 1.32 mmol) was then added. The mixture was shaken at room
temperature for 2 h. The solvent was removed under the reduced
pressure. The solid was then purified by HPLC purification and
converted to HCl salt by treating with HCl to give the desired
product 86 (31.6 mg, 28.63%). LC-MS (ESI): m/e=564.5 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.82 (q, J=12.4 Hz,
2H), 2.32 (S, 3H), 2.74 (t, J=10.4 Hz, 2H), 2.88 (t, J=10.4 Hz,
2H), 3.26 (m, 4H), 4.96 (s, br, 2H), 5.43 (d, J=10.8 Hz, 2H), 6.81
(t, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H),
7.93(d, J=7.6 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.45-8.80 (m, 12H),
9.10 (s, 1H), 10.11 (s, 1H), 10.58 (s, 1H), 11.63 (s, 1H).
Elemental analysis calculated (%) for
C.sub.27H.sub.37N.sub.11O.sub.3.5H.sub.2O.5HCl: C, 38.79; H, 6.27;
N, 18.43. found: C, 39.00; H, 5.95; N, 18.03.
4.5.15 Method B-2: Amide Coupling Using HBTU (Scheme 17a)
[0385] Scheme 17a describes the general procedure for preparing
salicylic acid derivative of Formula Ia using method B-2.
##STR50##
[0386] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0387] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0388] The salicylic acid (27) (1 equiv.), .sup.iPr.sub.2EtN (1.1
equiv.) and HBTU (1.1 equiv.) were dissolved in DMF (0.2 M) and
shaken in a Teflon septum-capped vial for 25 minutes. The aniline
(80) (1 equiv.) was added and the mixture was heated to 80.degree.
C. for 3-16 h. Upon completion of the reaction, the mixture was
concentrated under reduced pressure and the crude product was
dissolved in CHCl.sub.3, washed with aqueous saturated NaHCO.sub.3
and water via extraction. The organic layer was concentrated to
dryness in vacuo. Purification by flash chromatography on silica
gel gave the desired product (53). When R.sup.6 was ortho-Cl, the
reaction time was as long as 16 h.
4.5.16 EXAMPLE 10
Synthesis of Salicylic Acid Derivative 89 Using Method B-2 (Scheme
18)
[0389] ##STR51## ##STR52##
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-pipe-
ridin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-2-hydroxy-6-methoxy-benzamid-
e (88)
[0390] 2-Hydroxy-6-methoxy-benzoic acid (87) (0.067 g=0.4 mmol),
iPr.sub.2EtN (0.6 mmol) and HBTU (0.44 mmol) were dissolved in DMF
(2 mL) and shaken in a sealed vial for 25 min.
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piper-
idin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.184 g,
0.2 mmol) was added and the mixture was heated to 80.degree. C. for
3 h. LC-MS indicated complete coupling at this point. Upon
concentrating, the crude product was dissolved in CHCl.sub.3 (4
mL), washed with aqueous sat. NaHCO.sub.3 (2.times.2 mL), water
(2.times.2 mL) and concentrated to dryness. Purification by ISCO
(15-100% EtOAc/hexanes) gave the desired product (88) (0.073 g,
0.069 mmol, 34.5% yield). LC-MS (ESI): (exact mass: 1069.56)
m/e=1070.9 [M+1].sup.+ (100%).
N-[4-(4,6-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-[1,3,5]triazin-2-ylamin-
o)-2-hydroxy-phenyl]-2-hydroxy-6-methoxy-benzamide (89)
[0391]
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylami-
no)-piperidin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-2-hydroxy-6-methoxy--
benzamide (88) (0.073 g, 0.069 mmol) was dissolved in a mixture of
thioanisole and TFA (1:4, 0.1 M) and shaken in a sealed vial for 3
h. LC-MS indicated complete reaction at this point. The mixture was
concentrated to an oil, dissolved in aqueous 1.0 M HCl and washed
with a mixture of hexane/EtOAc (4:1, 5 times). The aqueous phase
was concentrated to dryness. Purification by reverse phase HPLC
followed by lyophilization twice from aqueous 0.25 M HCl gave the
desired product (89) as the HCl salt (0.028 mg, 0.0386 mmol, 56%
yield. LC-MS (ESI): (exact mass: 579.30) m/e=580.3 [M+H.sup.+]
(100%).
4.5.17 Method B-3: Amide Coupling with Benzo-Dioxine-Diones (Scheme
19)
[0392] Scheme 19 describes the general procedure for preparing
salicylic acid derivative 82 of Formula Ia using method B-3.
##STR53##
[0393] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0394] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0395] The triazine-substituted aniline (80) (1 equiv.) and the
benzo-dioxine-dione (90) (3 equiv.) were combined and dissolved in
NMP (0.4 M). The mixture was heated to 110.degree. C. for 24 h. The
mixture was diluted with EtOAc, washed with water, saturated
aqueous NaHCO.sub.3 and water via extraction, dried over
MgSO.sub.4, concentrated under reduced pressure. Purification by
flash chromatography on silica gel gave the desired product (82) in
low to moderate yield. When R.sup.5 is an e-donating group, longer
reaction times may be necessary. This reaction is suitable for
R.sup.5.dbd.OH.
4.5.18 EXAMPLE 11
Synthesis of the Salicylic Acid Derivative (93) of Formula Ia Using
Method B-3 (Scheme 20)
[0396] ##STR54## ##STR55##
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-pipe-
ridin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-4-chloro-2-hydroxy-benzamide
(92)
[0397]
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino-
)piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83)
(0.16 g, 0.174 mmol) and 7-chloro-benzo[1,3]dioxine-2,4-dione (91)
(0.2 g, 1.0 mmol) were combined and dissolved in NMP (8 mL). The
mixture was heated to 80.degree. C. for 16 h. LC-MS indicated
complete reaction at this point. The mixture was diluted with EtOAc
(30 mL), washed with water (2.times.15 mL), saturated aqueous
NaHCO.sub.3 (2.times.15 mL) and brine (2.times.15 mL) via
extraction, dried over MgSO.sub.4 and concentrated to give a brown
oil. Purification by flash chromatography on silica gel using a
gradient of hexane and EtOAc (15-100% EtOAc in hexane) gave the
desired product (92) as a yellow powder upon concentration (0.111
g, 0.103 mmol, 60% yield). LC-MS (ESI): (exact mass: 1073.51)
m/e=1074.6 [M+1].sup.+ (100%).
N-[4-(4-chloro-2-hydroxy-benzoylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)--
3,5-diamino-piperidin-1-yl)-[1,3,5]triazine-2-amine (93)
[0398]
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylami-
no)piperidin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-4-chloro-2-hydroxy-be-
nzamide (92) (0.111 g, 0.103 mmol) was dissolved in a mixture of
thioanisole and TFA (1:4, 1.5 mL) and shaken in a sealed vial for
90 minutes. LC-MS indicated complete reaction at this point. The
mixture was concentrated, dissolved in aqueous 1.0 M HCl (15 mL)
and washed with a mixture of hexanes/EtOAc (4:1, 5.times.5 mL) via
extraction. The aqueous phase was concentrated to give a yellow
powder. Purification by reverse phase HPLC followed by
lyophilization twice from aqueous 0.25 M HCl gave the desired
product (93) as a yellow powder as the HCl salt [0.0295 g, 0.036
mmol (based on 4HCl+5H.sub.2O salt form), 34.9% yield, 13.5% total
yield for 5 steps). LC-MS (ESI): (exact mass: 583.25) m/e=584.3
[M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.23 (s,
2H), 1.77 (q, 2H, J=11.2 Hz), 2.70 (t, 2H, J=10.4 Hz), 2.84 (t, 2H,
J=10.4 Hz), 3.18 (m, 4H), 4.91 (s, br, 2H), 5.31 (m, 2H), 7.01 (t,
2H, J=8.4 Hz), 7.08 (s, 1-H), 8.00 (d, 1H, J=8.4 Hz), 8.19 (d, 1H,
J=8.8 Hz), 8.56 (s, br, 6H), 8.66 (s, br, 6H), 9.09 (s, 1H), 10.15
(s, 1H), 10.57 (s, 1H), 12.27 (s, 1H). Elemental analysis
calculated (%) for
C.sub.26H.sub.34ClN.sub.11O.sub.3.5H.sub.2O-4HCl: C, 38.08; H, 5.9;
N, 18.79. found: C, 37.96; H, 5.91; N, 18.64.
4.5.19 Method B-4: Amide Coupling of Salicylic Acid Chloride Using
K.sub.2CO.sub.3 (Scheme 21)
[0399] Scheme 21 describes the synthetic procedure for preparing
compound of Formula Ia using method B-4. ##STR56##
[0400] R.sup.1 and R.sup.2 are substitutents as defined on p.
3.
[0401] R.sup.5 and R.sup.6 are substitutents as defined for
substituted aryls.
[0402] In this general method, the triazine substituted aniline
(80) (1 equiv.), acid chloride (94) (1 equiv.), K.sub.2CO.sub.3 (10
equiv.) and THF was mixed. The mixture was shaken at room
temperature overnight. The inorganic solid was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
first purified by liquid-liquid extraction (CH.sub.2Cl.sub.2/sat'd
NH.sub.4Cl/H.sub.2O) and then purified by flash chromatography on
silica gel using a gradient of hexane and EtOAc to give the desired
product (95).
4.5.20 EXAMPLE 12
Synthesis of Salicylic Acid Derivative of Formula Ia Using Method
B-4 (Scheme 21a)
[0403] ##STR57##
[0404] The triazine substituted aniline (96) (174.8 mg, 214.9
.mu.mol), acid chloride
[0405] 97 (0.25 M in THF, 214.9 .mu.mol), K.sub.2CO.sub.3 (300 mg,
2.17 mmol) and 3 mL of THF was mixed. The mixture was shaken at
r.t. overnight. The inorganic solid was filtered off and the
filtrate was concentrated down under reduced pressure. The residue
was first purified by liquid-liquid extraction
(CH.sub.2Cl.sub.2/sat'd NH.sub.4Cl/H.sub.2O) and then purified by
flash chromatography on silica gel using a gradient of hexane and
EtOAc to give the desired product (98) as a white solid. LC-MS: m/e
1130.7 [M+1].sup.+ (exact ms: 1129.60).
[0406] Compound 98 was dissolved in 20 mL of methanol and 20 mL of
EtOAc. The solution was purged with N.sub.2 and Pd/C (10 wt %, dry,
350 mg) was added under N.sub.2 atmosphere. The solution was
degassed by alternately connecting the system to vacuum, and then
to N.sub.2 for three times. A balloon containing H.sub.2 was then
attached to the reaction system. The mixture was stirred at room
temperature overnight under slightly positive pressure of H.sub.2.
LC-MS confirmed the completion of the reaction. Methanol (5 mL) and
EtOAc (5 mL) was added to dilute the reaction mixture and the
inorganic solid was filtered off through the Celite under reduced
pressure. The filtrate was concentrated under reduced pressure to
give desired product 99 (157.9 mg, 166 .mu.mol, 77.3% isolated
yield for 2 steps) as an off-white solid. LC-MS: m/e 950.8
[M+1].sup.+ (exact ms: 949.50).
[0407] Compound 99 (157.9 mg, 166 .mu.mol) was dissolved in 3 mL of
methanol. HCl (4.0 M in dioxane, 3 mL) was added and the mixture
was shaken at room temperature for 6.5 hours. LC-MS confirmed the
completion of the reaction. The solvent was evaporated under
reduced pressure to give the desired product (76.4 mg) as a white
solid. This crude product was purified by reverse-phase HPLC using
a gradient of CH.sub.3CN and H.sub.2O to give the pure desired
product 100 (37.6 mg, 46.77 .mu.mol, 28.2% isolated yield
calculated based on the molecular weigh of the HCl salt determined
by elemental analysis) as the HCl salt. LC-MS: m/e 550.3
[M+1].sup.+ (exact ms: 549.29). Elemental analysis calculated (%)
for C.sub.26H.sub.35N.sub.11O.sub.3.5HCl.4H.sub.2O (803.99): C,
38.84; H, 6.02; N, 19.16. found: C, 38.56; H, 6.16; N, 19.11.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=10.22 (s, 1H),
9.20-9.30 (m, 1H), 8.44-8.78 (m, 12H), 8.22-8.34 (m, 1H), 7.81 (d,
J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 7.12-7.18
(m, 1H), 6.45 (d, J=2 Hz, 1H), 6.36 (dd, J=9.0 Hz, J.sub.2=2.2 Hz,
1H), 5.30-5.42 (m, 2H), 4.82-5.02 (m, 2H), 3.06-3.28 (m, 4H), 2.88
(t, J=11.6 Hz, 2H), 2.72 (t, J=11.4 Hz, 2H), 2.42-2.56 (m, 2H),
1.78 (q, J=11.3 Hz, 1H).
4.6 General Method of Synthesis of Formula IA Compounds
[0408] Scheme 22 describes a general synthetic procedure for
preparing compounds 17 and 18 of Formula Ia. ##STR58##
[0409] In this general method, cyanuric chloride, (5) (or any other
tri-halogenated (homo or mixed) triazine can be used) is treated
sequentially by different nucleophile reagents at increasing
temperatures. Preferably the less reactive amines (101), such as
aromatic or heteroaromatic amines are used first to displace the
most reactive chloride, followed by reactive amines to displace the
second chloride and finally replace the last chloride by the
nucleophile to form compound 106. The
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) is used to
displace the second chloride atom to give compound 103. Compound
103 can either directly undergo de-protection to give product 104
or continue to react with M.sup.1-transfer reagent (wherein the
transfer reagent is, e.g., MeOH, Ph.sub.4Sn and the like) (105) to
give compound 106. Deprotection of the BOC and other groups of
compound 106 furnish the targets of compound 107. Compound 103 can
undergo the reduction reaction either by using Raney Nickel and
hydrazine or by hydrogenation catalyzed by Pd/C to remove the
chloride group followed by the deprotection of the Boc group to
give the desired product 108.
[0410] This methodology is useful for the production of various
derivatives represented by Formula Ia. Other variations of this
methodology would be apparent to those skilled in the art. See,
e.g., WO 03/101980A1, and the references therein.
4.6.1 EXAMPLE 13
Synthesis of Formula Ia Compound 110 (Scheme 4)
[0411] ##STR59##
[0412] A solution of cyanuric chloride, (5) (100 .mu.mol) in 400 uL
of THF was mixed with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (63.1 mg,
200 mmol) in 1.6 mL of THF and 200 uL of 1 M .sup.iPr.sub.2NEt in
THF (200 .mu.mol). The mixture was shaken at room temperature
overnight. LC-MS results confirmed the completion of the reaction.
The reaction mixture was dried and worked up by liquid-liquid
extraction between CHCl.sub.3 and H.sub.2O layers. The organic
layer was dried to give crude product 109 with HPLC purity of 100%
(ELSD). LC-MS: m/e 742.5 [M+1].sup.+.
[0413] Compound 109 was dissolved in 2 mL of MeOH. 2 mL of 4 M of
HCl in dioxane was then added at room temperature and the resulting
mixture was shaken at room temperature overnight. The mixture was
dried and gave 42.9 mg of the desired product 110 as the HCl salt
with a purity by HPLC of 100% (ELSD) in 88% yield. LC-MS: m/e 342.3
[M+1].sup.+, 344.3.
4.6.2 EXAMPLE 14
Synthesis of Formula Ia Compound 115 (Scheme 24)
[0414] ##STR60##
[0415] Compound III (56 mg, 200 .mu.mol) in 500 .mu.L of THF and
200 .mu.L of .sup.iPr.sub.2NEt in 1.0 M THF was combined and cooled
at -25.degree. C. for 13 minutes. Cyanuric chloride, compound 5 (37
mg, 200 .mu.mol) was dissolved in 500 .mu.L of THF and first cooled
to -25.degree. C. for 15 minutes and then added into above
solution. After vortexing, the mixture was let sit at -25.degree.
C. overnight.
[0416] A slurry of 63 mg of compound 4 in 500 .mu.L of THF and 500
.mu.L of DMF along with .sup.iPr.sub.2NEt (200 .mu.L Of 1.0 M in
THF) was added into the reaction mixture. The mixture was shaken at
room temperature for 19 hours. The LC-MS result indicated the
completion of the reaction. The mixture was dried under reduced
pressure and the crude product (113) was directly used in the next
step.
[0417] The above crude product (113) was dissolved in 2 mL of THF
and heated at 50.degree. C. Hydrazine (98%, 200 .mu.L) was added
followed by 400 .mu.L of Raney Nickel (50% slurry in water). The
mixture was heated at 50.degree. C. without cap for 20 minutes. The
reaction was cooled and concentrated under reduced pressure to give
the crude product (114) as a grey solid. The crude was purified by
flash chromatography on silica gel using a gradient of hexane and
EtOAc to give the desired product (114). LC-MS: m/e 671.5
[M+1].sup.+.
[0418] Compound 114 was dissolved in 1 mL of MeOH and 1 mL of 4.0 M
HCl in dioxane was added and the mixture was shaken at room
temperature overnight. The mixture was dried to give final product
(115) (5.17 mg). LC-MS m/e 471.2 [M+1].sup.+.
4.7 General Method for Synthesis of O-Attached Triazines of Formula
Ia (SCHEME 25)
[0419] Scheme 25 describes a general method for synthesis of
O-attached triazines of Formula Ia. ##STR61##
[0420] R.sup.1 and R.sup.2 refer to substitutents as defined on
page 5.
[0421] In this general method, to a cooled (-20.degree. C.)
solution of cyanuric chloride (5) (100 .mu.mol) in dry THF (1.5 mL)
in an 8 mL vial is added a cooled (-20.degree. C.) solution of the
desired aniline (101) (100 mmol) and iPr.sub.2NEt (100 .mu.mol) in
dry THF (2 mL). The solution is allowed to stand in a -20.degree.
C. freezer for 16 h at which point the progress of the reaction is
assessed via TLC (R.sub.f dependent on aniline used) to give
compound 102. The solution containing compound 102 is allowed to
warm to 5.degree. C. and a suspension of
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (100
.mu.mol) in THF (1 mL) and N,N-di-isopropyl-ethylamine (100
.mu.mol) is added with agitation. After 1 h at 5.degree. C., the
solution (of 103) is allowed to warm to room temperature and ROH
(116) (500 .mu.mol) and .sup.iPr.sub.2NEt (500 .mu.mol) in THF is
added with agitation. The vial is then capped and placed on a
heated shaker at 20.degree. C. to 100.degree. C., preferably from
20.degree. C. to 80.degree. C. for 18 h to 24 h at which point the
progress of the reaction is assessed either by TLC or LC-MS.
[0422] The solution is diluted (CHCl.sub.3, 50 mL), transferred to
a separatory funnel and washed with H.sub.2O (50 mL), saturated
NaHCO.sub.3 (50 mL), brine (50 mL), dried (MgSO.sub.4) and
concentrated to give a material that is purified either by flash
chromatography (0-5% MeOH in CHCl.sub.3) or HPLC to give compound
117. This material is dissolved in MeOH (2 mL) and 5 M HCl (in
2-propanol; 2 mL) is added with agitation. This solution is allowed
to stand overnight for 16 h at which point H.sub.2O (1 mL) is added
with agitation and allowed to stand for 2 h. The solution is then
concentrated to dryness and the solid is purified by HPLC to give
the compound 118 as an HCl salt.
[0423] Other alkoxy, aryloxy, heteroaryloxy, arylalkoxy,
heteroarylalkoxy or hydroxy substituted diaminotriazines were
prepared in a similar manner to the protocol exemplified above.
4.7.1 EXAMPLE 15
Synthesis of Formula Ia Compound 123
[0424] Scheme 25a describes the synthesis of methoxy-diamino
substituted triazine (123). ##STR62##
[0425] To a cooled (-20.degree. C.) solution of cyanuric chloride
(5) (100 .mu.mol) in dry THF (1.5 mL) in an 8 mL vial was added a
cooled (-20.degree. C.) solution of the desired aniline (119) (100
mmol) and N,N-di-isopropyl-ethylamine (100 .mu.mol) in dry THF (-2
mL). The solution was allowed to stand in a -20.degree. C. freezer
for 16 h at which point the progress of the reaction was assessed
via TLC (R.sub.f dependent on aniline used) to give compound 120.
The solution containing compound 120 was allowed to warm to
5.degree. C. and a suspension of
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (100
.mu.mol) in THF (1 mL) and iPr.sub.2NEt (100 .mu.mol) was added
with agitation. After 1 h at 5.degree. C., the solution (of 121)
was allowed to warm to room temperature and MeOH (500 mmol) and
iPr.sub.2NEt (500 .mu.mol) in THF was added with agitation. The
vial was then capped and placed on a heated shaker at 70.degree. C.
for 18 h at which point the progress of the reaction was assessed
either by TLC or LC-MS.
[0426] The solution was diluted (CHCl.sub.3, 50 mL), transferred to
a separatory funnel and washed with H.sub.2O (50 mL), saturated
NaHCO.sub.3 (50 mL), brine (50 mL), dried (MgSO.sub.4) and
concentrated to give a material that was purified either by flash
chromatography (0-5% MeOH in CHCl.sub.3) or HPLC to give compound
122. This material was dissolved in MeOH (2 mL) and 5 M HCl (in
2-propanol; 2 mL) was added with agitation. This solution was
allowed to stand overnight for 16 h at which point H.sub.2O (1 mL)
was added with agitation and allowed to stand for 2 h. The solution
was then concentrated to dryness and the solid was purified by HPLC
to give the compound 123. .sup.1H NMR (400 MHz, D.sub.2O)
.delta.=1.77 ppm (m, 1H), 2.25 (s, 3H), 2.49-2.59 (m, 1H), 2.87 (m,
2H), 3.26-3.42 (m, 2H), 3.86 (s, 3H), 4.76-4.93 (m, 2H), 6.80-6.93
(m, 1H), 6.98 (br s, 1H), 7.13-7.21 (m, 2H), 7.29 (br d, 1H, J=8
Hz), 7.52-7.62 (m, 2H). LC-MS: m/e 465.0 [M+1].sup.+.
[0427] Other methoxy diamino triazines of the Formula Ia compounds
shown in Table 1 were prepared in a similar manner to the protocol
exemplified above.
4.8 General Methods of Synthesis of Formula Ia Compounds with
C-Attachment
[0428] Schemes 26 and 27 describe the general procedure for
synthesis of the C-attached triazines (129). These methods can also
be applied to other cores described in Formula I. ##STR63##
[0429] R.sup.1 and R.sup.2 refer to substitutents as defined on
page 5.
[0430] In this general method, cyanuric chloride (5) reacts with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in the
presence of .sup.iPr.sub.2NEt at -25.degree. C. to give compound
124 that further reacts with amine 101 at room temperature in the
presence of .sup.iPr.sub.2NEt to give compound 103.
[0431] Compound 103 can be optionally converted to the
corresponding bromo-derivative (125) by the treatment with alkali
metal or alkaline earth bromide selected from LiBr, NaBr,
MgBr.sub.2 in a solvent selected from THF, DMF, Dioxane, HMPA, NMP,
toluene and/or a mixture thereof.
[0432] Compound 103 (or 125) can react with Bu.sub.3SnR (126) or
optionally R.sub.4Sn (127) in the presence of Pd-catalyst selected
from PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4,
Pd(OAc).sub.2, Pd.sub.2(dba).sub.3, PdCl.sub.2 and
Pd(P(.sup.tBu.sub.3).sub.2), PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH] with or without ligand selected
from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(Di-t-butylphosphino)biphenyl,
2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and
(R)-(+)-2,2'-Bis(dicyclohexylphosphino)-1,1'-Binaphthyl and with or
without an additive selected from Et.sub.4NCl, CsF and the
imidazolium salt IPr.HCl
(IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) in
combination with TBAF (.sup.nBu.sub.4NF) as reported in Grasa G. A.
and Nolan P., Org. Lett., 3 (1), 119-122, 2001, in a solvent
selected from PhMe, DME, xylenes, dioxane, MeCN, DMF, benzene, THF
and HMPA at a temperature from 20.degree. C. to 140.degree. C.
preferentially between 20-120.degree. C. for 16-72 hours under
N.sub.2 atmosphere.
[0433] The reaction is checked for progress by TLC or LC-MS and
upon completion the mixture is diluted with chloroform or other
suitable solvent, extracted with water, dried with magnesium or
sodium sulfate and concentrated in vacuo. The residue is purified
by column chromatography on a silica gel column using a gradient of
chloroform-ethyl acetate or chloroform-methanol to give the desired
product 29. A related synthesis is described in Littke A. F. and Fu
G. C., Angew. Chem. Int. Ed. 2000, 41, 4176-4211.
[0434] Treatment of 128 with an excess of 2 M HCl in dioxane and
methanol at room temperature, followed by evaporation under reduced
pressure provides the target 129.
4.8.1 Another General Method of Synthesis of Formula Ia Compounds
with C-Attachment
[0435] Scheme 28 describes another general procedure for synthesis
of the C-attached triazines as an example. This method can be
applied to other cores described in Formula I. ##STR64##
[0436] R.sup.1 and R.sup.2 refer to substitutents as defined on
page 5.
[0437] In this general method 1, cyanuric chloride (5) can react
with Bu.sub.3SnR (126) or optionally R.sup.4Sn (127) in the
presence of Pd-catalyst selected from PdCl.sub.2(PPh.sub.3).sub.2,
Pd(PPh.sub.3).sub.4, Pd(OAc).sub.2, Pd.sub.2(dba).sub.3, PdCl.sub.2
and Pd(P(Bu.sub.3).sub.2), PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH] with or without ligand selected
from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl,
2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and
(R)-(+)-2,2'-Bis(dicyclohexylphosphino)-1,1'-Binaphthyl and with or
without additive selected from Et.sub.4NCl, CsF and the imidazolium
salt IPr.HCl (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
in combination with TBAF (.sup.nBu.sub.4NF) as reported in Grasa G.
A. and Nolan P., Org. Lett., 3 (1), 119-122, 2001, in a solvent
selected from PhMe, DME, O-xylene, Dioxane, MeCN, DMF, benzene, THF
and HMPA at a temperature from 20.degree. C. to 140.degree. C.
preferentially between 20-120.degree. C. for 16-72 hours under
N.sub.2 atmosphere. The reaction is checked for progress by TLC or
LC-MS and upon completion the mixture (130) is directly used in the
next step. A related synthesis is described in Littke A. F. and Fu
G. C., Angew. Chem. Int. Ed. 2000, 41, 4176-4211.
[0438] In another alternative general method 2, a cooled
(-20.degree. C.) THF solution of cyanuric chloride is treated with
an ethereal THF solution (Et.sub.2O:THF 2:3 v/v) of RMgBr
([cyanuric chloride]/[RMgBr]=1/1 molar ratio). The temperature is
raised to 5.degree. C. and the mixture is stirred until the
complete conversion of cyanuric chloride into the intermediate 130
is observed (TLC, LC-MS). The mixture is directly used in the next
step. A related synthesis is described in Rita Menicagli, Simona
Samaritani, Giovanni Signore, Francesca Vaglin and Lisa Dalla Via,
J. Med. Chem. 2004, 47, 4649-4652.
[0439] Compound 130 is treated with slight excess of
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) in the
presence of .sup.iPr.sub.2NEt at room temperature. The reaction is
checked for progress by TLC or LC-MS and upon completion the
resulting mixture (131) is treated with amine 101 in the presence
of .sup.iPr.sub.2NEt and is heated at 80.degree. C. for 16-72
hours. The reaction is checked for progress by TLC or LC-MS and
upon completion the mixture is diluted with chloroform or other
suitable solvent, extracted with water, dried with magnesium or
sodium sulfate and concentrated in vacuo. The residue is purified
by column chromatography on a silica gel column using a gradient of
hexane-ethyl acetate to give the desired product 128.
[0440] Treatment of 128 with excess of 2.0 M HCl in dioxane and
methanol at room temperature, followed by evaporation under reduced
pressure provides the target 129.
4.9 General Method of Synthesis of Formula Ib Compounds (135)
[0441] Scheme 29 describes a general synthetic procedure for
preparing compound of Formula Ib. ##STR65##
[0442] 4-Amino-3,5-dichloro-2,6-difluoropyridine (82) is reacted
with (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in a
solvent selected from acetonitrile, THF, ethyl acetate, ethylene
glycol dimethyl ether, dioxane, DMF, toluene or chlorobenzene,
optionally in the presence of a base, selected from
diisopropylethylamine, triethylamine, potassium or cesium
carbonate, potassium or cesium fluoride or DBU at a temperature
from 20.degree. C. to 120.degree. C., preferentially between 30 to
110.degree. C. The reaction is checked for progress by TLC or HPLC
and upon completion the mixture is diluted with chloroform or other
suitable solvent extracted with water, dried with magnesium or
sodium sulfate and concentrated in vacuo. The residue is column
chromatographed on a silica gel column, using a gradient of
chloroform-ethyl acetate or chloroform-methanol.
[0443] The purified bis-piperidino-dichloro derivative 131a is then
hydrogenated over Pd--C or Pd--BaSO.sub.4 at atmospheric, or
elevated pressure of 1 to 500 psi, preferably 10 to 50 psi in a
solvent selected from methanol, ethanol, tetrahydrofuran or ethyl
acetate, optionally in the presence of a base, such as
triethylamine, sodium, potassium or calcium carbonate. When the
reaction is complete by LC/MS, the catalyst is removed by
filtration and the product 132 is isolated by column chromatography
on silica gel using a dichloromethane-ethyl acetate gradient,
followed by concentration in vacuo. Related chemical
transformations are described in Menichincheri et al., Tetrahedron
Letters, 44 519-522 (2003).
[0444] Subsequent reaction of the 4-aminopyridine derivative 132
with an iodoarene derivative 133 in a solvent selected from
toluene, xylenes, anisole or chlorobenzene in the presence of
tris-triphenylphosphine copper bromide [Cu(PPh.sub.3).sub.3Br] and
cesium carbonate at an elevated temperature between 80 to
120.degree. C., preferably 100 to 110.degree. C., in an argon
atmosphere furnishes after column chromatography on silica gel the
arylamino derivative 134. Related chemical transformations are
described in Gujadhur, R. et al., Tetrahedron Letters, 42,
4791-4793 (2001).
[0445] Treatment of 134 with excess of 4 M HCl in dioxane in
methanol at room temperature, followed by evaporation under reduced
pressure provides the target 135.
[0446] This methodology is useful for the production of various
derivatives represented by Formula Ib. Other variations of this
methodology would be apparent to those skilled in the art.
[0447] Another general method to synthesize Formula Ib compounds
would follow Scheme 29, but using a different starting material
with following changes shown in the scheme 30.
4.9.1 EXAMPLE 16
Synthesis of Compound 144 of Formula Ib
[0448] Scheme 30 describes the synthetic procedure for preparing
compound 144 of Formula Ib. ##STR66## ##STR67##
N-[4-(3,5-dichloro-2,6-difluoro-pyridin-4-ylamino)-phenyl]-acetamide
(138)
[0449] 3,5-Dichloro-2,4,6-trifluoro-pyridine (136) (1 g, 4.95 mmol)
and N-(4-Aminophenyl)-acetamide (137) (0.743 g, 4.95 mmol) were
dissolved in NMP (12 mL), .sup.iPr.sub.2EtN (9.9 mmol) was added
and the mixture was shaken at room temperature for 5 hours. TLC and
LC-MS indicated complete reaction at this point. The mixture was
diluted with EtOAc (50 mL), washed with NaHCO.sub.3 (aqueous sat.,
50 mL) and passed through a plug of silica gel to remove any
baseline impurities. Upon concentration, the desired product (138)
precipitated as a beige/pink powder that was collected by
filtration under reduced pressure followed by drying under high
vacuum for 16 h (1.43 g, 2.88 mmol, 58% yield). LC-MS (ESI): (exact
mass: 331.01) m/e=332.1 [M+1].sup.+ (100%), 664.9 [2M+1].sup.+
(30%), 996.2 [3M+1].sup.+ (10%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 2.03 (s, 3H), 6.99 (d, 2H, J=7.2 Hz), 7.49
(d, 2H, J=6.8 Hz), 9.00 (s, 1H), 9.89 (s, 1H). .sup.19F NMR (400
MHz, DMSO-d.sub.6): .delta.-76.55 (TFA reference), -75.89 (s,
2F).
N-[4-(3,5-dichloro-Z
6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-pyridin-
-4-ylamino)-phenyl]-acetamide (139)
[0450]
N-[4-(3,5-dichloro-2,6-difluoro-pyridin-4-ylamino)-phenyl]-acetami-
de (138) (0.5 g, 1.5 mmol) and
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (1.01 g,
3.2 mmol) were combined in NMP (16 mL) and .sup.iPr.sub.2EtN (4.8
mmol) was added. The mixture was heated at 110.degree. C. for 120 h
in a Teflon septum capped 40 mL I-Chem vial. LC-MS indicated nearly
complete reaction at this point. The mixture was diluted with EtOAc
(50 mL), washed with water (25 mL), NaHCO.sub.3 (aqueous sat., 25
mL) and brine (25 mL) via extraction, dried over MgSO.sub.4 and
concentrated to give a white powder. Purification by flash
chromatography on silica gel using a gradient of hexane and EtOAc
(eluding with 15-100% EtOAc in hexane for 30 minutes) gave the
desired product (139) as a white powder upon concentration (0.849
g, 0.92 mmol, 61.4% yield). LC-MS (ESI): (exact mass: 921.43)
m/e=922.5 [M+1].sup.+ (100%).
N-(3,5-dichloro-2,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperi-
din-1-yl)-pyridin-4-yl)-benzene-1,4-diamine (140)
[0451]
N-[4-(3,5-dichloro-2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylam-
ino)-piperidin-1-yl)-pyridin-4-ylamino)-phenyl]-acetamide (139)
(0.849 g, 0.92 mmol) was dissolved in MeOH (5 mL) and NMP (10 mL).
Hydrazine (10 mL) was added and the mixture was heated at 80 C with
shaking in a 40 mL I-Chem vial for 5 days. LC-MS at this point
indicated nearly complete deprotection. The mixture was diluted
with EtOAc (50 mL), washed with water (4.times.25 mL) and brine (25
mL) via extraction, dried over MgSO.sub.4 and concentrated to give
a yellow oil. Purification by flash chromatography using a gradient
of hexane and EtOAc (eluding with 15-100% EtOAc in hexane in 30
minutes) gave the desired product (140) as a beige powder upon
concentration (0.728 g, 0.826 mmol, 89.8% yield). LC-MS (ESI):
(exact mass: 879.42) m/e=880.5 [M+1].sup.+ (100%).
N-(2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-pyr-
idin-4-yl)-benzene-1,4-diamine (141)
[0452]
N-(3,5-dichloro-2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino-
)-piperidin-1-yl)-pyridin-4-yl)-benzene-1,4-diamine (140) (0.205 g,
0.233 mmol) was dissolved in MeOH (15 mL). Pd/C (1 g, 10%, wet) was
added followed by ammonium-formate (2 g). The mixture was shaken in
a Teflon septum capped 40 mL I-Chem vial, with occasional venting,
for 3 hours. LC-MS indicated complete de-chlorination at this
point. The mixture was filtered through a plug of Celite and the
filtrate was concentrated and purified by flash chromatography
using a gradient of hexane and EtOAc (eluding with 15-100% EtOAc in
hexane in 30 minutes followed by 100% EtOAc in 10 minutes) to give
the desired product (141) as a yellow/green oil (0.08 g, 0.098
mmol, 42.3% yield). LC-MS (ESI): (exact mass: 811.50) m/e=812.7
[M+1].sup.+ (100%).
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-p-
yridin-4-ylamino)-phenyl]-amide (143)
[0453] 1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.028 g,
0.148 mmol) was dissolved in DMF (1 mL), .sup.iPr.sub.2EtN (0.222
mmol) was added followed by
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium
hexafluorophosphate (HBTU) (0.062 g, 0.163 mmol) and the mixture
was shaken in an 8 mL Teflon septum capped vial at room temperature
for 20 minutes.
N-(2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-
-1-yl)-pyridin-4-yl)-benzene-1,4-diamine (141) (0.08 g, 0.0986
mmol) was added and the mixture was shaken at room temperature for
16 h. LC-MS indicated complete coupling at this point. The mixture
was diluted with EtOAc (25 mL), washed with water (15 mL),
NaHCO.sub.3 (aqueous sat., 15 mL) and brine (15 mL) via extraction,
dried over MgSO.sub.4 and concentrated to give an orange/green oil.
Purification by flash chromatography using a gradient of hexane and
EtOAc (eluding with 15-100% EtOAc in hexane in 30 minutes) gave the
desired product (143) as a greenish-white powder upon concentration
(0.063 g, 0.064 mmol, 65% yield). LC-MS (ESI): (exact mass: 981.53)
m/e=982.6 [M+1].sup.+ (100%).
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,6-bis-((3R,5S)-3,5-bis-aminopiperidin-1-yl)-pyridin-4-ylamino)-phen-
yl]-amide (144)
[0454] 1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,6-(3R,5S)-((3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidin-1-yl-
)-pyridin-4-ylamino)-phenyl]-amide (143) (0.06 g=0.0611 mmol) was
dissolved in MeOH (2 mL) and 4.0 M HCl/dioxane (2 mL) was added.
The mixture was shaken at room temperature for 16 h in a sealed 40
mL I-Chem vial. LC-MS indicated complete deprotection at this
point. The mixture was concentrated to give a greenish-brown solid.
Purification by reverse-phase HPLC followed by concentrating and
lyophilization from 0.25 M HCl/H.sub.2O twice gave the desired
product (144) as the HCl salt form as a green powder [0.028 g,
0.033 mmol (calculated based on the molecular weigh of the HCl salt
determined by elemental analysis), 53.7% yield, 4.72% total yield
for 6 steps]. LC-MS (ESI): (exact mass: 581.32) m/e=582.3
[M+1].sup.+ (100%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
1.71 (q, 2H, J=12 Hz), 2.44 (s, br, 2H), 2.68 (t, 4H, J=11.6 Hz),
3.17 (s, br, 4H), 3.85 (s, br, 2H), 4.60 (s, br, 4H), 5.80 (s, 2H),
7.20 (d, 2H, J=8.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.56 (t, 1H, J=7.2
Hz), 7.70-7.63 (m, 3H), 7.86 (d, 1H, J=8 Hz), 8.16 (d, 1H, J=8.8
Hz), 8.28 (d, 1H, J=8.4 Hz), 8.52 (s, br, 12H), 10.49 (s, 1H).
Elemental analysis calculated (%) for
C.sub.32H.sub.39N.sub.9O.sub.2.5H.sub.2O.5HCl: C, 45.0; H, 6.37; N,
14.76. found: C, 44.66; H, 6.10; N, 14.39.
4.10 General Method of Synthesis of Formula Ic Compounds
[0455] Scheme 31 describes a general synthetic procedure for
preparing compound of Formula Ic. ##STR68##
[0456] 2-chloro-3,5-di-bromo-pyridine (145), in 30% excess relative
to compound 4, reacts with (3R.sup.10,
5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in the
presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, O-xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C., preferentially
between 100.degree. C. and 120.degree. C. for 16-72 hours under
N.sub.2 atmosphere. The reaction is checked for progress by TLC or
HPLC and upon completion, the mixture is diluted with chloroform or
other suitable solvents and the inorganic solid was filtered off
through Celite.
[0457] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the bis-aminated pure product 146. Related chemical
transformations and the selectivity of the reaction are described
in Jianguo Ji, Tao Liu and William H. Bunnelle, Organic Letters, 5
(24), 4611-4614 (2003).
[0458] Compound 146 is treated with an aniline (147) to react the
same way as in the previous step using excess aniline to give
compound 148.
[0459] Treatment of 148 with excess of 2 M HCl in dioxane and
methanol at room temperature overnight, followed by evaporation
under reduced pressure provides the target 149.
4.10.1 Another General Method of Synthesis of Formula Ic
Compounds
[0460] Scheme 32 describes a general synthetic procedure for
preparing compound 149 of Formula Ic. ##STR69##
[0461] The 3,5-dibromo-2-chloro-pyridine (145) (1 equiv.), aniline
(147) (3 equiv.), NaHCO.sub.3 (2 equiv.) were mixed and suspended
in NMP (0.5 M). The mixture was heated to 180.degree. C. for 120 h.
The reaction is monitored by TLC and LC-MS. Upon completion of the
reaction, the mixture is diluted with EtOAc, washed with saturated
aqueous NaHCO.sub.3 and brine via extraction, dried over MgSO.sub.4
and concentrated to give a crude product that is purified by flash
chromatography on silica gel using a gradient of hexane and EtOAc
to give the desired product 150.
[0462] Compound 150 reacts with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in the
presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, O-xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C., preferentially
between 100.degree. C. and 120.degree. C. for 16-72 hours under
N.sub.2 atmosphere. The reaction is checked for progress by TLC or
HPLC and upon completion, the mixture is diluted with chloroform or
other suitable solvents and the inorganic solid was filtered off
through Celite. The resulting filtrate washed with water via
extraction, dried with magnesium or sodium sulfate and concentrated
in vacuo. The residue is column chromatographed on a silica gel
column, using a gradient of chloroform-ethyl acetate or
chloroform-methanol to generate the bis-aminated pure product 148.
Related chemical transformations and the selectivity of the
reaction are described in Jianguo Ji, Tao Li and William H.
Bunnelle, Organic Letters, 5 (24), 4611-4614 (2003).
[0463] The Boc-groups of compound 148 can be removed by treating
with 2.0 M HCl in dioxane/MeOH at room temperature. The reaction is
monitored by LC-MS. Upon completion of the reaction, the mixture is
concentrated under reduced pressure to give a crude that is
purified by reverse phase HPLC followed by lyophilization twice
from aqueous 0.25 M HCl to give the desired product (149) as the
HCl salt.
4.11 General Methods of Synthesis of Formula Ib and Id
Compounds
4.11.1 Synthesis of Formula Ib and Id Compounds by Schemes 33 and
34
[0464] Schemes 33 & 34 describe the general synthetic
procedures for preparing compounds 156 and 161 of Formulas Ib and
Id. ##STR70##
[0465] 2,3,5,6-tetrachloro-4-iodo-pyridine (151) reacts with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in a
solvent selected from toluene, xylenes, anisole or chlorobenzene in
the presence of tris-triphenylphosphine copper bromide
[Cu(PPh.sub.3).sub.3Br] and cesium carbonate at an elevated
temperature between 80 to 120.degree. C., preferably 100 to
110.degree. C., in an argon atmosphere to furnish after silica gel
column chromatography, the arylamino derivative 152. Related
chemical transformations are described in Gujadhur, R. et al.,
Tetrahedron Letters, 42, 4791-4793 (2001).
[0466] Compound 152 reacts with aniline 147 in the presence of
Pd-catalyst selected from Pd.sub.2(dba).sub.3, Pd(OAc).sub.2,
PdCl.sub.2(PCy.sub.3).sub.2, PdCl.sub.2[P(.sup.tBu).sub.2OH],
ligand selected from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, O-xylene, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is chromatographed on a silica gel column, using a
gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the bis-animated pure product 153.
[0467] Compound 153 is reacted with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)piperidine (4) in a
solvent selected from acetonitrile, THF, ethyl acetate, ethylene
glycol dimethyl ether, dioxane, DMF, toluene or chlorobenzene,
optionally in the presence of a base, selected from
diisopropylethylamine, triethylamine, potassium or cesium
carbonate, potassium or cesium fluoride or DBU at a temperature
from 20.degree. C. to 120.degree. C., preferentially between 30 to
110.degree. C. The reaction is checked for progress by TLC or HPLC
and upon completion the mixture is diluted with chloroform or other
suitable solvent extracted with water, dried with magnesium or
sodium sulfate and concentrated in vacuo. The residue is column
chromatographed on a silica gel column, using a gradient of
chloroform-ethyl acetate or chloroform-methanol to give desired
product 154.
[0468] Compound 154 is then hydrogenated over Pd--C or
Pd--BaSO.sub.4 at atmospheric, or elevated pressure of 1 to 500
psi, preferably 10 to 50 psi in a solvent selected from methanol,
ethanol, tetrahydrofuran or ethyl acetate, optionally in the
presence of a base, such as triethylamine, sodium, potassium or
calcium carbonate. When the reaction is complete by LC/MS, the
catalyst is removed by filtration and the product 155 is isolated
by column chromatography on silica gel using a
dichloromethane-ethyl acetate gradient, followed by concentration
in vacuo. Related chemical transformations are described in
Menichincheri et al., Tetrahedron Letters, 44 519-522 (2003).
[0469] Treatment of 155 with excess of 2 M HCl in dioxane and
methanol at room temperature, followed by evaporation under reduced
pressure provides the target 156.
[0470] This methodology is useful for the production of various
derivatives represented by Formula Ib and Id. Other variations of
this methodology would be apparent to those skilled in the art.
4.11.2 Synthesis of Formula Ib and Id Compounds by Scheme 34
[0471] ##STR71##
[0472] 2-Fluoro-4-iodo-5-chloro-6-methylpyridine (157) is reacted
with (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in a
solvent selected from acetonitrile, THF, ethyl acetate, ethylene
glycol dimethyl ether, dioxane, DMF, toluene or chlorobenzene,
optionally in the presence of a base, selected from
diisopropylethylamine, triethylamine, potassium or cesium
carbonate, potassium or cesium fluoride or DBU at a temperature
from 20.degree. C. to 120.degree. C., preferentially between 30 to
80.degree. C. The reaction is checked for progress by TLC or HPLC
and upon completion the mixture is diluted with chloroform or other
suitable solvent extracted with water, dried with magnesium or
sodium sulfate and concentrated in vacuo. The residue is column
chromatographed on a silica gel column, using a gradient of
chloroform-ethyl acetate or chloroform-methanol to give 2-aminated
desired product 158.
[0473] Compound 158 reacts with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)piperidine (4) in a
solvent selected from toluene, xylenes, anisole or chlorobenzene in
the presence of tris-triphenylphosphine copper bromide
[Cu(PPh.sub.3).sub.3Br] as catalyst and cesium carbonate at an
elevated temperature between 80 to 140.degree. C., preferably 100
to 110.degree. C., in an argon atmosphere to furnish, after column
chromatography on silica gel, the 4-aminated pyridine derivative
159. Related chemical transformations are described in Gujadhur, R.
et al., Tetrahedron Letters, 42, 4791-4793 (2001).
[0474] Compound 159 reacts with aniline 147 in the presence of
Pd-catalyst selected from Pd.sub.2(dba).sub.3, Pd(OAc).sub.2,
PdCl.sub.2(PCy.sub.3).sub.2, PdCl.sub.2[P(.sup.tBu).sub.2OH],
ligand selected from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, O-xylene, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 160.
[0475] Treatment of 160 with excess of 2 M HCl in dioxane and
methanol at room temperature, followed by evaporation under reduced
pressure provides the target 161 as HCl salt.
[0476] This methodology is useful for the production of various
derivatives represented by Formulas Ib and Id. Other variations of
this methodology would be apparent to those skilled in the art.
4.11.3 Another General Method of Synthesis of Formula Ib & Id
Compounds
[0477] Scheme 35 describes the general synthetic procedures for
preparing compounds of Formula Ib & Id. ##STR72##
[0478] In this scheme R is as defined for substituted aryl.
[0479] Compound (4) (1 equiv.) was first dissolved in warm DMA,
cooled to 0.degree. C. and (.sup.iPr).sub.2EtN (1.1 equiv.) and
then added to a solution of 3,5-dichloro-2,4,6-trifluoro-pyridine
(136) (1 equiv.) in THF. The reaction mixture was shaken at
0.degree. C. to room temp over 5 h. The precipitate was collected
by filtration and dried under high vacuum to give the desired
product (163). A related chemical transformation is described in
Menichincheri, M.; Bassini, D. F.; Gude, M; Angiolini, M.
Tetrahedron Letters 2003, 44, 519-522.
[0480] Compound 163 (1 equiv.) and aniline 147 (1.25 equiv.) were
combined and suspended in NMP. (.sup.iPr).sub.2EtN (1.5 equiv.) was
added and the mixture was heated at 110.degree. C. for 10 days in a
Teflon septum capped vial. Upon nearly complete consumption of the
di-fluoro starting material (163) indicated by LC-MS, the mixture
was diluted with EtOAc, washed with water, saturated aqueous
NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel to give the desired product (164).
[0481] Compound 164 (1 equiv.) and
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)piperidine (6) (1.5
equiv.) were combined and suspended in NMP. .sup.iPr.sub.2EtN (2
equiv.) was added and the mixture was heated at 110.degree. C. with
shaking for 5 days. Upon the completion of the reaction indicated
by LC-MS, the solution was diluted with EtOAc, washed with
H.sub.2O, brine, dried over MgSO.sub.4 and concentrated to give a
crude that was purified by trituration with EtOAc gave the desired
product (165).
[0482] Compound 165 was dissolved in MeOH. Pd/C (10%, wet) was
added followed by ammonium-formate. The mixture was shaken at room
temperature for 16 hours. Upon the completion of the
de-chlorination indicated by LC-MS, the mixture was filtered
through a plug of Celite. The filtrate was concentrated and the
resulting crude was purified by flash chromatography to give the
desired product (166).
[0483] Compound 166 (0.042 g=0.043 mmol) was dissolved in MeOH and
an equal volume of 4.0 M of HCl in dioxane was added. The mixture
was shaken at room temperature for 16 h, concentrated under reduced
pressure to give a crude product that was purified by HPLC to give
the desired product (167) as the HCl salt.
4.11.4 EXAMPLE 17
Synthesis of Formula Ib & Id Compound 171
[0484] Scheme 36 describes the synthetic procedure for preparing
171 of Formula Ib & Id. ##STR73## ##STR74##
4-(3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-3,5-dichloro--
2,6-difluoro-pyridine (163)
[0485] (3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidine (4)
(0.25 g, 0.8 mmol) was dissolved in warm DMA (4 mL, via sonication
and warming with the heat gun to .about.60.degree. C.). Upon
cooling, the solution was chilled to 0.degree. C. and
(.sup.iPr).sub.2EtN (0.88 mmol) and
3,5-dichloro-2,4,6-trifluoro-pyridine (136) (0.161 g, 0.8 mmol) was
added as a pre-dissolved mixture in THF (4 mL). The solution was
shaken in a sealed 40 mL I-Chem vial while warming to room temp
over 5 h. A white precipitate had formed. The precipitate was
collected by filtration followed by rinsing with THF and water. The
solid was dried under high vacuum for 16 h to give the desired
product (163) as a white powder (0.343 g, 0.691 mmol, 86% yield).
LC-MS (ESI): (exact mass: 496.15) m/e=497.1 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.39 (s, br, 20H), 2.09-1.95
(m, 2H), 3.49 (s, br, 2H), 3.89 (s, br, 2H), 7.00 (s, 2H).
4-(3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-3,5-dichloro--
2-(4-acetylamino-phenyl-amino)-6-fluoro-pyridine (165)
[0486]
4-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-3,5--
dichloro-2,6-difluoro-pyridine (163) (0.343 g, 0.69 mmol) and
N-(4-amino-phenyl)-acetamide
[0487] (162) (0.129 g, 0.863 mmol) were combined and suspended in
NMP (12 mL). .sup.iPr.sub.2EtN (1.04 mmol) was added and the
mixture was sonicated for 2 minutes. The mixture was heated to
110.degree. C. in a Teflon septum capped vial. The solids dissolved
within 2 h. Shaking of the solution was continued at 110.degree. C.
for 10 days. LC-MS indicated nearly complete consumption of the
di-fluoro starting material. The mixture was diluted with EtOAc (50
mL), washed with water (25 mL), NaHCO.sub.3 (aqueous sat., 25 mL),
brine (25 mL), dried over MgSO.sub.4 and concentrated to give a
brown oil. Purification by flash chromatography on silica gel using
a gradient of hexane and EtOAc (eluding with 15-100% EtOAc/hexane
in 30 minutes) gave the desired product (165) as a beige powder
upon concentration (0.290 g, 0.463 mmol, 54% yield). LC-MS (ESI):
(exact mass: 626.22) m/e=627.3 [M+1].sup.+.
4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-3,5-di-
chloro-2-(4-acetylamino-phenyl-amino)-pyridine (166)
[0488]
4-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-3,5--
dichloro-2-(4-acetylamino-phenyl-amino)-6-fluoro-pyridine (165)
(0.29 g, 0.463 mmol) and
cis-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (0.219 g,
0.695 mmol) were combined and suspended in NMP (3.5 mL) in a 40 mL
I-Chem vial. .sup.iPr.sub.2EtN (0.926 mmol) was added and the
mixture was sonicated for 2 minutes. The mixture was heated to
110.degree. C. and within 30 minutes all of the solids had
dissolved. The solution continued to shake in the Teflon septum
capped vial for 5 days. LC-MS indicated nearly complete reaction at
this point. The solution was diluted with EtOAc (100 mL), washed
with H.sub.2O (50 mL) and brine (50 mL), dried over MgSO.sub.4 and
concentrated to give a brown oil which eventually solidified.
Trituration of the solid with EtOAc followed by collection via
filtration under reduced pressure gave the desired product (166) as
a beige powder (0.183 g, 0.198 mmol, 43% yield). LC-MS (ESI):
(exact mass: 921.43) m/e=922.6 [M+1].sup.+.
4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-3,5-di-
chloro-2-(4-aminophenyl-amino)-pyridine (167)
[0489]
4,6-Bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl-
)-3,5-dichloro-2-(4-acetylamino-phenyl-amino)-pyridine (166) (0.183
g, 0.198 mmol) was dissolved in NMP (6 mL) and MeOH (8 mL).
Hydrazine (8 mL) was added and the mixture was heated to 80.degree.
C. in a Teflon septum capped 40 mL I-Chem vial for 4 days. LCMS
indicated incomplete deprotection at this point. An additional
portion of hydrazine (8 mL) was added and the solution was heated
for an additional 4 days. LC-MS indicated nearly complete
deprotection at this point. The mixture was diluted with EtOAc (50
mL) and the organic layer washed with water (25 mL), NaHCO.sub.3
(aqueous sat., 25 mL) and brine (25 mL) via extraction, dried over
MgSO.sub.4 and concentrated to give a brown oil. Purification by
flash chromatography on silica gel using a gradient of hexane and
EtOAc (eluding with 15-100% EtOAc in hexane in 30 minutes) gave the
desired product (166) as a beige powder upon concentration (0.127
g, 0.144 mmol, 72.7% yield). LC-MS (ESI): (exact mass: 879.42)
m/e=880.5 [M+1].sup.+.
4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-2-(4-a-
minophenyl-amino)-pyridine (168)
[0490]
4,6-Bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl-
)-3,5-dichloro-2-(4-aminophenyl-amino)-pyridine (167) (0.127 g,
0.144 mmol) was dissolved in MeOH (15 mL). Pd/C (0.33 g, 10%, wet)
was added followed by ammonium-formate (0.66 g). The mixture was
shaken in a Teflon septum capped 40 mL I-Chem vial, with occasional
venting, for 16 hours. LC-MS indicated complete de-chlorination at
this point. The mixture was filtered through a plug of Celite and
the filtrate was concentrated and purified by flash chromatography
on silica gel (eluting with 15-100% EtOAc in hexane for 30 minutes
followed by 100% EtOAc for 10 minutes) to give the desired product
(168) as an off-white powder (0.055 g, 0.0677 mmol, 47% yield).
LC-MS (ESI): (exact mass: 811.5) m/e=812.6 [M+1].sup.+.
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-p-
yridin-2-ylamino)-phenyl]-amide (170)
[0491] 1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.018 g,
0.096 mmol) was dissolved in DMA (2 mL), .sup.iPr.sub.2EtN (0.096
mmol) was added followed by HBTU (0.036 g, 0.096 mmol) and the
mixture was shaken in an 8 mL Teflon septum capped vial at room
temperature for 20 minutes.
4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-2-(4--
aminophenyl-amino)-pyridine (168) (0.055 g, 0.0677 mmol) was added
and the mixture was shaken at room temperature for 16 h. LC-MS
indicated complete coupling at this point. The mixture was diluted
with EtOAc (25 mL) and the organic layer washed with water (15 mL),
NaHCO.sub.3 (aqueous sat., 15 mL) and brine (15 mL) via extraction,
dried over MgSO.sub.4 and concentrated to give a brown oil.
Purification by flash chromatography on silica gel using a gradient
of hexane and EtOAc (eluding with 15-100% EtOAc in hexane for 30
min) gave the desired product (170) as an off-white powder upon
concentration (0.042 g, 0.043 mmol, 64% yield). LC-MS (ESI): (exact
mass: 981.53) m/e=982.6 [M+H.sup.+].
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(4,6-bis-((3R,5S)-3,5-bis-aminopiperidin-1-yl)-pyridin-2-ylamino)-phen-
yl]-amide (171)
[0492] 1-Hydroxy-naphthalene-2-carboxylic acid
[4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-p-
yridin-2-ylamino)-phenyl]-amide (170) (0.042 g, 0.043 mmol) was
dissolved in MeOH (4 mL) and 4.0 M HCl in dioxane (4 mL) was added.
The mixture was shaken at room temperature for 16 h in a Teflon
septum capped 40 mL I-Chem vial. LC-MS indicated complete
deprotection at this point. The mixture was concentrated to give a
solid that was triturated with MeOH (1 mL) followed by collection
by filtration under reduced pressure. The solid was lyophilized
from 0.25 M of HCl in H.sub.2O twice to give the desired product
(171) as the HCl salt form as a slightly yellow powder [0.021 g,
0.024 mmol (calculated based on the molecular weigh of the HCl salt
determined by elemental analysis), 57.2% yield, 2.5% total yield
for 7 steps]. LC-MS (ESI): (exact mass: 581.32) m/e=582.3
[M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.66 (q,
2H, J=11.6 Hz), 2.38 (s, br, 2H), 2.61 (t, 4H, J=11.2 Hz), 3.11 (s,
br, 4H), 3.62 (s, br, 2H), 4.54 (s, br, 4H), 5.73 (s, 2H), 7.13 (d,
2H, J=8.8 Hz), 7.37 (d, 1H, J=9.2 Hz), 7.49 (t, 1H, J=7.2 Hz),
7.63-7.56 (m, 3H), 7.83 (d, 1H, J=8 Hz), 8.10 (d, 1H, J=8.8 Hz),
8.21 (d, 1H, J=8 Hz), 8.48 (s, br, 12H), 10.44 (s, 1H). Elemental
analysis calcd (%) for
C.sub.32H.sub.39N.sub.9O.sub.2.5H.sub.2O.5HCl: C, 45.00; H, 6.37;
N, 14.76. found: C, 44.82; H, 6.12; N, 14.38.
4.12 General Method of Synthesis of Formula Ie & If
Compounds
[0493] Scheme 37 describes a general synthetic procedure for
preparing compound of Formula Ie and If. ##STR75##
[0494] The trichloropurine (172) reacted with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) under
refluxing condition in the mixed solvents of EtOH and H.sub.2O to
give the bis-aminated product 173. This product was purified by
column chromatographed on a silica gel column, using a gradient of
hexane-ethyl acetate to generate the desired pure product 173.
[0495] Compound 173 is reacted with aniline 147 in the presence of
Pd.sub.2(dba).sub.3 catalyst and Xantphos ligand, and
Cs.sub.2CO.sub.3 as base in a toluene at 100.degree. C. The
reaction is checked for progress by LC-MS and upon completion, the
mixture is diluted with EtOAc and methanol and the inorganic solid
was filtered off through Celite. The resulting filtrate is
concentrated in vacuo. The residue is purified by flash
chromatography on a silica gel column, using a gradient of
hexane-ethyl acetate to generate the desired pure product 147.
[0496] Treatment of 174 with excess of 2 M HCl in dioxane and
methanol at room temperature overnight, followed by evaporation of
the solvents under reduced pressure can provide the target 175 as a
HCl salt.
[0497] A related chemical transformation is described in S. R.
Breshears, S. S. Wang, S. G. Bechtolt and B. E. Christensen, J. Am.
Chem. Soc., Vol. 81, 1959, P3789-3792.
[0498] The methodology described in this section is useful for the
production of various derivatives represented by Formula Ie &
If.
4.12.1 EXAMPLE 18
Synthesis of Formula Ie & If Compound 178
[0499] Scheme 38 describes the synthesis of compound 178.
##STR76##
[0500] The trichloropurine (172) (483 mg, 2 mmol), was mixed with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (2.52 g, 8
mmol) in 15 mL of EtOH and 15 mL of H.sub.2O. This mixture was
heated to reflux (oil bath at 105.degree. C.) for 22 hours. The
mixture was then dried under vacuum. The crude material was
purified by flash chromatography on a silica gel column using a
gradient of hexane-ethyl acetate to generate the desired product
173 (620 mg, 0.794 mmol) as a white solid in 39.7% isolated yield.
LC-MS: m/e 781.6 [M+1].sup.+ (exact ms: 780.4).
[0501] Compound 173 (479.4 mg, 613.6 .mu.mol) was mixed with
aniline 176 (256.2 mg, 920.6 .mu.mol), CsCO.sub.3 (700 mg, 2.15
mmol), Pd.sub.2(dba).sub.3 (58.2 mg, 63.6 .mu.mol), Xantphos (107.5
mg, 185.8 .mu.mol) and 9 mL of toluene and then, purged with
N.sub.2 for a few minutes. The mixture was heated at 100.degree. C.
with stirring for 92 hours. The reaction mixture was cooled down,
diluted with EtOAc (4 mL) and MeOH (4 mL) and the inorganic solid
was filtered off through Celite. The resulting filtrate was
concentrated in vacuo. The residue was purified by flash
chromatography on a silica gel column using a gradient of
hexane-ethyl acetate to generate the desired product 177 (192 mg,
187.8 .mu.mol) in 42.5% isolated yield (the isolated yield was
calculated base on the consideration of the fact that 134 mg of the
starting material of 173 was recovered during the purification).
LC-MS: m/e 1023.9 [M+1].sup.+ (exact ms: 1022.53).
[0502] Compound 177 (192 mg, 187.8 .mu.mol) was dissolved in 4 mL
of methanol. HCl (4.0 M, 4 mL) was added and the mixture was shaken
at room temperature for 15 hours. The solvent was evaporated under
vacuum and the residue was purified by MS-triggered HPLC using a
gradient of CH.sub.3CN and H.sub.2O with 0.5% TFA to give the
desired product (178) as a THF salt. This TFA salt was converted to
HCl salt by first re-dissolving it in MeOH (8 mL) and then treating
it with HCl (4.0 M in dioxane, 4 mL). The solvent was evaporated
under reduced pressure on rotary evaporator and the residue was
dried over oil pump for 2 days to give the desired product 178
(56.6 mg, 90.95 .mu.mol) in 48.4% isolated yield as the HCl salt
with HPLC purity of 100% by ELSD. LC-MS: m/e 623.5 [M+1].sup.+
(exact ms: 622.32). .sup.1H NMR (DMSO-d.sub.6): .delta.=10.47 (s,
1H), 8.44-8.78 (m, 13H), 8.27 (d, J=8 Hz, 1H), 8.16 (d, J=9.2 Hz,
1H), 7.89 (d, J=8.8 Hz, 1H), 7.60-7.74 (m, 5H), 7.56 (t, J=8 Hz,
1H), 7.43 (d, J=8.8 Hz, 1H), 5.45 (br, 1H), 4.52-4.62 (m, 1H),
3.12-3.44 (m, 6H), 2.82-3.06 (m, 4H), 2.70 (t, J=11.8 Hz, 1H),
2.42-2.58 (m, 2H), 1.66-1.86 (m, 3H). Elemental analysis calcd (%)
for C.sub.32H.sub.38N.sub.12O.sub.2.5.5HCl.5H.sub.2O (913.324): C,
42.08; H, 5.90; N, 18.40. found C, 42.02; H, 5.99; N, 18.08.
[0503] This methodology is useful for the production of various
derivatives represented by Formula Ie & If.
[0504] Other variations of this methodology would be apparent to
those skilled in the art.
4.13 General Method of Synthesis of Formula If & Ig
Compounds
4.13.1 Synthesis of Formula If and Ig Compounds by Scheme 39
[0505] Scheme 39 describes a general synthetic procedure for
preparing compound 181 of Formula If and Ig. ##STR77##
[0506] The trichloropurine (172) reacts with aniline 147 under
refluxing condition in the mixed solvents of EtOH and H.sub.2O to
give the 6-position aminated product 179.
[0507] Compound 179 reacts with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)piperidine (4, >2
equiv.) in the presence of a Pd-catalyst selected from
Pd.sub.2(dba).sub.3, Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-Binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid was filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 180.
[0508] Treatment of 180 with an excess of 2 M HCl in dioxane and
methanol at room temperature overnight, followed by evaporation
under reduced pressure provides the target 181 as an HCl salt.
[0509] This methodology is useful for the production of various
derivatives represented by Formula If & Ig. Other variations of
this methodology would be apparent to those skilled in the art.
4.13.2 Another General Method of Synthesis of Formula If
Compounds
[0510] Scheme 40 describes a general synthetic procedure for
preparing compound 186 of Formula If ##STR78##
[0511] In this general method, starting material 182 reacts with
iodoarene derivative 133 in a solvent selected from toluene,
xylenes, anisole or chlorobenzene in the presence of
tris-triphenylphosphine copper bromide [Cu(PPh.sub.3).sub.3Br] as
catalyst and cesium carbonate as base at an elevated temperature
between 80 and 140.degree. C., preferably from 110 to 120.degree.
C., in an argon atmosphere to furnish, after column chromatography
on silica gel, the arylamino derivative 183. Related chemical
transformations are described in Gujadhur, R. et al., Tetrahedron
Letters, 42, 4791-4793 (2001).
[0512] Compound 183 reacts with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)piperidine (4) in the
presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
Celite.
[0513] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the pure product 184.
[0514] Deprotection of the Boc groups of the compound 184 using 2 M
HCl gives the desired product 185 as an HCl salt.
[0515] This methodology is useful for the production of various
derivatives represented by Formula If. Other variations of this
methodology would be apparent to those skilled in the art.
4.14 General Method of Synthesis of Formula Ih & Ii
Compounds
[0516] Scheme 41 describes a general synthetic procedure for
preparing compound 189 of Formula Ih & Ii. ##STR79##
[0517] In this general method of producing compounds of Formula Ih
and Ii, the 2,4,6-trichloropyrimidine (186) is reacted with an
aromatic amine 147 at a temperature between negative 20.degree. C.
and +120.degree. C., preferably between 0 to 80.degree. C. in a
solvent (or a mixture of solvents), selected from dioxane, ethylene
glycol dimethyl ether, diglyme, diethyl ether, dichloromethane,
chloroform, THF, DMF, dimethylacetamide, N-methylpyrrolidone, DMSO,
sulfolane, toluene, chlorobenzene or o-dichlorobenzene in the
presence of a base, such as diisopropylethylamine, triethylamine,
N-methylmorpholine, DBU, DBN, DABCO, pyridine, picoline, lutidine,
collidine, potassium carbonate, sodium carbonate, sodium hydride,
sodium methoxide, potassium or sodium t-butoxide, or potassium
fluoride in the presence, or absence of 18-crown-6. The progress of
the reaction is monitored by standard means such as TLC or HPLC or
LC/MS. Efficient stirring is maintained throughout the
reaction.
[0518] When the reaction is complete, the reaction mixture is
brought to room temperature, extracted with water, dried with
sodium or magnesium sulfate and concentrated in vacuo. The
above-obtained substituted pyrimidine derivative 187 is then
reacted with 4 in a solvent (or a mixture of solvents), selected
from dioxane, ethylene glycol dimethyl ether, diglyme, diethyl
ether, dichloromethane, chloroform, THF, DMF, dimethylacetamide,
N-methylpyrrolidone, DMSO, sulfolane, toluene, chlorobenzene or
o-dichlorobenzene in the presence of a base, selected from
diisopropylethylamine, triethylamine, N-methylmorpholine, DBU, DBN,
DABCO, potassium carbonate, sodium carbonate, sodium hydride,
sodium methoxide, potassium or sodium t-butoxide or potassium
fluoride in the presence, or absence of 18-crown-6, in the presence
or absence of a catalyst, selected from palladium acetate,
palladium chloride, tetrakis triphenylphosphine palladium,
tris(dibenzylideneacetone)dipalladium(0), nickel acetate, cuprous
chloride or cuprous iodide in the presence or absence of a
phosphine derivative, selected from triphenylphosphine,
tri-o-tolylphosphine, BINAP, 1,1'-bis(diphenylphosphino)ferrocene,
in a protective atmosphere of argon, at a temperature between 20 to
180.degree. C., preferably 60 to 140.degree. C. to give the
protected 2,4,6-trisubstituted pyrimidine derivative 188. Efficient
stirring is maintained throughout the reaction.
[0519] The reaction mixture is then concentrated in vacuo and the
product is distributed between water and suitable solvent, such as
chloroform, dichloromethane or ethyl acetate and purified by column
chromatography on silica gel or reverse phase HPLC. In a specific
example the aromatic amine 147 is 3,4-dichloroaniline, which gives
the pyrimidine derivative 190. Deprotection (removal of the BOC
protecting groups by HCl in dioxane provides the target compound
189. In case of the 3,4-dichlorophenylamino substitution, the
target compound is 191.
4.14.1 EXAMPLE 19
Synthesis of 191 (R=3,4-di-Cl)
[0520] 50 .mu.mol of 2,4,6-trichloropyrimidine (186), 50 .mu.mol
3,4-dichloroaniline, (50a) 110 mg of Na.sub.2CO.sub.3 and 1.4 mL of
ethanol were mixed and shaken at room temperature for 4.5 hours.
LC-MS of the reaction mixture confirmed the identity of the
intermediate (192: R=3,4-di-Cl) with 93.2% HPLC purity by ELSD. The
reaction mixture was then dried under vacuum. 2 mL of n-pentanol
was added to dissolve the intermediate followed by 64 mg (200
.mu.mol) of (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine
(4) and 500 .mu.L of 1M iPr.sub.2NEt and the resulting mixture was
heated at 140.degree. C. for 4 days. The reaction mixture was dried
under vacuum and purified by normal-phase HPLC using MS-triggered
Waters purification system to give the corresponding
BOC-intermediate (190). The Intermediate 88a was dissolved in 2 mL
of MeOH. 2.0 mL of 4.0 M HCl in 1,4-dioxane was then added. The
resulting reaction mixture was stirred at room temperature
overnight and concentrated under vacuum. This crude material was
then purified by reverse-phase HPLC to give the desired product,
3,4-dichloro-phenyl-(2,6-bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-pyrimid-
in-4-yl)-amine, (191) (2.2 mg). LC-MS was used to confirm the
identity of the desired product. LC-MS: MS m/e 466.5 [M+1].sup.+
(exact ms: 465.19).
[0521] This methodology is useful for the production of various
derivatives represented by Formula Ih & Ii.
4.14.2 EXAMPLE 20
Synthesis of 193
[0522] ##STR80##
[0523] Scheme 42 describes the procedure for preparing compound 193
of Formula Ih & Ii. ##STR81##
[0524] 1 mmol of 2,4,6-trichloropyrimidine (186), 1 mmol of aniline
(111), 504 mg (6 mmol) of NaHCO.sub.3 and 8 mL of NMP were mixed
and stirred at room temperature for 68 hours. LC-MS of the reaction
mixture confirmed the identity of the intermediate (195) with 90%
HPLC purity by ELSD. The reaction mixture was directly used in the
next step.
[0525] (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4)
(757 mg, 2.4 mmol) was added into the above mixture and the
resulting mixture was heated at 100.degree. C. for 15 hours. 1.26 g
(4 mmol) of additional compound 4 was added and the mixture was
heated at 110.degree. C. with stirring for 90 hours. LC-MS of the
reaction mixture confirmed the disappearance of the starting
material of 195 and the formation of the major desired product
(196). After the reaction was cooled down, 70 mL of CHCl.sub.3 and
20 mL of H.sub.2O was added. After liquid-liquid extraction, the
two layers were separated and the organic layer washed twice more
with H.sub.2O (30 mL.times.2). The organic layer was dried under
vacuum. The crude material was purified by flash chromatography
using hexane and EtOAc to give the desired product 196 (260.3 mg,
265 .mu.mol, 26.5% isolated yield for 2 steps). LC-MS: MS m/e 983.9
[M+1].sup.+ (exact ms: 982.53).
[0526] Compound 196 (260.3 mg, 265 .mu.mol) was dissolved in 4 mL
of MeOH. 4.0 mL of 4.0 M HCl in 1,4-dioxane was then added. The
reaction mixture was stirred at room temperature overnight and
concentrated under vacuum. This crude was then purified by
reverse-phase HPLC (CH.sub.3CN/H.sub.2O) to give the desired
product 193 (89.4 mg, 102.35 .mu.mol, 38.6% isolated yield based
the molecular weigh of the HCl salt determined by elemental
analysis) as the HCl salt with HPLC purity of 160% by ELSD. LC-MS:
m/e 583.3 [M+1].sup.+ (exact ms: 582.32). .sup.1H NMR (400 MHz,
D.sub.2O): 8.17 (d, J=8.4 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.60-7.68
(m, 2H), 7.55 (td, J.sub.1=8 Hz, J.sub.2=1.2 Hz, 1H), 7.37 (dd,
J.sub.1=8.6 Hz, J.sub.2=7.2 Hz, 4H), 7.23 (d, J=8.8 Hz, 2H),
4.52-4.62 (m, 2H), 4.38-4.48 (m, 2H), 3.28-3.42 (m, 4H), 2.87 (dt,
J.sub.1=12.6 Hz, J.sub.2=18.8 Hz, 4H), 2.56-2.66 (m, 2H), 1.76-1.90
(m, 2H). Elemental analysis calcd (%) for
C.sub.31H.sub.38N.sub.10O.sub.2.6HCl.4H.sub.2O (873.514): C, 42.62;
H, 6.00; N, 16.04. found C, 42.35; H, 6.14; N, 16.28.
4.15 General Method of Synthesis of Formula Ij Compounds
[0527] Scheme 43 describes a general synthetic procedure for
preparing compound 200 of Formula Ij. ##STR82##
[0528] In this general method, starting material 192 reacts with
2-4 equivalents of
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in the
presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is chromatographed on a silica gel column, using a
gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the bis-aminated pure product 91.
[0529] Compound 198 reacts with iodoarene derivative 133 in a
solvent selected from toluene, xylenes, anisole or chlorobenzene in
the presence of tris-triphenylphosphine copper bromide
[Cu(PPh.sub.3).sub.3Br] as catalyst and cesium carbonate as base at
an elevated temperature between 80 to 120.degree. C., preferably
110 to 120.degree. C., in an argon atmosphere to furnish after
column chromatography on silica gel the arylamino derivative 199.
Related chemical transformations are described in Gujadhur, R. et
al., Tetrahedron Letters, 42, 4791-4793 (2001).
[0530] Compound 199 undergoes the deprotection of the Boc groups to
give the crude product that is subsequently purified by HPLC to
give the pure compound 200 as HCl salt.
[0531] This methodology is useful for the production of various
derivatives represented by Formula Ij. Other variations of this
methodology would be apparent to those skilled in the art.
4.15.1 Another General Method of Synthesis of Formula Ij Compound
(SCHEME 44)
[0532] Scheme 44 describes the general synthetic procedures for
preparing compound of Formula Ij. ##STR83##
[0533] One equivalent of 3,6-dichloro-pyridazine-4-carboxylic acid
(201), 3 equivalents of
3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) and 3 equivalents
of .sup.iPr.sub.2NEt in DMF are mixed. The mixture is heated at
100.degree. C. with shaking. The reaction was monitored by TLC
analysis and LC-MS. Upon the completion of the reaction, the
solvent was removed under reduced pressure. When
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) was used,
compound 202 with the following characteristics was obtained after
purification by HPLC. LC-MS (ESI): m/e=472.3 [M+H].sup.+.
[0534] A solution of four equivalents of .sup.iPr.sub.2NEt in THF
was added into a mixture of compound 2 and aniline (147) in THF and
DMF. A solution of two equivalents of HOBT in THF (0.5 M) is added
and the mixture is shaken at room temperature for 5 minutes. A
solution of 2 equivalents of EDCl in CH.sub.2Cl.sub.2 (0.25 M) is
added. The reaction mixture is shaken at room temperature for 24 h
to 2 days. The solvent is removed under reduced pressure. The
residue is dissolved in CHCl.sub.3. The organic layer is washed
with 10% aqueous NaHCO.sub.3, followed by H.sub.2O via extraction,
dried over MgSO.sub.4 and concentrated under reduced pressure. The
crude material is purified by flash chromatography on silica gel
using a gradient of hexane and ethyl acetate to give compound
203.
[0535] Excess of 3,5-bis-(tert-butoxycarbonylamino)-piperidine (4)
is added into compound 203 in NMP, followed by NaHCO.sub.3 (6
equiv.). The reaction mixture is heated at 110.degree. C. for a few
days with shaking. The reaction mixture is diluted with CHCl.sub.3
and washed with H.sub.2O via extraction. The organic layer is dried
under reduced pressure and the crude is purified by flash
chromatography to give the desired product (204).
[0536] Compound 204 is dissolved in MeOH. An equal volume of 4.0 M
HCl in dioxane is then added and the reaction mixture is shaken at
room temperature overnight. The solvent is evaporated and the
residue is purified by HPLC using a gradient of CH.sub.3CN and
H.sub.2O to give the desired product 205 as the HCl salt.
[0537] This methodology is useful for the production of various
derivatives represented by Formula Ij. Other variations of this
methodology would be apparent to those skilled in the art.
4.15.2 EXAMPLE 21
Scheme 45 Describes the Synthetic Procedures for Preparation of
Compound
[0538] ##STR84##
6-(3,5-Bis-tert-butoxycarbonylamino-piperidin-1-yl)-3-chloro-pyridazine-4--
carboxylic acid (207)
[0539] A mixture of 3,6-Dichloro-pyridazine-4-carboxylic acid (201)
(400 mg, 2 mmol) and (3R,5S)-3,5-bis-tert butoxy carbonyl amino
piperidine (4) (1.3 g, 4 mmol) in 14 ml DMF containing
.sup.iPr.sub.2NEt (718 .mu.l, 4 mmol) was heated at 100.degree. C.
for 25.6 h with shaking. The solvent was removed under reduced
pressure. After HPLC purification, compound 207 (483 mg, 51.1%) was
obtained as a solid. LC-MS (ESI): m/e=472.3 [M+1].sup.+
[5-tert-Butoxycarbonylamino-1-(6-chloro-5-(4-[(1-hydroxy-naphthalene-2-car-
bonyl)-amino]-phenylcarbamoyl)-pyridazin-3-yl)-piperidin-3-yl]-carbamic
acid tert-butyl ester (209)
[0540] .sup.iPr.sub.2NEt (360 .mu.L, 2 mmol) in THF (1 ml) was
added to a mixture of 207 (483 mg, 1.02 mmol) and
1-hydroxy-naphthalene-2-carboxylic acid 111 (4-amino-phenyl)-amide
(283.88 mg, 1.02 .mu.mol) in THF (5 mL). HOBT (306.3 mg, 2 mmol) in
THF (2 mL) was added. The reaction mixture was vortexed for 1
minute. EDCl (383.4 mg, 2 mmol) in CH.sub.2Cl.sub.2 (4 mL) was
added into the above reaction mixture. The reaction mixture was
shaken at room temperature for 16 h. The solvent was removed under
reduced pressure. The solid was dissolved in CHCl.sub.3 (5 .mu.L),
washed with 10% NaHCO.sub.3 (3 mL), H.sub.2O (3 mL) and dried over
MgSO.sub.4. Solvent was removed under reduced pressure. After flash
chromatography purification using ethyl acetate and hexane, 730 mg
of compound 209 (98.4% yield) was obtained as a solid. LC-MS (ESI):
m/z=732.5 [M+1].sup.+.
[0541] (3R,5S)-3,5-bis-tert butoxy carbonyl amino piperidine (4)
(32 mg, 2 mmol) was added into compound 209 (730 mg, 1 mmol) in NMP
(6 mL) followed by NaHCO.sub.3 (504 mg, 6 mmol). The reaction
mixture was heated at 110.degree. C. for 107 h with shaking. The
reaction mixture was diluted with CHCl.sub.3 (8 mL) and washed with
H.sub.2O (4 mL.times.2). The water was back-extracted with
CHC.sub.3 (4 ml). The combined organic layers are dried under
reduced pressure. After flash chromatography purification, compound
210 (25 mg, 2.5% yield) was obtained as a solid. LC-MS (ESI):
m/e=1011.9 [M+1].sup.+;
3,6-Bis-(3,5-diamino-piperidin-1-yl)-pyridazine-4-carboxylic acid
{4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-phenyl)-amide
(211)
[0542] Compound 210 (25 mg, 25 .mu.mol) was dissolved in MeOH (1
mL). HCl (4 M) in dioxane (1 mL) was then added at room
temperature. After stirring at room temperature for 4 h, the
reaction mixture was concentrated and the crude product was
purified by HPLC to give the desired product (211) (2.6 mg, 13.6%
yield) as a light yellow solid as HCl salt. LC-MS (ESI): m/e=611.3
[M+1].sup.+; .sup.1H NMR (400 MHz, D.sub.2O): .delta. 1.83-1.96 (m,
2H), 2.70 (s, br, 2H), 3.13 (t, 3H, J=11.6 Hz), 3.60-3.73 (m, 4H),
3.77-3.78 (m, 3H), 3.80-3.87 (m, 1H), 3.93 (d, 1H, J=8.4 Hz), 7.49
(d, 1H, J=8.8 Hz), 7.59 (s, 1H), 7.64 (m, 3H), 7.70 (m, 3H), 7.80
(d, 1H, J=8 Hz), 7.91 (d, 1H, J=7.2 Hz), 8.32 (d, 1H, J=7.6
Hz).
4.16 General Method of Synthesis of Formula Ij & Ik
Compounds
[0543] Scheme 46 describes a general synthetic procedure for
preparing compound of Formula Ij & Ik. ##STR85##
[0544] In this general method, 3-4 equivalents of starting material
212 react with one equivalent of aniline 147 in the presence of
Pd-catalyst selected from Pd.sub.2(dba).sub.3, Pd(OAc).sub.2,
PdCl.sub.2(PCy.sub.3).sub.2, PdCl.sub.2[P(.sup.tBu).sub.2OH],
ligand selected from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere.
[0545] The reaction is checked for progress by TLC or HPLC and upon
completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid was filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the bis-aminated pure product 213.
[0546] Bis-amination of the compound 213 by reacting with 2-3
equivalents of (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine
(4) in the presence of Pd-catalyst selected from
Pd.sub.2(dba).sub.3, Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid was filtered off through
Celite.
[0547] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 214. Related chemical
transformations are described in Donald E. Ames and Richard J.
Ward, Journal of the Chemical Society, Perkin Transactions 1:
Organic and Bio-Organic Chemistry (1972-1999), 6, 534-8 (1975).
[0548] Deprotection of the Boc groups of compound 214 gives the
crude product that is subsequently purified by HPLC to give the
pure compound 215 as HCl salt.
[0549] This methodology is useful for the production of various
derivatives represented by Formula Ij & Ik. Other variations of
this methodology would be apparent to those skilled in the art.
4.17 General Method of Synthesis of Formula II Compounds
[0550] Scheme 47 describes a general synthetic procedure for
preparing compound 200 of Formula II. ##STR86##
[0551] In this general method based on the procedure described in
the reference below, 3.55 g of tetrabromocyclopropene (216) (10
mmol) and 1.26 g trimethylsilylazide (11 mmol) are mixed and heated
at 85.degree. C. for 3 h. Upon cooling, a golden brown solid is
precipitated out and that is filtered under vacuum.
Recrystallization from CHCl.sub.3/benzene gives 1.46 g product 217
in 46% yield. Compound 217 reacts with large excess of
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in a
solvent selected from diethyl ether, THF and DMF at a temperature
from -30.degree. C. to room temperature. Extraction with H.sub.2O
followed by drying the organic layer with Na.sub.2SO.sub.4 gives
the crude product that was purified by re-crystallization to give
the pure product 218. Related chemical transformations for the
above 2 steps are described in R. Gompper and Schonafinger, Chem.
Ber, 112, 1535-1544 (1979).
[0552] The mono-bromo compound 218 is then aminated by reacting
with aniline derivative 147 in the presence of Pd-catalyst selected
from Pd.sub.2(dba).sub.3, Pd(OAc).sub.2,
PdCl.sub.2(PCy.sub.3).sub.2, PdCl.sub.2[P(.sup.tBu).sub.2OH],
ligand selected from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 219.
[0553] Deprotection of the Boc groups of compound 219 gives the
crude product that is subsequently purified by HPLC to give the
pure compound 220 as HCl salt.
[0554] This methodology is useful for the production of various
derivatives represented by Formula II. Other variations of this
methodology would be apparent to those skilled in the art.
4.18 EXAMPLE 22
Synthesis of Formula Im Compounds
[0555] Scheme 48 describes a synthetic procedure for preparing
compound of 221 of Formula Im. ##STR87##
[0556] In the synthesis of compound 221 as shown above,
triamination of the tribromo compound 217 is accomplished by
reacting 3-4 equivalents of di-Boc-protected 3,5-diaminopiperidine
(4) in the presence of Pd-catalyst selected from
Pd.sub.2(dba).sub.3, Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(Di-t-butylphosphino)biphenyl,
2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-Bis(dicyclohexylphosphino)-1,1'-Binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid was filtered off through
celite.
[0557] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 194. Related chemical
transformations are described in R. Gompper and Schonafinger, Chem.
Ber, 112(5), 1535-1544 (1979).
[0558] Deprotection of the Boc groups of compound 194 gives the
crude product that is subsequently purified by HPLC to give the
pure compound 221 as HCl salt.
[0559] This methodology is useful for the production of various
derivatives represented by Formula Im. Other variations of this
methodology would be apparent to those skilled in the art.
4.19 General Method of Synthesis of Formula In Compounds
[0560] Scheme 49 describes a general synthetic procedure for
preparing compound 225 of Formula In. ##STR88##
[0561] In this general method, starting material 222 reacts with
iodoarene derivative 133 in a solvent selected from toluene,
xylenes, anisole or chlorobenzene in the presence of
tris-triphenylphosphine copper bromide [Cu(PPh.sub.3).sub.3Br] as
catalyst and cesium carbonate as base at an elevated temperature
between 80 to 140.degree. C., preferably 110 to 120.degree. C., in
an argon atmosphere, and furnishes after column chromatography on
silica gel the arylamino derivative 223. Related chemical
transformations are described in Gujadhur, R. et al., Tetrahedron
Letters, 42, 4791-4793 (2001).
[0562] Bis-amination of compound 223 is accomplished by reacting
with 2-3 equivalents of
(3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) in the
presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'bBinaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid was filtered off through
Celite. The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel, column,
using a gradient of chloroform-ethyl acetate or chloroform-methanol
to generate the Boc-protected pure product 224.
[0563] Compound 224 undergoes the de-protection of the Boc groups
to give the crude product that is subsequently purified by HPLC to
give the pure compound 225 as HCl salt.
[0564] This methodology is useful for the production of various
derivatives represented by Formula In. Other variations of this
methodology would be apparent to those skilled in the art.
4.20 General Method of Synthesis of Formula Io and Ip Compounds
[0565] Scheme 50 describes a general synthetic procedure for
preparing compound of Formula Io and Ip. ##STR89##
[0566] In this general method, dichloro starting material 226
reacts with (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine 4
in the presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, NaHCO.sub.3,
K.sub.3PO.sub.4 and Et.sub.3N in a solvent selected from PhMe, DME,
O-xylene, dioxane, DMF and HMPA at a temperature from 50.degree. C.
to 140.degree. C. preferentially between 80.degree. C. and
110.degree. C. for 16-72 hours under N.sub.2 atmosphere. The
reaction is checked for progress by TLC or HPLC and upon
completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
celite.
[0567] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 227. Related chemical
transformations are described in W. Karminski et al., Journal of
Environmental Science and Health, Part B: Pesticides, Food
Contaminants, and Agricultural Wastes, B18(4-5), 599-610
(1983).
[0568] After purification by column chromatography using silica
gel, compound 227 is deprotected to give the crude product 228
which is further purified by HPLC to give desired pure product 228
as HCl salt.
[0569] Starting material (226) is made according to the literature
method described in Robert J. Ife, Thomas H. Brown, Peter Blurton,
David J. Keeling, Colin A. Leach, Malcolm L. Meeson, Michael E.
Parsons and Colin, J. Theobald, J. Med. Chem. 1995, 38,
2763-2773.
[0570] This methodology is useful for the production of various
derivatives represented by Formula Io and Ip. Other variations of
this methodology would be apparent to those skilled in the art.
4.20.1 Another General Method of Synthesis of Formula Io and/or Ip
Compounds
[0571] Scheme 51 describes the procedure to prepare compound 235 of
Formula Io and/or Formula Ip. ##STR90##
[0572] R refers to (C.sub.1-C.sub.6)alkyl or alkylaryl.
[0573] In this general method, compound 229 is prepared in the same
way as compound 226, as above, according to the literature method.
Compound 229 is first treated with
(3R,5S)-bis-(tert-butoxycarbonylamino)-piperidine (4) at room
temperature in a solvent selected from THF, EtOH, dioxane, DMF and
NMP in the presence of a base selected from .sup.iPrNEt,
NaHCO.sub.3, Et.sub.3N, K.sub.2CO.sub.3 and Cs.sub.2CO.sub.3 to
give compound 230 that is further treated with amine 101 in the
presence of a base selected .sup.iPr.sub.2NEt, NaHCO.sub.3,
Et.sub.3N, K.sub.2CO.sub.3 and Cs.sub.2CO.sub.3 with heating
(100-120.degree. C.) to give compound 231. In the case in which
amine 101 is (3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine
(4), compound 229 is treated with amine (4) in refluxing THF to
give compound 230.
[0574] The nitro-group in compound 230 is reduced to the
corresponding amino-group using the reducing agent of Raney Nickel
with hydrazine or, alternatively, hydrogenation in the presence of
Pd/C catalyst to give compound 232.
[0575] Compound 232 is then coupled with acid chloride 233 in the
presence of Et.sub.3N or NaHCO.sub.3 at room temperature to give
compound 234. After removing the protecting groups of compound 234
using HCl, the desired product (235) is obtained as the HCl
salt.
[0576] Chemical transformations related to above syntheses are
described in (1) Robert J. Ife, Thomas H. Brown, Peter Blurton,
David J. Keeling, Colin A. Leach, Malcolm L. Meeson, Michael E.
Parsons and Colin J. Theobald, J. Med. Chem. 1995, 38, 2763-2773;
and (2) Sung J. Lee, Yoshitaka Konishi, Dingwei T. Yu, Tamara A.
Miskowski, Christopher M. Riviello, Orest T. Macina, Manton R.
Frierson, Kigen Kondo, Masafumi Sugitani, Jagadish C. Sircar and
Kimberly M. Blazejewski, J. Med. Chem. 1995, 38, 3547-3557.
4.21 General Method of Synthesis of Formula Iq Compounds
[0577] Scheme 52 describes a general synthetic procedure for
preparing compound of Formula Iq. ##STR91##
[0578] In this general method, starting material 236 reacts with
2-3 equivalents of
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) in the
presence of Pd-catalyst selected from Pd.sub.2(dba).sub.3,
Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
Celite.
[0579] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 237.
[0580] Compound 237 reacts with aniline 147 in the presence of
Pd-catalyst selected from Pd.sub.2(dba).sub.3, Pd(OAc).sub.2,
PdCl.sub.2(PCy.sub.3).sub.2, PdCl.sub.2[P(.sup.tBu).sub.2OH],
ligand selected from Xantphos, P(.sup.tBu).sub.3, BINAP,
2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane and HMPA at a
temperature from 80.degree. C. to 140.degree. C. preferentially
between 100-120.degree. C. for 16-72 hours under N.sub.2
atmosphere. The reaction is checked for progress by TLC or HPLC and
upon completion, the mixture is diluted with chloroform or other
suitable solvents and the inorganic solid is filtered off through
celite.
[0581] The resulting filtrate is washed with water via extraction,
dried with magnesium or sodium sulfate and concentrated in vacuo.
The residue is column chromatographed on a silica gel column, using
a gradient of chloroform-ethyl acetate or chloroform-methanol to
generate the Boc-protected pure product 238.
[0582] Deprotection of the Boc groups of compound 238 gives the
crude product that is subsequently purified by HPLC to give the
pure compound 239 as HCl salt.
[0583] This methodology is useful for the preparation of various
derivatives represented by Formula Iq (for example 240). Other
variations of this methodology would be apparent to those skilled
in the art. ##STR92##
4.21.1 EXAMPLE 23
Synthesis of Bis-3,5-Diaminopiperidine Substituted Quinoline 119 of
Formula Iq
[0584] Scheme 53 shows an exemplary synthetic procedure for
preparing Formula Iq compounds (243) of the present invention.
##STR93##
[0585] 65 mg of 2,4-dichloro-3-carbomethoxyquinoline (241), 139 mg
of (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine 4, 500
.mu.L of 1M iPr.sub.2Net in DMF and DMF (2 mL) were mixed and
heated at 100.degree. C. overnight. LC-MS of the reaction mixture
showed that only a small amount of desired product and majority was
the mono-substituted product.
[0586] The reaction mixture was dried under vacuum and purified by
HPLC to give 6.6 mg of the desired product (242) (yellow oil). The
BOC-intermediate was dissolved in 1 mL of MeOH, then 1 mL of 4 M
HCl in 1,4-dioxane was added. The resulting reaction mixture was
stirred at room temperature overnight and concentrated under vacuum
to give the desired product (243) (3.6 mg). LC-MS was used to
confirm the identity of the desired product. LC-MS: a single peak
(both ELSD and UV-254) with MS m/e 414.2 [M+1] was found (exact
mass: 413.25).
4.22 General Method of Synthesis of Formula Ir Compounds
[0587] Scheme 54 describes another general synthetic procedure for
preparing compound 249 of Formula Ir. ##STR94## R refers to
subtituants defined for substituted aryls.
[0588] 2,3-Dichloro-6-nitro-quinoxaline (244) (1 equiv.),
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (2.4
equiv.), NaHCO.sub.3 (6 equiv.) and NMP were mixed. The mixture was
heated at 110.degree. C. in a Teflon septum capped 8 mL vial for 5
h. The reaction was monitored by TLC and LC-MS. The mixture was
poured into ice-water and the resulting precipitate was collected
by filtration under reduced pressure. The solid was purified by
flash chromatography to give the desired product 245.
[0589] Compound 245 was dissolved in a mixture of EtOAc and MeOH.
The solution was heated to 60.degree. C. Raney Nickel (catalytic
amount) was added followed by hydrazine (excess). The mixture
continued to stir for 15 minutes at 60.degree. C. in an opened
vial. The reaction was monitored by TLC. After cooling, the mixture
was passed through a plug of silica gel and the filtrate was
concentrated. The crude was dissolved in EtOAc, washed with water
and brine via extraction, dried over MgSO.sub.4 and concentrated to
give the desired product 246.
[0590] Same equivalent of compound 246, acid chloride (247) and
.sup.iPr.sub.2EtN were combined and dissolved in DMF (0.2 M). The
mixture was shaken at room temperature for 16-24 h. Upon completion
of the reaction indicated by TLC and LC-MS, the mixture was diluted
with EtOAc, washed with saturated aqueous NaHCO.sub.3 and brine via
extraction, dried over MgSO.sub.4 and concentrated to give the
desired product 248.
[0591] Compound 248 is dissolved in MeOH and 4.0 M HCl in dioxane
is added. The mixture is shaken at room temp for 16-24 hours. The
solution is concentrated and the crude is purified by reverse phase
HPLC to give the desired product (249) as the HCl salt.
4.22.1 EXAMPLE 24
Synthesis of Compound of Formula Ir (Scheme 55)
[0592] ##STR95## ##STR96##
2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-6-nitr-
o-quinoxaline (245)
[0593] 2,3-Dichloro-6-nitro-quinoxaline (244) (0.1 g, 0.409 mmol)
and (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (0.315
g, 1 mmol) were combined with NaHCO.sub.3 (0.206 g, 2.45 mmol) and
suspended in NMP (2.5 mL). The mixture was heated in a Teflon
septum capped 8 mL vial for 5 h. TLC (R.sub.f: 0.45-0.5 compared to
R.sub.f: 0.95 for compound 245 in 1:1 hexanes/EtOAc) and LC-MS
indicated complete reaction at this point. The mixture was poured
into ice-water (25 mL) and the resulting precipitate was collected
by filtration under reduced pressure. The solid was purified by
flash chromatography using a gradient of hexane and EtOAc (15-100%
EtOAc in hexanes in 30 minutes) to give the desired product (245)
as a yellow powder upon concentrating (0.212 g, 0.264 mmol, 64%
yield). LC-MS (ESI): (exact mass: 801.44) m/e=802.5
[M+1].sup.+.
2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinox-
alin-6-ylamine (246)
[0594]
2,3-Bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl-
)-6-nitro-quinoxaline (3) (0.159 g, 0.198 mmol) was dissolved in a
mixture of EtOAc (3 mL) and MeOH (3 mL). The solution was heated to
60.degree. C. and Raney Nickel (0.25 mL, 50% slurry in water) and
hydrazine (0.5 mL, anhydrous) were added. Bubbling was observed.
The mixture continued to stir for 15 minutes at 60.degree. C. TLC
(R.sub.f: 0.05 compared to R.sub.f: 0.3 for compound 245 in 1:1
hexanes/EtOAc) indicated complete reduction at this point. The
mixture was passed through a plug of silica gel and concentrated to
give a white powder. The solid was dissolved in EtOAc (30 mL),
washed with water (2.times.20 mL) and brine (2.times.20 mL) via
extraction, dried over MgSO.sub.4 and concentrated to give the
desired product (246) as a white powder (0.135 g, 0.175 mmol, 88.3%
yield). LC-MS (ESI): (exact mass: 771.46) m/e=772.6
[M+1].sup.+.
N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-qui-
noxalin-6-yl)-4-nitro-benzamide (251)
[0595]
2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl-
)-quinoxalin-6-ylamine (246) (0.067 g, 0.087 mmol) and
p-nitro-benzoylchloride (0.0167 g, 0.09 mmol) were combined and
dissolved in DMF (0.45 mL). .sup.iPr.sub.2EtN (0.016 mL, 0.09 mmol)
was added and the mixture was shaken at room temperature for 16 h.
TLC (R.sub.f: 0.8 compared to R.sub.f: 0.05 for compound 246 in 1:1
hexane/EtOAc) and LC-MS indicated complete coupling at this point.
The mixture was diluted with EtOAc (30 mL), washed with saturated
aqueous NaHCO.sub.3 (2.times.10 mL) and brine (2.times.10 mL) via
extraction, dried over MgSO.sub.4 and concentrated to give the
desired product (251) as an orange solid (0.063 g, 0.068 mmol,
78.6% yield). LC-MS (ESI): (exact mass: 920.48) m/e=921.8
[M+1].sup.+.
4-Amino-N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-
-yl)-quinoxalin-6-yl)-benzamide (252)
[0596]
N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-
-yl)-quinoxalin-6-yl)-4-nitro-benzamide (251) (0.063 g, 0.068 mmol)
was dissolved in a mixture of EtOAc (3 mL) and MeOH (3 mL). The
solution was heated to 60.degree. C. and Raney Nickel (0.25 mL, 50%
slurry in water) and hydrazine (0.5 mL, anhydrous) were added.
Bubbling was observed. The mixture continued to stir for 15 minutes
at 60.degree. C. The mixture was passed through a plug of silica
gel and concentrated to give an orange powder. The solid was
dissolved in EtOAc (30 mL), washed with water (2.times.20 mL) and
brine (2.times.20 mL) via extraction, dried over MgSO.sub.4 and
concentrated to give the desired product as an orange powder (0.061
g, 0.0684 mmol, 99% yield). LC-MS (ESI): (exact mass: 890.50)
m/e=891.9 [M+1].sup.+.
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-q-
uinoxalin-6-ylcarbamoyl)-phenyl]-amide (253)
[0597] 1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.016 g,
0.085 mmol) was dissolved in DMF (0.8 mL) and HBTU (0.032 g, 0.085
mmol) followed by .sup.iPr.sub.2EtN (0.022 mL, 0.128 mmol) were
added. The mixture was shaken at room temperature for 25 minutes.
4-Amino-N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)piperidin-1-
-yl)-quinoxalin-6-yl)-benzamide (252) (0.06 g, 0.068 mmol) was
added and the mixture was shaken at room temperature for 16 h. The
mixture was diluted with EtOAc, washed with sodium bicarbonate and
brine via extraction, dried over MgSO.sub.4 and concentrated under
reduced pressure. Purification by flash chromatography on silica
gel using a gradient of hexane and EtOAc gave the desired product
(253) (0.009 g, 0.0085 mmol, 12.5% yield). LC-MS (ESI): (exact
mass: 1060.54, mol. wt: 1061.23) m/e=1062.0 [M+1].sup.+.
1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,3-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-quinoxalin-6-ylcarbamoyl-
)-phenyl]-amide (254)
[0598] 1-Hydroxy-naphthalene-2-carboxylic acid
[4-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-q-
uinoxalin-6-ylcarbamoyl)-phenyl]-amide (253) (9 mg, 8.5 .mu.mmol)
was dissolved in TFA (1 mL) and the mixture was shaken in a Teflon
septum capped vial at room temperature for 3 hours. LC-MS indicated
complete de-protection at this point. The solution was concentrated
to give an orange oil. The oil was dissolved in MeOH (1 mL) and HCl
(1 mL, 4.0 M in dioxane) was added and the mixture was vortexed for
20 seconds. A fine suspension was observed. The mixture was
concentrated to an orange powder. Ethyl ether (5 mL) was added to
the powder and vortexed for 2 minutes. The solid was collected by
filtration and dried under high vacuum for 16 hours to give the
desired product (254) as a yellow/green powder (5.4 mg, 6.69
.mu.mmol, 78.7% yield, assuming a 4 HCl salt). LC-MS (ESI): (exact
mass: 660.33) m/e=661.6 [M+1].sup.+. .sup.1H NMR (400 MHz,
D.sub.2O): .delta. 1.70-1.82 (m, 2H), 2.61-2.65 (m, 2H), 2.78-2.94
(m, 2H), 3.57-3.60 (m, 2H), 3.67-3.68 (m, 4H), 3.97 (d, 2H, J=9.6
Hz), 4.23 (d, 2H, J=9.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.14 (d, 1H,
J=8.4 Hz), 7.18-7.29 (m, 3H), 7.32-7.53 (m, 6H), 7.74 (d, 2H, J=7.6
Hz).
2,3-Bis-((3R,5S)-3,5-diamino-piperidin-1-yl)-quinoxalin-6-ylamine
(255)
[0599]
2,3-Bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl-
)-6-nitro-quinoxaline (245) (0.05 g, 0.135 mmol) was dissolved in
TFA (3 mL) and the mixture was shaken at room temperature in a
Teflon septum capped vial for 3 hours. LC-MS indicated complete
de-protection at this point. The solution was concentrated to give
an orange oil. The oil was dissolved in MeOH (1 mL) and HCl (1 mL,
4.0 M in dioxane) was added and the mixture was vortexed for 20
seconds. A fine suspension was observed. The mixture was
concentrated to an orange powder. Ethyl ether (5 mL) was added to
the powder and vortexed for 2 minutes. The solid was collected by
filtration and dried under high vacuum for 16 hours to give the
desired product (255) as an orange powder (0.023 g, 0.042 mmol, 31%
yield, assumed 4 HCl salt). LC-MS (ESI): (exact mass: 401.23)
m/e=402.2 [M+1].sup.+. .sup.1H NMR (400 MHz, D.sub.2O): .delta.
1.72 (q, 2H, J=12 Hz), 2.49 (d, 2H, J=10 Hz), 2.94 (q, 4H, J=12
Hz), 3.51-3.67 (m, 4H), 4.44 (dd, 2H, J=12 Hz, J.sub.2=4.4 Hz),
4.57 (dd, 2H, J=12.8 Hz, J.sub.2=3.6 Hz), 7.71 (d, 1H, J=9.2 Hz),
8.10 (dd, 1H, J=9.2 Hz, J.sub.2=2.8 Hz), 8.44 (d, 1H, J=2.4
Hz).
4.23 General Method of Synthesis of Formula Is Compounds
[0600] Scheme 56 describes the general synthetic procedures for
preparing compound of Formula Is. ##STR97##
[0601] R refers to substitutents as defined for substituted
aryls.
[0602] One equivalent of 1,4-dichloro-phthalazine (246),
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) and 4
equivalents of .sup.iPr.sub.2NEt in DMF were mixed and the mixture
was heated at 100.degree. C. with shaking. Upon the completion of
the reaction, the solvent was removed under reduced pressure and
the crude was purified by flash chromatography to give the desired
product 257.
[0603] A solution of compound 257 in MeOH was treated with an equal
volume of 4.0 M of HCl in Dioxane. The reaction mixture was shaken
at room temperature overnight. The solvent was removed under
reduced pressure and the residue was purified by HPLC to give the
desired product (258) as the HCl salt.
4.23.1 EXAMPLE 25
Synthesis of Formula Is Compound (Scheme 57)
[0604] ##STR98##
[0605] 1,4-Dichloro-phthalazine (259) (199.04 mg, 1 mmol),
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (1.26 g, 4
mmol) in 5 mL of DMF and .sup.iPr.sub.2NEt (699 .mu.L, 4 mmol) were
mixed and the mixture was heated at 100.degree. C. for 38 h with
shaking. The solvent was removed under reduced pressure. After
flash chromatography purification on silica gel using a gradient of
hexane and ethyl acetate followed by reverse-phase HPLC
purification, compound 260 (15.7 mg) was obtained as a solid. LC-MS
(ESI): m/e=757.7 [M+H].sup.+
[0606] Compound 260 was dissolved in MeOH (2 mL). HCl (4.0 M) in
dioxane (2 mL) was then added. After stirring at room temperature
overnight, the reaction mixture was concentrated under reduced
pressure. The crude was purified by reverse-phase HPLC using a
gradient of CH.sub.3CN and H.sub.2O to give 32.3 mg of the desired
product (261) as a light yellow solid as the HCl salt in 4.9%
isolated yield for 2 steps. LC-MS (ESI): m/e=357.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, D.sub.2O): .delta.=1.91 (q, J=12 Hz, 2H),
2.76 (s, br, 2H), 3.24 (t, J=12 Hz, 4H), 3.92 (m, 4H), 4.20 (m,
4H), 8.11 (m, 2H), 8.19 (m, 2H).
4.24 General Method of Synthesis of Formula It Compounds
[0607] Scheme 58 describes a general synthetic procedure for
preparing compound of Formula It. ##STR99##
[0608] In this general method of producing compounds of Formula It,
the amination of the both halides of 3,5-dibromonitrobenzene (262)
is accomplished by treating with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) using
Pd.sub.2(dba).sub.3 catalyst, Xantphos as ligand and
Cs.sub.2CO.sub.3 as base to give compound 263. The nitro group is
then reduced by Raney Nickel and hydrazine combination.
[0609] The resulting aniline (264) reacts with aromatic bromide
(265) in the presence of Pd-catalyst selected from
Pd.sub.2(dba).sub.3, Pd(OAc).sub.2, PdCl.sub.2(PCy.sub.3).sub.2,
PdCl.sub.2[P(.sup.tBu).sub.2OH], ligand selected from Xantphos,
P(.sup.tBu).sub.3, BINAP, 2-(dicyclohexylphosphino)biphenyl,
2-(di-t-butylphosphino)biphenyl,
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,
(R)-(+)-2,2'-bis(dicyclohexylphosphino)-1,1'-binaphthyl, and base
selected from Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4 in
a solvent selected from PhMe, DME, xylenes, dioxane, HMPA in the
temperature range of 80-140.degree. C. preferably at
100-110.degree. C. to generate crude product 266 that is purified
by column chromatography to give the desired pure product 266.
[0610] Finally, all the Boc-protecting groups of compound 266 are
removed by 2 M HCl in the mixed solvents of dioxane and methanol to
give the desired product 267 as HCl salt.
[0611] This methodology is useful for the production of various
derivatives represented by Formula It. Other variations of this
methodology would be apparent to those skilled in the art.
4.24.1 EXAMPLE 26
Synthesis of Formula It Compounds 268 and 269
[0612] ##STR100##
Step 1: Buchwald Reaction to Give Compound 263
[0613] 1,3-di-bromo-5-NO.sub.2-benzene (262) (140.5 mg, 0.5 mmol),
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (410 mg,
1.3 mmol), Cs.sub.2CO.sub.3 (488.7 mg, 1.5 mmol), Xantphos (87 mg,
0.15 mmol), Pd.sub.2(dba).sub.3 (46 mg, 0.05 mmol) and 5 mL of
anhydrous toluene were added into a 40-mL vial. N.sub.2 was purged
and bubbled through the mixture for 2 minutes. The vial was capped
with a piercing septa cap right away. A N.sub.2 balloon was then
added on the cap through a needle. The reaction mixture was heated
at 100.degree. C. with good stirring for 27 h. The reaction mixture
was checked by LC-MS. The mixture had 50% desired product, 45% of
compound 4 and 5% (by ELSD) of other undefined impurity. The
reaction mixture was diluted by a mixture of CHCl.sub.3, MeOH and
EtOAc (total 10 mL) first and the solid was then filtered off
through Celite under vacuum. The majority of the excess
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) was
removed by scavenger resin by adding isocyanate-resin (800 mg) and
heating at 80.degree. C. in THF (15 mL) overnight. After the resin
was removed, the solution was concentrated down on rotary
evaporator and was further purified by flash chromatography using
neutral Al.sub.2O.sub.3 (CHCl.sub.3/MeOH/NH.sub.4OH=20:1:0.1). The
final product (263) was confirmed by LC-MS with MS of 750.5
[M+1].sup.+ with HPLC purity of 90% by ELSD.
Step 2: Nitro Reduction to give Compound 264
[0614] Compound 263 (57.9 mg) and 4 mL of absolute EtOH were added
into an 8-mL vial and the mixture was preheated at 55.degree. C. to
get more homogeneous solution. 24 .mu.L of anhydrous
NH.sub.2--NH.sub.2 was added followed immediately by 216 uL of
Raney Nickel (50% slurry in H.sub.2O). The reaction mixture
immediately started bubbling. The bubbling stopped after 10
minutes. The reaction mixture was monitored by LC-MS and the
reaction was not completed yet. 24 .mu.L of anhydrous
NH.sub.2NH.sub.2 and 216 .mu.L of Raney Nickel were added again and
this addition was repeated 3 more times. At that point, the
reaction was completed based on LC-MS spectrum. The solid was
filtered off through Celite and washed with EtOH and MeOH. The
filtrate was concentrated down under vacuum and dried on oil pump
vacuum for 3 h. 50.5 mg of gray solid of the desired product 264
was obtained (90.9% yield). LC-MS: (m/e: 720.4 [M+1].sup.+) with
HPLC purity of 95% (with 5% remaining
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine 4 as the
impurity based on ELSD).
Step 3: The Second Buchwald Reaction with Aniline 264
[0615] 50.5 mg of compound 264 (70.14 .mu.mol),
1-bromo-4-nitro-benzene (208) (14.2 mg, 70.14 .mu.mol),
Cs.sub.2CO.sub.3 (34.3 mg, 105.3 .mu.mol), Xantphos (12.2 mg, 21.1
.mu.mol), Pd.sub.2(dba).sub.3 (6.4 mg, 7 .mu.mol) and toluene (1
mL) were added into a 40-mL vial. N.sub.2 was purged through the
mixture (bubbled through) for 2 minutes, the vial was capped and
heated at 100.degree. C. for 15 hours with good stirring. The
reaction was monitored by LC-MS. After the reaction was completed,
CHCl.sub.3 (2 mL) and MeOH (2 mL) were added to dilute the mixture.
The solid was filtered off through Celite under vacuum and washed
with CHCl.sub.3 (2 mL) and MeOH (2 mL). The filtrate was
concentrated and the crude product was first purified by
liquid-liquid extraction between CHCl.sub.3 (6 mL) and H.sub.2O (3
mL.times.2). The organic layer was dried and a dark brown solid
(product 266a and 266b) as a mixture of mono- (55% by ELSD) and
bis-adducts (45% by ELSD) was obtained. LC-MS: m/e 841.5
[M+1].sup.+ mono-adduct and 962.7 [M+1].sup.+ for bis-adduct.
Step 4: De-Protection of Boc to Give Compound 268 and 269
[0616] The above crude product (a mixture of 266a and 266b) was
dissolved in MeOH (2 mL) first with assistance of sonication. 2 mL
of 4 M HCl in dioxane was then added at r.t. and the resulting
mixture was shaken at room temperature overnight. The reaction was
completed based on the LC-MS result. The mixture was concentrated
to give 70.3 mg dark yellow solid as the crude product (a mixture
of 268 and 269). The crude product was further purified by reverse
phase HPLC purification to give 8.02 mg of compound 268 and 9.05 mg
of compound 268 in total yield of 32.2% for 2 steps (step 3 &
4) as HCl salt with HPLC purity>95% for both products.
4.24.2 Another General Method of Synthesis of Compounds of Formula
It
[0617] Scheme 59 describes another general synthetic procedure for
preparing compound 284 of Formula It. ##STR101## R=optionally
substituted (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heteroaryl,
--(CH.dbd.CH).sub.n-aryl, --(CH.dbd.CH).sub.n-heteroaryl,
--(C.dbd.C).sub.n-aryl, and --(C.dbd.C).sub.n-heteroaryl.
[0618] In this general method of producing compounds of Formula It,
the 3,5-di-bromo-nitro-benzene (262) is reduced to
3,5-di-bromo-aniline (273), followed by reductive amination to form
the benzylated secondary aniline (275). Compound 275 is then
reacted with 4-F-nitrobenzene (276) to give 3,5-dibromo-tertiary
aniline (271) that is then de-benzylated to give the secondary
aniline 278. Aniline 278 is protected by Boc to give compound 279.
Dibromo-compound 279 is aminated by reacting with
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) using
palladium catalyst to give compound 280. The reduction of the nitro
group of compound 280 followed by an amide coupling with carboxylic
acid 281 affords compound 283. De-protection of Boc and other
protecting groups if R contains other protecting groups give
compound 284 as HCl salt.
[0619] This methodology is useful for the production of various
derivatives represented by Formula It. Other variations of this
methodology would be apparent to those skilled in the art.
4.24.3 EXAMPLE 27
Synthesis of Formula It Compounds 285 and 286
[0620] ##STR102## Scheme 60 describes the synthetic procedure for
preparing compounds 285 and 286 of Formula It. ##STR103##
##STR104##
Step 1: NO.sub.2 Reduction of 3,5-dibromonitrobenzene (262) to give
Compound 273
[0621] 3,5-dibromo-nitro-benzene (262) (500 mg, 1.78 mmol) was
dissolved in 4 mL of glacial acetic acid first. TiCl.sub.3 with 30
wt % in 2 N HCl was added gradually until the purple color
disappeared even after long stirring at room temperature. The
reaction was monitored by TLC. After the reaction was completed,
the reaction mixture was concentrated down under vacuum to remove
the acetic acid. H.sub.2O and 1 M NaOH was then added to neutralize
the product followed by adding EtOAc solvent. The resulting wax
like solid was filtered off under vacuum. Liquid-liquid extraction
was then performed twice using EtOAc and H.sub.2O as solvents and
the organic layer was dried over anhydrous Na.sub.2SO.sub.4 for 0.5
h. The drying reagent was then filtered off under vacuum and the
filtrate was first dried under vacuum on rotary evaporator and then
dried over oil pump overnight. 387.3 mg of the desired product
(273) was obtained as a neutral base in 86.7% yield with HPLC
purity of >95% (ELSD). LC-MS: m/e 250 [M+1].sup.+, 252.
[0622] In a scale up reaction using the same procedure as described
above, 5 g (17.9 mmol) of 3,5-dibromonitrobenzene (262), 30 mL of
TiCl.sub.3 (30% wt. in 2.0 N aqueous HCl) and AcOH (125 mL) were
used. After 4 h reaction and subsequent work-up, 3.85 g (85.7%
yield) of 3,5-dibromoaniline (273) was obtained.
Step 2: Reductive Amination Gave Compound 275
[0623] 3,5-dibromoaniline (273) (295 mg, 1.18 mmol), benzaldehyde
(274) (120 uL, 1.18 mmol), NaBH(OAc).sub.3 (400 mg, 1.89 mmol),
AcOH (142 mg, 2.36 mmol) and 6 mL of dichloroethane (DCE) were
mixed and shaken at room temperature for 3.5 hours. TLC by analysis
showed some remaining starting material but mostly product 275
while LC-MS spectrum showed mostly product with very little
starting material left. The reaction was then stopped and the
reaction mixture was concentrated down on a rotary evaporator.
Liquid-liquid extraction was then performed three times between
EtOAc (6 mL) and 1M NaOH (3 mL), H.sub.2O (3 mL) and H.sub.2O (3
mL). The organic layer was dried under vacuum and the crude product
was purified by preparative TLC plate using developing solvent of
hexane and ethyl acetate (hexane/ethyl acetate=4:1). 208 mg of the
pure desired product (271) was obtained in 51.7% isolated yield
with HPLC purity of 100%. LC-MS: m/e 340 [M+1].sup.+, 342.
[0624] The same procedure as described above was used in a scale up
reaction where 3,5-dibromoaniline (273) (3.85 g, 15.35 mmol),
benzaldehyde (274) (1.61 g, 15.35 mmol), Na(OAc).sub.3BH (6.47 g,
30.7 mmol), AcOH (1.11 g, 18.42 mmol) and DCE (38 mL) were used.
After 3 h reaction and purification (flash chromatography),
benzyl(3,5-dibromo-phenyl)-amine (275) (3.64 g, 10.67 mmol) was
obtained in 69.6% isolated yield.
Step 3: Secondary Aniline 275 Reaction with 4-F-Nitrobenzene (276)
to Give Compound 277
[0625] 3,5-dibromo-secondary aniline (275) (208 mg, 0.61 mmol), 1
mL of 4-F-nitro-benzene (276) (large excess),
1,4-diazabicyclo[2,2,2]octane (68.4 mg, 0.61 mmol) and
K.sub.2CO.sub.3 300 mg) were mixed together and heated to melt at
200.degree. C. under N.sub.2 for 8 hours. The reaction was stopped
and cooled down. Liquid-liquid extraction was performed
(CHCl.sub.3/H.sub.2O.times.2) and the organic layer was dried down.
The crude product was purified by preparative TLC plate
(hexane/EtOAc=6/1). 196 mg desired product (277) was obtained in
70% isolated yield with HPLC purity of >95% (by ELSD). LC-MS:
m/e 460.9 [M+1].sup.+, 462.9; .sup.1H NMR (DMSO-d.sub.6): .delta.
8.30 ppm (d, 2H, J=9.2 Hz), 8.05 (d, 2H, J=9.2 Hz), 7.65 (t, 1H,
J=1.6 Hz), 7.57 (d, 2H, J=1.2 Hz), 7.20-7.32 (m, 3H), 6.97 (d, 2H,
J=9.2 Hz), 5.12 (s, 2H).
[0626] This reaction was scaled up to gram-scale using the same
method. In this case, 3.64 g (10.7 mmol) of
benzyl-(3,5-dibromophenyl)-amine (275), 1-fluoro-4-nitro-benzene
(276) (4.5 g, 32 mmol) and 1,4-diazabicyclo[2,2,2]octane (2.4 g,
21.3 mmol) were mixed and heated to 170.degree. C. for 16 h then
205.degree. C. for 8 h without solvent. After flash column
chromatography purification, 1.35 g (27.4% isolated yield) of
benzyl-(3,5-dibromo-phenyl)-(4-nitro-phenyl)-amine (42) was
obtained.
Step 4: De-Benzylation of 277 to Give Compound 278
[0627] Compound 277 (850 mg, 1.84 mmol) was dissolved in a mixture
of methanesulfonic acid (MSA), trifluoroacetic acid and thioanisole
(1:8:2, total 10 mL). The mixture was shaken in a sealed 40 mL
I-Chem vial for 30 minutes. TLC indicated complete de-benzylation
at this point. The mixture was diluted with EtOAc (50 mL), washed
with H.sub.2O (3.times.20 mL), NaHCO.sub.3 (3.times.20 mL, sat.
aqueous), dried over MgSO.sub.4 and concentrated to give an orange
powder. The powder was prepared as a slurry in a mixture of EtOAc
and hexanes (3:1, total 6 mL), filtered and dried under high vacuum
to give the desired product (278) as a yellow powder (478 mg, 1.28
mmol) in 70% isolated yield with HPLC purity>99% by ELSD.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.15 (d, 2H, J=9.6
Hz), 7.36 (d, 2H, J=1.6 Hz), 7.42 (t, 1H, J=1.6 Hz), 8.13 (d, 2H,
J=9.2 Hz), 9.45 (s, 1H).
Step 5: Boc Protection of Compound 278 to Give Compound 279
[0628] Compound 278 (478 mg, 1.28 mmol) and (Boc).sub.2O (2.79 g,
12.8 mmol) were combined and heated to 75.degree. C. Addition of
300 uL of DMA dissolved all solids. The mixture was kept at
75.degree. C. with shaking for 3 h. A distinct color change from an
orange solution to a pale yellow solution was observed. TLC
indicated complete protection at this point (R.sub.f: 0.7 compared
to R.sub.f: 0.4 for compound 278 in 4:1 hexanes/EtOAc). In order to
consume the excess (Boc).sub.2O, N,N-Dimethylethylenediamine (1.13
g, 12.8 mmol) was added followed by CH.sub.2Cl.sub.2 (8 mL) and
MeOH (2 mL). The mixture was shaken for 24 h in a sealed 40 mL
I-Chem vial at room temperature. The mixture was diluted with
CH.sub.2Cl.sub.2 (20 mL) and hexanes (10 mL) and passed through a
plug of silica gel, rinsing with a mixture of
CH.sub.2Cl.sub.2/hexane (1:1) to give the desired product (279) as
a yellow oil upon concentration (562 mg, 1.19 mmol) in 93% isolated
yield with HPLC purity>99% by ELSD.
Step 6: Buchwald Reaction to Give Compound 280
[0629] Compound 279 (562 mg, 1.19 mmol),
(3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (4) (968 mg,
3.07 mmol), Cs.sub.2CO.sub.3 (1.157 g, 3.55 mmol), Xantphos (216
mg, 0.373 mmol), Pd.sub.2(dba).sub.3 (109 mg, 0.119 mmol) were
combined in a 40 mL I-Chem vial. N.sub.2 was purged and bubbled
through 20 mL of anhydrous toluene for 10 minutes. The N.sub.2
purged toluene (11.84 mL) was added to the vial containing the
above mixture. The vial was charged with N.sub.2 and sealed. The
mixture was then heated at 100.degree. C. with stirring for 20 h.
LC-MS and TLC results indicated complete consumption of compound
279, with no indication of the mono-substituted intermediate. The
mixture was diluted with EtOAc (50 mL) and filtered through Celite
to remove the solids. The filtrate was concentrated to give a
greenish brown oil. Purification by flash column chromatography
(eluted with 25-30% EtOAc in CH.sub.2Cl.sub.2) gave the desired
product 280 as a yellow powder upon drying (248 mg, 0.264 mmol) in
22.2% isolated yield with HPLC purity of >99% by ELSD. LC-MS:
m/e: 941.7 [M+1].sup.+.
Step 7: Nitro Reduction of 280 to Give Compound 281
[0630] Compound 280 (150 mg, 0.159 mmol), 12 mL of absolute EtOH
and 4 mL of EtOAc were added into an open 40 mL I-Chem vial. While
stirring and with a stream of N.sub.2 blowing into the vial, the
mixture was heated to 55.degree. C. 51 .mu.L of anhydrous hydrazine
was added followed immediately by 450 uL of Raney Nickel (50%
slurry in H.sub.2O). The reaction mixture immediately started
bubbling. The temperature was maintained at 55.degree. C. with
stirring. The bubbling ceased within 5 min. An additional 51 .mu.L
of anhydrous hydrazine was added and the reaction mixture
immediately started bubbling. The temperature was maintained at
55.degree. C. with stirring. TLC and LC-MS results indicated
complete reduction after a total reaction time of 10 minutes. The
solution was passed through a plug of Celite and rinsed with MeOH
and EtOAc. The solution was concentrated to give 281 as an
off-white powder (146 mg, 160 .mu.mol) with quantitative yield.
LC-MS: m/e: 911.6 [M+1].sup.+ with HPLC purity>99% by ELSD.
Step 8: Amide Coupling of 281 and 287a to Give Compound 288
[0631] Compound 281 (146 mg, 0.160 mmol) and compound 287 (0.278 g,
0.176 mmol) were combined and dissolved in anhydrous THF (1 mL).
HOBT (0.64 uL of 0.5 M solution in THF, 0.32 mmol) and
.sup.iPr.sub.2NEt (111 uL, 0.64 mmol) were added. The mixture was
shaken at room temperature for 10 minutes. EDCl (2.56 mL of 0.25M
solution in CH.sub.2Cl.sub.2, 0.64 mmol) was added and the mixture
was shaken at room temperature for 20 h. TLC and LC-MS results
indicated complete coupling at this point. The mixture was diluted
with EtOAc (30 mL), washed with NaHCO.sub.3 (2.times.10 mL, sat.
aqueous), dried over MgSO.sub.4 and concentrated to a beige
foam-like oil. Purification by flash column chromatography (30%
EtOAc in CH.sub.2Cl.sub.2) gave the desired product 288 as a beige
powder (91 mg, 77.7 .mu.mol) in 49% isolated yield with HPLC purity
of >99% by ELSD. LC-MS: m/e 1171.8 [M+1].sup.+.
Step 9: De-Benzylation of Compound 288 to Give Compound 289 via
Pd/C and H.sub.2
[0632] Compound 288 (50 mg, 0.0427 mmol) was dissolved in EtOAc (2
mL) in a 40 mL I-Chem vial. 10% Pd/C (18 mg) was added. The
solution was degassed and the vial was charged with H.sub.2 via
balloon. The mixture was stirred at room temperature under the
H.sub.2 atmosphere for 4 h. TLC and LC-MS results indicated >95%
de-benzylation at this point. The mixture was filtered through
Celite and rinsed with MeOH and EtOAc to give compound 289 as a
clear oil upon concentration (43 mg, 0.0398 mmol) in 93% yield with
HPLC purity of >95% by ELSD. LC-MS: m/e 1081.8 [M+1].sup.+.
Step 10: De-Boc of Compound 289 to Give Compound 285
[0633] Compound 289 (43 mg, 0.0398 mmol) was dissolved in MeOH (2
mL) in a 40 mL I-Chem vial. 4.0 M HCl in dioxane (2 mL) was added
and the mixture was shaken overnight at room temperature. A yellow
precipitate was observed. LC-MS result indicated complete
de-protection after 20 h. The mixture was concentrated to give a
yellow powder (33 mg). MeOH (2 mL) was added and the mixture was
sonicated for 2 minutes. The vial was centrifuged, the supernatant
decanted, and the solid was dried under high vacuum for 4 h to give
285 as a yellow powder as the HCl salt with HPLC purity>98% by
ELSD (20 mg, 69.1% isolated yield assuming 4 HCl based on NMR).
LC-MS: m/e 581.3 [M+1].sup.+ (60%), 291.4 [M/2+1].sup.+ (100%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.66 (q, 2H, J=12 Hz),
2.38 (s, br, 2H), 2.72 (t, 4H, J=11.6 Hz), 3.18 (s, br, 4H), 3.992
(d, 4H, J=9.2 Hz), 6.00 (s, 1H), 6.08 (s, 2H), 7.03 (d, 2H, J=8.8
Hz), 7.36 (d, 1H, J=8.4 Hz), 7.50 (m, 3H), 7.58 (t, 1H, J=6.4 Hz),
7.82 (d, 1H, J=7.6 Hz), 8.08 (d, 1H, J=8.8 Hz), 8.20 (d, 1H, J=8.4
Hz), 8.39 (s, br, 12H), 10.34 (s, 1H).
Step 11: De-Boc of Compound 288 to Give Compound 286
[0634] Compound 288 (41 mg, 0.035 mmol) was dissolved in MeOH (2
mL) in a 40 mL I-Chem vial. 4.0 M HCl in dioxane (2 mL) was added
and the mixture was shaken for 20 h at room temperature. LC-MS
result indicated complete de-protection at this point. The mixture
was concentrated to give a yellow powder. MeOH (1 mL) was added and
the mixture was sonicated for 1 minute. The vial was centrifuged
and the supernatant was decanted. The solid was dried under high
vacuum for 2 h to give 286 as an orange-yellow powder as the HCl
salt form (23 mg, assuming 4 HCl, 80.6% isolated yield). LC-MS: m/e
671.5 [M+1].sup.+ with HPLC purity of >99% by ELSD.
4.25 Synthesis Of cis-3,5-diaminopiperidine and determination of
the stereo-configuration of
3,5-bis-(tert-butoxycarbonylamino)-piperidine (4)
[0635] Scheme 71 describes the transformation of
(3R,5S)-bis(tert-butoxycarbonylamino)-piperidine (4) to
3,5-Cis-diaminopiperidine (4a). ##STR105##
[0636] (3R,5S)-bis(tert-butoxycarbonylamino)-piperidine (4) (0.5 g,
1.59 mmol) as made in scheme 1 was dissolved in TFA (4 mL) and the
mixture was shaken in a Teflon-septum capped 40 mL I-Chem vial for
16 hours. HCl (4.0 M in dioxane, 15 mL) was added to precipitate
the product as the HCl salt form. The solid was collected by
filtration, dried under high vacuum for 16 hours, dissolved in
aqueous HCl (1.0 M, 10 mL) and concentrated to give the desired
product (290) as a white powder upon drying under high vacuum for
16 hours (0.12 g, 1.04 mmol, 65.6% isolated yield). Elemental
analysis calcd (%) for C.sub.5H.sub.13N.sub.3.0.25H.sub.2O.3HCl: C,
26.22; H, 7.26; N, 18.34. found C, 26.35; H, 7.22; N, 18.13.
.sup.13C NMR (400 MHz, DMSO-d.sub.6): .delta.=31.01, 43.60, 44.10.
.sup.1H NMR (400 MHz, D.sub.2O-d.sub.6, pD=3-5): .delta.=1.92 (q,
1H, J=11.6 Hz), 2.66-2.69 (1H), 3.13 (t, 2H, J=13.2 Hz), 3.74-3.82
(m, 4H).
[0637] The H-NMR data matched the reported literature data for the
cis-3,5-diaminopiperidine-3-HCl, the absolute structure of which
was determined by X-ray crystal structure. Therefore
3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) synthesized by
this method was the cis-isomer. A related synthesis, NMR data and
x-ray data for the cis-3,5-diaminopiperidine are described in Jorg
W. Pauly, Jurgen Sander, Dirk Kuppert, Manuela Winter, Guido J.
Reiss, Fabio Zuircher, Rudolf Hoffmann, Thomas F. Fassler, and
Kaspar Hegetschweiler, Chem. Eur. J. 6, No. 15, 2830-2846
(2000).
4.26 Synthesis of Amine Intermediates
4.26.1 Synthesis of 291
[0638] Scheme 62 describes the synthesis of compound 291.
##STR106##
[0639] To a solution of 292 (1.00 g, 5.16 mmol) in 30 mL
dichloromethane (DCM) was added (1.24 g, 5.68 mmol) of
di-tert-butyl dicarbonate and the mixture was stirred at room
temperature for 20 h. The solution washed with water and dried
(MgSO.sub.4), concentrated and purified by column chromatography.
The product was eluted with 30% ethyl acetate in hexanes to give
the product 293 in quantitative yield.
[0640] Compound 293 was prepared according to a procedure given in
the literature (Knight, D. W.; Lewis, N.; Share, A.; W. Haigh, D.
J. Chem. Soc. Perks Trans. 1. 1998, 3673-3683). To a suspension of
the .beta.-keto ester, 293 (1.33 g, 5.17 mmol) in 50 mL autoclaved
water, was added 5 g of sucrose and 3 g of Bakers yeast. The
suspension was stirred for 4 days at room temperature under aerobic
conditions. The suspension was filtered through celite and the
filtrate extracted with DCM, 5.times.10 mL. The combined organic
phase washed with brine, dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash chromatography
(70% ethyl acetate in hexane) to give a yellow oil, 294 (1.03 g,
77% yield).
[0641] Protection of the 2.degree. alcohol was effected by treating
a solution of 294 (520 mg, 2.00 mmol) in 8 mL DCM at -78.degree. C.
with lutidine (584 uL, 5.01 mmol) followed by
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (599
.mu.L, 2.61 mmol) drop wise. The reaction was allowed to warm to
room temperature in 2 h. and the mixture carefully quenched with
saturated NaHCO.sub.3 aqueous, 10 mL. The aqueous phase was
extracted by DCM (2.times.8 mL). The combined organic phase was
dried (MgSO.sub.4), concentrated and purified by flash
chromatography (30% ethyl acetate in hexane) to give 295 (680 mg,
90% yield).
[0642] A stirred solution of 295 (890 mg, 2.38 mmol) in 40 mL dry
THF was treated with LiBH.sub.4 (2.38 mL; 2M solution, 4.76 mmol)
and refluxed for 24 h. The reaction mixture was cooled to room
temperature and carefully quenched with saturated NaHSO.sub.4
(aqueous, 30 mL). The aqueous phase was extracted with DCM,
4.times.15 mL. The combined organic phase washed with brine, dried
(MgSO.sub.4), and the solution concentrated under reduced pressure.
The residue was purified by flash chromatography (30% ethyl acetate
in hexane) to give 296 (600 mg, 73% yield).
[0643] A solution of 296 (600 mg, 1.74 mmol) in 10 mL of dry
pyridine at 0.degree. C. was treated with MsCl (269 .mu.L, 3.47
mmol) and stirred for 0.5 h. The ice bath was removed and the
solution was allowed to warm to room temperature over 3.5 h. The
solvent was removed under reduced pressure and the residue was
taken up in DCM, washed with water, dried over (MgSO.sub.4), and
concentrated. The product (297) was used for the next step without
further purification.
[0644] A mixture of crude 297 and sodium azide (226 mg, 3.47 mmol)
in DMF was heated at 80.degree. C. for 16 h. The solvent was
removed under reduced pressure and the residue dissolved in ethyl
acetate, washed with saturated aqueous NaHCO.sub.3, and
concentrated. The residue was purified by flash chromatography (30%
ethyl acetate in hexane) to give 298 (440 mg, 68% yield).
[0645] To a stirred solution of 298 (440 mg, 1.19 mmol) in 10 mL
THF was added TBAF (1.5 mL; 1M solution, 1.54 mmol) and stirred at
room temperature for 3 h. The solvent was concentrated down and DCM
added. The solution washed with water 3.times.5 mL, brine, dried
(MgSO.sub.4), and the solvent removed under reduced pressure. The
residue (299) was used without further purification.
[0646] A solution of 299 in 20% TFA in DCM was stirred at room
temperature for 16 h. The solution was concentrated under reduced
pressure and the residue dissolved in DCM. This was then washed
with dilute NaHCO.sub.3 aqueous solution, and dried over
MgSO.sub.4. The solution was concentrated and the residue was
purified by column chromatography with 10% methanol in DCM to give
291 (150 mg) in 81% yield over two steps with HPLC purity of 96% by
ELSD. LC-MS: m/e 157.1 [M+1].sup.+.
4.26.2 Synthesis of 306
[0647] Scheme 63 describes the synthesis of compound 306.
##STR107##
[0648] To the commercially available 301 (1.00 g, 7.63 mmol) in a
mixture of THF/dioxane (40 mL, 1:1) was added NaHCO.sub.3 (1.92 g,
22.88 mmol) and di-tert-butyl dicarbonate (1.99 g, 9.15 mmol), and
the mixture was stirred for 14 h. The solvent was removed under
reduced pressure and the residue dissolved in DCM, washed with
water dried (MgSO.sub.4) and concentrated. The residue was purified
by flash chromatography (20% methanol in DCM) to give 302 (940 mg,
53% yield).
[0649] To a flame dried flask was transferred 302 (840 mg, 3.63
mmol) under nitrogen and dissolved in dry THF. To the stirring
mixture was added BH.sub.3.MeS (3.63 mL; 1M solution, 7.26 mmol)
and stirred at room temperature for 18 h. The excess
BH.sub.3.Me.sub.2S was carefully quenched with water and
concentrated under reduced pressure. To the residue was added
dilute NaHCO.sub.3 aqueous solution and extracted with DCM
5.times.10 mL. The combined organic phase was dried (MgSO.sub.4)
and concentrated. The residue (303) was used in the subsequent step
without further purification.
[0650] Intermediate 304 was synthesized following the same
procedure for compound 297: 303 (832 mg, 3.83 mmol), TsCl (912 mg,
4.79 mmol) in 30 mL pyridine, to give 304 (890 mg, 63% yield) after
purification by column chromatography.
[0651] Intermediate 305 was synthesized following the same
procedure for compound 298: 304 (890 mg, 2.40 mmol), sodium azide
(311 mg, 4.80 mmol), to give 305 (420 mg, 72% yield) after
purification by flash chromatography.
[0652] Intermediate 306 was synthesized following the same
procedure for compound 291 to give 306 (246 mg, 100% yield) with
95% HPLC purity by ELSD. LC-MS: m/e 143.2 [M+1].sup.+ 1H NMR
(CD.sub.3OD): .delta. 1.65 ppm (1H, d, J=14 Hz), 2.29 (1H, m), 3.19
(2H, d, J=3.6 Hz), 3.60-3.80 (4H, m) and 4.45 (1H, m).
4.26.3 Synthesis of 310
[0653] Scheme 64 describes the synthesis of compound 310.
##STR108##
[0654] Synthesis of bis(azidomethyl)piperidine, 310, proceeded from
the intermediate 308, which was synthesized according to literature
procedure (1, Danieli, B. Lesma, G.; Passarella, D.; Silvani, A. J.
Org. Chem. 1998, 63, 3492-3496. 2, Danieli, B. Lesma, G.;
Passarella, D.; Silvani, A; Viviani, N. Tetrahedron 1999, 55,
11871-11878). Further manipulation was effected in a similar manner
to treatment of 294 in scheme 62 to afford the azido compound 309,
in overall yield of 95%. To complete the synthesis, the
Carbobenzyloxy(Cbz)-protected bis(azidomethyl)piperidine (309) (460
mg, 1.40 mmol) was refluxed at 100.degree. C. in 8M KOH/MeOH for 5
h. The mixture was concentrated to approximately 2 mL and extracted
with DCM. The combined organic phase was dried (MgSO.sub.4) and
concentrated. The residue was purified by column chromatography
with 20% NH.sub.4OH in methanol to give 310 (234 mg, 86% yield)
with 99% HPLC purity based on ELSD. LC-MS m/e 196.2 [M+1].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 0.80 (2H, q, J=12 Hz), 1.80 (4H,
m), 2.20 (2H, t, J=12 Hz) and 3.19 (6H, m).
4.26.4 Synthesis of 311
[0655] Scheme 65 describes the synthesis of compound 311.
##STR109##
[0656] To a stirring mixture of the commercially available
N-tert-butoxycarbonyl-imidazole (3.34 g, 19.85 mmol) in dry toluene
at 60.degree. C. and under nitrogen, was added 312 (1.00 g, 9.69
mmol) drop wise. Heating was continued for 3 h at 60.degree. C. The
solvent was removed and the residue dissolved in DCM, washed with
water (2.times.20 mL), saturated aqueous NaHCO.sub.3 and dried over
(MgSO.sub.4). The solution was concentrated under reduced pressure
to give the product 311 (2.55 g, 87% yield) with 100% HPLC pure
based on ELSD and was used without further purification. LC-MS: m/e
304.3 [M+1].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.45 (9H, s),
2.72 (4H, t, J=6.0 Hz), 3.21 (4H, q, J=5.2 Hz) and 4.90 (1H, bs).
This above synthesis was performed according to literature
procedure described in Steve P. Rannard and Nicola J. Davis,
Organic Letters, 2 (14), 2117-2120 (2000).
4.26.5 Synthesis of 313
[0657] Scheme 66 describes the synthesis of compound 313.
##STR110##
[0658] A solution of N,N-diallylamine (314) (40.6 mmol) in pyridine
(20 mL) was prepared and cooled to 0.degree. C. Di-tert-butyl
dicarbonate (48.7 mmol, 1.2 equiv.) was added in a single portion
with stirring and the solution was allowed to warm to room
temperature. After 2 h, TLC indicated complete conversion. The
reaction was diluted with toluene (80 mL) and concentrated. The
resulting syrup was dissolved in EtOAc (200 mL) and washed with
saturated NaHCO.sub.3 (200 mL), brine (100 mL), dried over
MgSO.sub.4 and concentrated to give compound 315 as a colorless oil
(31.7 mmol, 78% yield).
[0659] The above oil was dissolved in freshly distilled
CH.sub.2Cl.sub.2 (300 mL) and degassed. Under nitrogen (1 atm) the
Grubb's Catalyst
{RuCl.sub.2(CHC.sub.6H.sub.5)[P(C.sub.6H.sub.11).sub.2], 0.5 mol %}
was added. After 2.5 h reaction at room temperature, TLC indicated
complete conversion of the starting material to a more polar
product and the reaction was quenched by bubbling air through the
solution. The solution was concentrated and subjected to flash
chromatography purification (5-20% EtOAc in hexane) to yield the
compound 316 (27.0 mmol, 85% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.=1.48 ppm (s, 9H), 4.09 (m, 4H), 5.76 (m,
2H).
[0660] 2,5-Dihydro-pyrrole-1-carboxylic acid tert-butyl ester (316)
(27.0 mmol) and N-methylmorpholine N-oxide monohydrate (43.0 mmol)
were dissolved in acetone/H.sub.2O (1:1, v/v; 80 mL). OsO.sub.4
(0.4 mmol, 1.5 mol %) was added and the resulting pale yellow
solution was stirred at room temperature for 16 h.
Na.sub.2S.sub.2O.sub.5 (3.9 mmol) was then added and the solution
was stirred for 1 h. The solution was acidified to pH=4 with 6 M
HCl and extracted with CH.sub.2Cl.sub.2 (4.times.70 mL). The
organic phase washed with saturated NaHCO.sub.3 (50 mL), brine (50
mL), dried over MgSO.sub.4 and concentrated. The resulting foam
(317) was dissolved in MeOH (80 mL) and 4 M HCl in dioxane (18 mL)
was added with stirring.
[0661] After 2 h stirring at room temperature the reaction solution
was concentrated to yield an oil. This oil was dissolved in hot
ethanol (80 mL) and was allowed to stand at room temperature for
two days yielding the desired compound (313) as colorless needles
(17.2 mmol, 64% yield). .sup.1H NMR (400 MHz, D.sub.2O)
.delta.=3.16 (br d, 2H, J=12 Hz), 3.38 (br d, 2H, J=12 Hz), 4.30
(br s, 2H); .sup.13C NMR (100 MHz, D.sub.2O) .delta.=48.7, 70.0
ppm.
4.26.6 Synthesis of 318
[0662] Scheme 67 describes the synthesis of compound 318.
##STR111##
[0663] A solution of N,N-diallylamine (214) (40.6 mmol) in pyridine
(40 mL) was prepared and cooled to 0.degree. C. Trifluoroacetic
anhydride (TFAA) (52.8 mmol, 1.3 equiv.) was added dropwise with
stirring. After 2 h, TLC indicated complete conversion. The
reaction was diluted with 1M HCl (300 mL) and EtOAc (200 mL). The
organic phase washed with 1M HCl (200 mL), saturated NaHCO.sub.3
(200 mL), brine (100 mL), dried over MgSO.sub.4 and concentrated to
give N,N-Diallyl-2,2,2-trifluoro-acetamide (319) as a colorless oil
(26.9 mmol, 68% yield) that was used in next step without further
purification.
[0664] To a stirred solution of 319 (26.9 mmol) in freshly
distilled CH.sub.2Cl.sub.2 (250 mL), under nitrogen (1 atm) was
added Grubb's Catalyst
{RuCl.sub.2(CHC.sub.6H.sub.5)[P(C.sub.6H.sub.11).sub.2], 0.5 mol
%}. After 1.5 h stirring at room temperature, TLC indicated
complete conversion of the starting material to a more polar
product. The reaction was quenched by bubbling air through the
solution. The solution was concentrated and subjected to
chromatography purification (5-20% EtOAc in hexanes) to yield
1-(2,5-dihydro-pyrrol-1-yl)-2,2,2-trifluoro-ethanone (320) (22.0
mmol, 82% yield).
[0665] Compound 320 (22.0 mmol) and N-methylmorpholine N-oxide
monohydrate (35.0 mmol) were dissolved in a mixture of acetone and
H.sub.2O (1:1, v/v; 60 mL). OsO.sub.4 (0.4 mmol, 2 mol %) was added
and the resulting pale yellow solution was stirred at room
temperature for 16 h. Na.sub.2S.sub.2O.sub.5 (3.9 mmol) was then
added and the solution was stirred for an additional 1 h. The
solution was acidified to pH=2 with 6 M HCl and extracted with
CH.sub.2Cl.sub.2 (4.times.70 mL). The organic phase washed with
saturated NaHCO.sub.3 (50 mL), brine (50 mL), dried over
MgSO.sub.4, concentrated and purified by column chromatography
(0-5% MeOH in CH.sub.2Cl.sub.2) to give
1-(cis-3,4-Dihydroxy-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone
(321) (17 mmol, 78% yield) as a colorless oil. .sup.1H NMR (400
M}z, CD.sub.3OD) .delta.=3.95 ppm (dd, 1H, J=4, 13 Hz), 3.59 (dd,
1H, J=6, 12 Hz), 3.65 (dd, 1H, J=6, 13 Hz), 3.84 (dd, 1H, J=5, 12
Hz), 4.19-4.27 (m, 2H).
[0666] Compound 321 (10 mmol) was dissolved in dry pyridine (60 mL)
under nitrogen (1 atm) and the resulting solution was cooled to
-10.degree. C. (ice/NaCl). Methanesulfonyl chloride (22.0 mmol) was
added dropwise with stirring. The ice bath was removed and the
mixture was stirred for 2 h at room temperature. The resulting
suspension was diluted with Et.sub.2O (200 mL), filtered through a
pad of MgSO.sub.4 on a fritted funnel, concentrated and purified by
column chromatography (10-40% EtOAc in hexanes) to yield
1-(cis-3,4-di-O-(methanesulfonyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethano-
ne (322) as a foam (9.1 mmol, 91% yield). .sup.1H NMR (400 MHz,
acetone-d.sub.6) .delta.=3.30 ppm (s, 3H), 3.31 (s, 3H), 3.82 (dd,
1H, J=4, 13 Hz), 3.95 (dd, 1H, J=6, 12 Hz), 4.06 (dd, 1H, J=6, 14
Hz), 4.29 (dd, 1H, J=6, 12 Hz), 5.50-5.59 (m, 2H).
[0667] A stirred mixture of 322 (9.0 mmol) and NaN.sub.3 (45.0
mmol) in dry DMF (50 mL) was heated to 80.degree. C. for 16 h. TLC
analysis indicated complete conversion of the starting material to
a less polar compound that has higher R.sub.f on TLC (2:1,
hexanes/EtOAc). The reaction was cooled to room temperature,
diluted with EtOAc (200 mL), washed with water (100 mL), saturated
NaHCO.sub.3 (100 mL), brine (100 mL), dried over MgSO.sub.4,
concentrated. The residue was purified by column chromatograph
(5-15% EtOAc in hexanes) to give
1-(cis-3,4-diazido-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone (323)
as a colorless oil (8.4 mmol, 93% yield). Due to the potentially
hazardous nature of this compound, it was used immediately without
characterization.
[0668] To a stirred solution of 323 (8.4 mmol) in a mixture of
pyridine and NH.sub.4OH (7:1, v/v; 60 mL) was added PMe.sub.3 (2 M
in THF, 12.6 mL). A slight elevation in temperature occurred with a
concurrent evolution of gas. After 3 h stirring at room
temperature, TLC analysis indicated conversion to a compound that
had much lower R.sub.f(5% NH.sub.4OH in MeOH) on TLC plate that
stained with ninhydrin. The solution was diluted with EtOH (60 mL)
and water (5 mL) and concentrated. The resulting syrup was
dissolved in a mixture of toluene and EtOH (1:1, v/v; 80 mL) and
concentrated again. The resulting oil was placed on a high vacuum
line for 16 h. The oil was then dissolved in dry pyridine (70 mL),
cooled to 0.degree. C. and di-tert-butyl dicarbonate (25 mmol, 3
equiv) was added in portions with stirring. The solution was
allowed to warm to room temperature, stirred for 5 h, concentrated,
diluted with EtOAc (200 mL), washed with 0.1 M HCl (100 mL),
saturated NaHCO.sub.3 (100 mL), brine (100 mL), dried (MgSO.sub.4)
and concentrated.
[0669] The resulting oil was dissolved in 1,4-dioxane (30 mL) and
LiOH.H.sub.2O (20 mmol) was added with stirring. A precipitate
gradually formed in the solution and after 2 h stirring at room
temperature, TLC analysis indicated conversion to a more polar
product (15:2:0.1, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH). The
suspension was filtered through a glass wool plug, diluted with
CH.sub.2Cl.sub.2 (200 mL), washed with saturated NaHCO.sub.3 (100
mL), brine (100 mL), dried (MgSO.sub.4), concentrated and purified
by column chromatography (5% MeOH in CH.sub.2Cl.sub.2 with 0-1%
NH.sub.4OH) to yield
cis-3,4-(di-N-tert-butoxycarbonyl)-diaminopyrrolidine (318) as a
colorless foam (4.9 mmol, 58% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.=1.41-1.56 ppm (br s, 18H), 2.64 (dd, 2H, J=6,
11 Hz), 3.17 (dd, 2H, J=7, 12 Hz), 3.98-4.26 (br s, 2H).
4.26.7 Synthesis of 328, 331, and 336
[0670] Scheme 68 describes the synthesis of compound 145, 148 and
152. ##STR112##
[0671]
[4-(R)-(tert-Butyl-dimethyl-silanyloxy)-1-(4-methoxybenzyl)-pyrrol-
idin-2-(S)-yl]-methanol (324) was prepared according to the
literature procedure as described by P. W. Davis, S. A. Osgood, N.
Hebert, K. G. Sprankle and E. E. Swayze; Biotechnol Bioeng 1998,
61(3), 143-154.
[0672] A stirred suspension of 324 (28.4 mmol) and 10% Pd/C (1 mol
%) in MeOH (200 mL) was fitted with a hydrogen balloon and allowed
to stir at room temperature for 4 h at which point the balloon was
removed and a vacuum was applied to remove any traces of hydrogen.
The suspension was filtered through a pad of celite and
concentrated to yield a syrup which was dissolved in dry
CH.sub.2Cl.sub.2 (100 mL) and Et.sub.3N (140.0 mmol, 5 equiv). The
solution was stirred, cooled to 0.degree. C. and trifluoroacetic
anyhydride (57.0 mmol, 2 equiv) was added dropwise. The solution
was allowed to warm to room temperature and stirred under nitrogen
for 3 h at which point it was diluted with EtOH/H.sub.2O (5:1, 30
mL) and stirred for another hour.
[0673] The resulting solution was concentrated to dryness,
dissolved in EtOAc (200 mL) and washed with saturated NaHCO.sub.3
(100 mL), brine (100 mL), dried (MgSO.sub.4), adsorbed on to silica
gel (.about.30 g) and concentrated. The silica gel was rinsed with
hexane, filtered on a fritted funnel and rinsed with EtOAc (200
mL). Concentration of the EtOAc afforded
1-[4-(R)-(tert-butyl-dimethyl-silanyloxy)-2-(S)-hydroxymethyl-py-
rrolidin-1-yl]-2,2,2-trifluoro-ethanone (325) (24.1 mmol, 85%
yield) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.=0.08 ppm (s, 3H), 0.09 (s, 3H), 0.78 (s, 9H), 1.82-1.90 (m,
1H), 2.02-2.11 (m, 1H), 3.22-3.69 (m, 1/2H), 3.62-3.73 (m, 3H),
3.87-3.94 (m, 1H), 4.37-4.47 (m, 3/2H).
[0674] To a stirred solution of 325 (24.0 mmol) in MeOH (200 mL)
was added 5 M HCl in 2-propanol (20 mL, 100 mmol). The solution was
allowed to stand at room temperature for 3 h at which point it was
concentrated to yield a colorless foam. The resulting material was
dissolved in MeOH (200 mL) and concentrated again to insure removal
of any remaining HCl. The resulting syrup was dissolved in
CH.sub.2Cl.sub.2 (50 mL) and Et.sub.3N (145 mmol, 6 equiv), cooled
to 0.degree. C. with stirring and under a nitrogen atmosphere,
methanesulfonyl chloride (84 mmol, 3.5 equiv) was added dropwise.
The reaction was allowed to stir at room temperature for another 2
h at which point TLC analysis (10% MeOH in CH.sub.2Cl.sub.2)
indicated conversion to a single spot. The reaction was quenched by
the addition of water (30 mL) with vigorous stirring and
partitioned between EtOAc (200 mL) and water (100 mL). The organic
phase was washed again with H.sub.2O (100 mL), saturated
NaHCO.sub.3 (100 ml), brine (100 mL), dried (MgSO.sub.4) and
concentrated to give a white solid. DMF (50 mL) and NaN.sub.3 (190
mmol, 8 equiv) were added and the resulting suspension was stirred
at 70.degree. C. for 16 h at which time a new spot (R.sub.f=0.8,
2:1 hexanes:EtOAc) was observed on TLC.
[0675] The reaction was diluted with H.sub.2O (100 mL), brine (100
mL) and EtOAc (200 mL). The organic phase washed again with
H.sub.2O (100 mL), saturated NaHCO.sub.3 (100 mL), brine (100 mL),
dried (MgSO.sub.4), concentrated and purified by column
chromatography (5-15% EtOAc in hexanes) to give
[1-(4-(S)-Azido-2-(S)-azidomethyl-pyrrolidin-1-yl)-2,2,2-trifluoro-ethano-
ne](326) as a colorless oil (17.8 mmol, 74% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.=2.15 ppm (dt, 1H, J=5, 5, 14 Hz),
2.32-2.39 (m, 1H), 3.58 (dd, 1H, J=6, 12 Hz), 3.66-3.75 (m, 2H),
3.98 (dd, 1H, J=6, 12 Hz), 4.21-4.27 (m, 1H), 4.29-4.36 (m,
1H).
[0676] To a stirred solution of 326 (17.8 mmol) in a mixture of
pyridine and NH.sub.4OH (7:1, 80 mL) was added trimethylphosphine
(54 mL, 1 M in toluene, 3 equiv). The solution was allowed to stir
at room temperature for 3 h at which point it was diluted with EtOH
(100 mL) and concentrated to give a slightly yellow oil. The oil
was again dissolved in EtOH and concentrated to insure complete
removal of any residual NH.sub.4OH. The resulting syrup was
dissolved in 1,4-dioxane (80 mL) and saturated NaHCO.sub.3 (80 mL)
was added with cooling (0.degree. C.) and vigorous stirring.
Di-tert-butyl dicarbonate was added dropwise as a solution (72
mmol, 4 equiv, in 40 mL THF) with continued stirring and the
reaction was allowed to warm to room temperature over the course of
2 h. The suspension was diluted with EtOAc (200 mL) and filtered
through a glass frit. The resulting biphasic mixture was diluted
with H.sub.2O (100 mL) and the organic phase washed with saturated
NaHCO.sub.3 (100 mL), brine (100 mL), dried (NgSO.sub.4) and
purified via column chromatography (0-5% MeOH in CH.sub.2Cl.sub.2)
to give
[5-(S)-(tert-Butoxycarbonylamino-methyl)-1-(2,2,2-trifluoro-acetyl)-pyrro-
lidin-3-(S)-yl]-carbamic acid tert-butyl ester (327) (16.0 mmol,
90% yield) as a colorless foam. .sup.1H NMR (400 Mz, CDCl.sub.3)
.delta.=1.43 ppm (s, 9H), 1.54 (s, 9H), 1.85-1.88 (m, 1H),
2.44-2.51 (m, 1H), 3.11 (dd, 1H, J=6, 12 Hz), 3.60-3.66 (m, 1H),
3.73-3.77 (m, 1H), 3.85-3.90 (m, 1H), 4.04-4.16 (m, 2H), 4.68 (br
s, 1H).
[0677] To a stirred solution of 327 (16.0 mmol) in 1,4-dioxane (120
mL) was added LiOH.H.sub.2O (32.0 mmol, 2 equiv). The suspension
was allowed to stir at room temperature for 16 h at which point TLC
indicated complete consumption of starting material (KMnO.sub.4
stain for S.M.). The reaction was diluted with THF (120 mL),
filtered through a glass frit and concentrated. The resulting syrup
was diluted with THF/CHCl.sub.3 (1:1, 200 mL) and washed with
saturated NaHCO.sub.3 (100 mL), brine (100 mL), dried (MgSO.sub.4),
and purified via column chromatography (0-10% MeOH in
CH.sub.2Cl.sub.2 with 0-1% NH.sub.4OH) to give
[5-(S)-(tert-Butoxycarbonylamino-methyl)pyrrolidin-3-(S)-yl]-carbamic
acid tert-butyl ester (328) as a colorless foam. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta.=1.45 ppm (s, 9H), 1.47 (s, 9H), 1.69 (br
s, 1H), 2.32-2.39 (m, 1H), 2.82 (dd, 1H, J=6, 13 Hz), 2.89 (dd, 1H,
J=4, 13 Hz), 3.00 (dd, 1H, J=7, 11 Hz), 3.81 (dd, 1H, J=7, 11 Hz),
3.92-3.98 (m, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6)
.delta.=26.0, 29.0, 29.1, 58.9, 67.8, 78.5, 79.1, 154.3, 155.7
pm.
[0678]
5-(R)-(tert-butyl-dimethyl-silanyloxy)-1-(4-methoxy-benzyl)-piperi-
din-3-(S)-ol (329) was prepared according to the literature
procedure as described by P. W. Davis, S. A. Osgood, N. Hebert, K.
G. Sprankle and E. E. Swayze; Biotechnol Bioeng 1998, 61(3),
143-154.
[0679] A suspension of 329 (25.5 mmol) and 10% Pd/C (1 mol %) in
MeOH (250 mL) was fitted with a balloon of hydrogen and allowed to
stir at room temperature for 4 h. At that time, a vacuum was
applied to remove any remaining hydrogen, the vessel was purged
with nitrogen, diluted with MeOH (100 mL) and filtered through a
pad of Celite on a fritted funnel. The resulting solution was
concentrated to give
5-(R)-(tert-Butyl-dimethyl-silanyloxy)-piperidin-3-(R)-ol (330) as
a colorless oil (25.0 mmol, 98% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta.=0.13 ppm (s, 3H), 0.14 (s, 3H), 0.929 (s, 9H),
1.84 (br t, 2H, J=5 Hz), 2.71-2.78 (m, 2H), 2.97-3.05 (m, 2H),
4.04-4.09 (m, 1H), 4.19-4.24 (m, 1H).
[0680] To a stirred solution of 330 (5.0 mmol) in EtOH (30 mL) was
added 10 M HCl (15 mL). The solution was heated to reflux for 16 h
and allowed to cool to room temperature and concentrated to yield a
syrup. This syrup was dissolved in a minimal amount of hot EtOH
(.about.20 mL) and allowed to stand at room temperature overnight
to yield the compound 331 as colorless crystals (4.2 mmol, 84%
yield).
[0681] To a stirred solution of 330 (25.0 mmol) in dry pyridine (40
mL) at 0.degree. C. was added trifluoroacetic anhydride (50 mmol, 2
equiv.). The reaction was allowed to warm to room temperature and
stirring was continued under a nitrogen atmosphere for 3 h.
H.sub.2O was added (5 mL) and stirring was continued for 1 h. At
this time the reaction was diluted with EtOH (100 mL) and the
resulting solution was concentrated. The solid was dissolved in
EtOAc (150 mL) and washed with 0.1 M HCl (2.times.100 mL),
saturated NaHCO.sub.3 (100 mL), brine (100 mL), dried (MgSO.sub.4)
and concentrated to yield
1-[3-(tert-Butyl-dimethyl-silanyloxy)-5-hydroxy-piperidin-1-yl]-2,2,2-tri-
fluoro-ethanone (332) (23.8 mmol, 95% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.=0.08 (s, 2H), 0.11 (s, 4H), 0.79 (s, 3H), 0.81
(s, 6H), 1.70-1.76 (m, 1H), 1.82-1.89 (m, 1H), 3.16-3.26 (m, 1H),
3.42-3.68 (m, 3H), 3.98-4.13 (m, 2H). LC-MS; m/e 327.42
[M+1].sup.+=328.2
[0682] To a cooled (0.degree. C.), stirred solution of 332 (18.2
mmol) and Et.sub.3N (50.0 mmol) in dry CH.sub.2Cl.sub.2 (60 mL) was
added methanesulfonyl chloride (37 mmol, 2 equiv). The solution was
allowed to warm to room temperature and stirred for 2 h. The
suspension was diluted with Et.sub.2O (140 mL), filtered through a
frit to remove solids and the supernatant washed with cold 0.1 M
HCl (100 mL), saturated NaHCO.sub.3 (100 mL), brine (100 mL), dried
(MgSO.sub.4) and concentrated to afford
1-[3-(R)-(tert-Butyl-dimethyl-silanyloxy)-5-(R)--O-Methanesulfonyl-piperi-
din-1-yl]-2,2,2-trifluoro-ethanone (333) (17.9 mmol, 98% yield) as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=0.1 ppm
(s, 2H), 0.11 (s, 4H), 0.89 (s, 3H), 0.90 (s, 6H), 1.93-2.05 (m,
1H), 2.14-2.30 (m, 1H), 3.03 (s, 1H), 3.06 (s, 2H), 3.21 (dd, 2/3H,
J=8, 14 Hz), 3.41-3.51 (m, 1H), 3.69 (dd, 1/3H, J=6, 14 Hz),
3.76-3.81 (m, 1H), 4.02-4.18 (m, 1H), 4.99-5.08 (m, 1H).
[0683] To a solution of 333 (17.9 mmol) in DMF (50 mL) was added
NaN.sub.3 (60 mmol, 3.3 equiv). The reaction was stirred and heated
to 80.degree. C. for 16 h at which point it was allowed to cool and
quenched by the addition of H.sub.2O (20 mL). The solution was
diluted with EtOAc (200 mL) and the organic phase washed with
saturated NaHCO.sub.3 (2.times.100 mL), brine (3.times.100 mL),
dried (MgSO.sub.4), concentrated and passed through a silica gel
plug on a fritted funnel. Concentration of the resulting solution
gave
1-[3-(S)-Azido-5-(R)-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-2,2-
,2-trifluoro-ethanone (334) as a dense oil (15.1 mmol, 84% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=0.10 ppm (d, 4H, J=2 Hz),
0.12 (d, 2H, J=3 Hz), 0.90 (s, 6H), 0.91 (s, 3H), 1.52-1.61 (m,
1H), 2.35-2.39 (m, 1H), 2.55-2.61 (m, 1H), 2.85-2.94 (m, 1H),
3.41-3.46 (m, 1H), 3.66-3.72 (m, 1H), 3.90-4.02 (m, 1H), 4.43-4.48
(m, 1/3H), 4.57-4.62 (m, 2/3H)
[0684] To a stirred solution of 334 (15.0 mmol) in a mixture of
pyridine and NH.sub.4OH (7:1, v/v, 80 mL) was added
trimethylphosphine (1 M in toluene, 22.5 mL, 1.5 equiv.). The
addition was followed by a slight increase in temperature, coupled
with effervescence. After stirring at room temperature for 4 h, the
solution was diluted with EtOH (100 mL) and concentrated to yield a
slightly yellow oil. The oil was again dissolved in EtOH (100 mL)
and concentrated. The resulting syrup was dissolved in 1,4-dioxane
(60 mL) and saturated NaHCO.sub.3 was added with stirring and
cooling (0.degree. C.). Di-tert-butyl dicarbonate (30 mmol) was
added dropwise (as a solution in 40 mL of MeOH) with vigorous
stirring. After the addition was complete, the reaction was allowed
to stir for 3 h at room temperature at which time it was diluted
with EtOAc (100 mL), filtered through a fritted funnel and
concentrated to yield a stiff syrup. The syrup was dissolved in
EtOAc (200 mL) and the organic phase washed with H.sub.2O (100 mL),
saturated NaHCO.sub.3 (100 mL), brine (100 mL), dried (MgSO.sub.4)
and concentrated. The resulting residue was dissolved in
CH.sub.2Cl.sub.2 (50 mL) and silica gel was added (.about.15 g).
The suspension was diluted with hexanes (200 mL) and poured on to a
fritted funnel, rinsed with hexane and the desired product was
eluted with EtOAc (200 mL) and concentrated to give the desired
product (335) as an oil.
[0685] The above oil (335) was dissolved in 1,4-dioxane (100 mL),
LiOH.H.sub.2O (60.0 mmol) was added and the suspension was allowed
to stir at room temperature for 16 h. TLC indicated complete
conversion to a more polar compound (R.sub.f=0.6, 15:2:0.1
CHCl.sub.3/MeOH/NH.sub.4OH, stained with ninhydrin). The solution
was diluted with THF (100 mL), filtered through a glass frit,
concentrated to dryness and purified by column chromatography
(CHCl.sub.3/MeOH/NH.sub.4OH) to afford
[5-(R)-(tert-Butyldimethyl-silanyloxy)-piperidin-3-(S)-yl]-carbamic
acid tert-butyl ester (336) (10.9 mmol, 73% yield) as a colorless
oil that solidified on standing. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.=0.01 ppm (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.35 (s, 9H),
1.52-1.68 (m, 3H), 1.75-1.86 (m, 1H), 2.62-2.78 (m, 4H), 3.51-3.59
(m, 1H), 3.67-3.74 (m, 1H), 5.82-5.96 (m, 1H); .sup.13C NMR (100
MHz, CDCl.sub.3) .delta.=-4.6, -4.4, 18.3, 26.2, 28.8, 36.6, 45.5,
50.7, 52.9, 67.1, 79.0, 155.2 ppm; LC-MS: m/e 331.0
[M+1].sup.+.
4.26.8 Synthesis of Intermediate 340.
[0686] Scheme 69 describes the synthetic procedure for preparation
of intermediate 340. ##STR113##
[0687] Compound 335 (crude material, 12.2 mmol) was dissolved in
THF and 2 equivalents of TBAF was added at 0.degree. C. The
reaction mixture was stirred at 0.degree. C.--room temperature for
2 hours. TLC (R.sub.f=0.4 EtOAc/Hexane=2:1) confirmed the
completion of reaction. The mixture was concentrated and purified
by flash chromatography. It was dissolved in 1,4-dioxane (20 mL),
LiOH.H.sub.2O (800 mg) in 4 mL of H.sub.2O was added and the
suspension was allowed to stir at room temperature for 30 minutes.
TLC indicated the complete conversion to a more polar compound
(R.sub.f=0.6, 2% of NH.sub.4OH in MeOH). The mixture was
concentrated under reduced pressure, dissolved the residue in MeOH
that resulted in the formation of crystals, filtered, concentrated
under reduced pressure and purified by column chromatography to
afford 1.2 g of compound 337.
[0688] Compound 337 (1.42 g, 6.55 mmol), pyridine (15 mL) and TFAA
(1 mL, 1.1 equiv.) were mixed and cooled to 0.degree. C. and
stirred for 30 minutes. Second equivalent of TFAA was added and the
mixture was stirred at room temperature for 1 hour. EtOH (20 mL)
was added and the mixture was then concentrated under reduced
pressure and purified by flash chromatography to give the desired
product 338.
[0689] Compound 338 (800 mg, 2.63 mmol), Et.sub.3N (750 .mu.L, 2
equiv.) and 10 mL of CH.sub.2Cl.sub.2 were mixed and the resulting
solution was cooled down to 0.degree. C. MsCl (244 .mu.L, 1.2
equiv.) was added and the reaction mixture was stirred at 0.degree.
C. to room temperature. The reaction progress was monitored by TLC
(5% MeOH in CH.sub.2Cl.sub.2, stained with KMnO.sub.4). Upon the
completion of the reaction, the suspension was concentrated to
yield a solid. This solid was dissolved in DMF. NaN.sub.3 (3.3
equiv.) was added and the mixture was heated at 60.degree. C. Upon
the completion of the reaction as determined by TLC, the reaction
mixture was allowed to cool and quenched by the addition of
H.sub.2O. The solution was diluted with EtOAc and the organic phase
was washed with saturated NaHCO.sub.3, brine, dried (MgSO.sub.4),
concentrated and passed through a silica gel plug on a fritted
funnel. Concentration of the resulting solution gave the desired
product (339).
[0690] Compound 339 was dissolved in 1,4-dioxane. LiOH.H.sub.2O (4
equiv.) in H.sub.2O was added and the suspension was allowed to
stir at room temperature for 16 hours. TLC indicated the complete
reaction. The solution was diluted with THF, filtered through a
glass frit, concentrated to dryness and purified by column
chromatography to afford the desired product 340 (266.7 mg).
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.=3.81 (s, br, 1H),
3.64-3.74 (m, 1H), 2.95 (dd, 1H, J=12.8 Hz, J.sub.2=3.6 Hz), 2.77
(d, 2H, J=3.6 Hz), 2.44 (dd, 1H, J=12.8 Hz, J.sub.2=8.4 Hz),
1.92-2.01 (m, 1H), 1.70-1.80 (m, 1H), 1.44 (s, 9H).
4.26.9 Synthesis of 341
[0691] ##STR114##
[0692] Compound 341 was prepared using a similar reaction sequence
as that used for the synthesis of 336. This process used 325 as a
starting material and invoked an eight-step reaction sequence to
appropriately displace the secondary hydroxyl group with a nitrogen
moiety, and remove any unnecessary protecting groups.
4.26.10 Scheme 70 Describes the Synthesis of Intermediate 349
[0693] ##STR115##
4-Hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl
ester (344)
[0694] To a stirred solution of N-Boc-hydroxyproline-methyl ester
(343) (15 g, 65 mmol) in THF (70 mL) was added BH.sub.3.SMe.sub.2
(55 mL, 2.0 M in Et.sub.2O, 110 mmol). The solution was heated to
reflux with stirring for four hours and reaction progress was
monitored by TLC (5% MeOH/CHCl.sub.3, product had lower R.sub.f
than starting material, stained with K.sub.2MnO.sub.4). The heat
was removed and the reaction was quenched by the slow addition of
MeOH (40 mL). The resulting solution was heated to reflux again for
45 minutes, allowed to cool and concentrated to yield an oil that
was purified by flash chromatography (1-15% MeOH in CHCl.sub.3) to
give 12.68 g (.about.90% yield) of the desired product (344).
4-Methanesulonyloxy-2-methanesulonyloxymethyl-pyrrolidine-1-carboxylic
acid tert-butyl ester (345)
[0695] To a stirred solution of the diol (344) (12.7 g, 58.5 mmol)
and triethylamine (5 equiv., 41 mL) in CH.sub.2Cl.sub.2 (200 mL) at
0.degree. C. was added methanesulfonyl chloride (MsCl) (2.4 equiv.,
10.9 mL). The resulting suspension was removed from the ice bath
and allowed to warm to room temperature with stirring at which
point TLC analysis indicated complete consumption of the starting
material and conversion to a single spot of higher R.sub.f (5%
MeOH/CHCl.sub.3, stained with K.sub.2MnO.sub.4). The reaction was
quenched by the addition of water (20 mL) with vigorous stirring.
NaHCO.sub.3 (sat., aqueous, 200 mL) was added and the organic layer
was separated, washed with brine, dried (MgSO.sub.4) and purified
by flash chromatography (1-10% MeOH/CHCl.sub.3) to yield the
desired compound (345) as a colorless oil.
4-Azido-2-azidomethyl-pyrrolidine-1-carboxylic acid tert-butyl
ester (346)
[0696] To a stirred solution of the di-methanesulfonate (345) in
DMF (100 mL) was added NaN.sub.3 (13.0 g, 4 equiv.). The suspension
was heated to 80.degree. C. and allowed to stir under a nitrogen
atmosphere for 16 h at which point TLC (5% MeOH/CHCl.sub.3, stained
with Ce/PMA) indicated the complete consumption of the starting
material. The reaction was allowed to cool to room temperature,
diluted with toluene (200 mL) to precipitate the inorganic matter
and filtered through a pad of celite on a glass frit. The resulting
solution was concentrated to yield a brown liquid that was purified
by flash chromatography (5-30% EtOAc in hexanes) to provide the
desired compound (346) as a golden liquid.
1-(4-Azido-2-azidomethyl-pyrrolidin-1-yl)-Z Z 2-trifluoro-ethanone
(347)
[0697] To a solution of the above diazide (5) in CH.sub.2Cl.sub.2
(60 mL) at 0.degree. C. was added trifluoroacetic acid (40 mL)
which was accompanied by a vigorous evolution of gas and immediate
color change. After warming to room temperature, TLC analysis (20%
EtOAc in hexanes, stained with Ce/PMA) indicated the complete
conversion of the starting material (R.sub.f=0.6) to a spot at the
baseline. The reaction was concentrated to dryness to yield a dark
brown liquid that was diluted with EtOH (50 mL) and concentrated
again. The resulting oil was dissolved in CH.sub.2Cl.sub.2 (50 mL)
and pyridine (25 mL, 5 equiv.) and cooled to 0.degree. C. To this
stirred solution was added trifluoroacetic anhydride (16 mL, 2
equiv.). TLC analysis indicated immediate conversion to a less
polar spot (R.sub.f=0.5, 20% EtOAc/hexanes, stained with Ce/PMA)
and the solution was concentrated to dryness. The resulting oil was
partitioned between toluene (200 mL) and NaHCO.sub.3 (sat., aqueous
200 mL). The aqueous phase was discarded and the toluene layer was
again washed with NaHCO.sub.3 (200 mL), brine (200 mL), dried
(MgSO.sub.4), concentrated and subjected to chromatography
purification (5-25% EtOAc in hexanes) to yield the desired compound
(347) as a golden liquid (8.64 g, 32.8 mmol, 56% total yield for
four steps).
[5-(tert-Butoxycarbonylamino-methyl)-1-(2,2,2-trifluoro-acetyl)-pyrrolidin-
-3-yl]-carbamic acid tert-butyl ester (348)
[0698] To the above compound 348 (8.64 g, 32.8 mmol) in a stirred
solution of pyridine (50 mL) and NH.sub.4OH (10 mL) was added
PMe.sub.3 (1 M in THF, 75 mL, 2.2 equiv). The reaction was stirred
for 2 h at room temperature at which point TLC analysis (20%
NH.sub.4OH in MeOH, stained with ninhydrin) indicated conversion to
a single spot. The reaction was concentrated to dryness to yield an
oil that began to solidify. The resulting solid was suspended in
THF (120 mL) and NaHCO.sub.3 (sat., 100 mL). To the stirred
suspension (cooled to 0.degree. C.) was added a solution of
Boc.sub.2O in THF (28.2 g, 4 equiv, in 50 mL). The suspension was
stirred for 2 h at room temperature at which point TLC analysis
indicated the complete conversion of the diamine to a less polar
spot (R.sub.f=0.85 1:1 hexanes/EtOAc, stained with ninhydrin). The
suspension was diluted with EtOAc (200 mL) and the organic phase
was decanted, washed with brine, dried (MgSO.sub.4) and
concentrated to yield an oil that was subjected to flash
chromatography purification (5-30% EtOAc in hexanes).
Chromatography did not yield an entirely pure material with
indication that there was some di-protection of one of the amines.
This material (348) was directly used in the next step.
[5-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-3-yl]-carbamic acid
tert-butyl ester (349)
[0699] To a stirred solution of the oil (348) in 1,4-dioxane (95
mL) was added LiOH.H.sub.2O (11.0 g, 8 equiv). Water (5 mL) was
added and the reaction mixture was sonicated briefly to disperse
the solids, then stirred overnight at room temperature. TLC
analysis indicated the complete consumption of the starting
material (top for starting material, R.sub.f=0.35 for product
15:2:0.1 CHCl.sub.3/MeOH/NH.sub.4OH). The reaction was diluted with
CHCl.sub.3 (150 mL) and dried over MgSO.sub.4. The suspension was
filtered and the resulting yellow solution was concentrated to
yield an oil that was purified by flash chromatography on a short
column of silica (0-10% MeOH in CHCl.sub.3, with a small amount of
NH.sub.4OH added at the end to insure complete elution of the
product). The desired compound was collected as a sticky syrup (7.0
g, 68% total yield for 3 steps). .sup.1H NMR (CD.sub.3OD):
.delta.=1.45 (s, 9H), 1.49 (s, 9H), 1.60-1.74 (m, 1H), 2.41 (1H,
dt, J.sub.1=7.2 Hz, J.sub.2=12.8 Hz), 2.96-3.12 (m, 3H), 3.83 (dd,
1H, J.sub.1=7.2 Hz, J.sub.2=11.2 Hz), 3.90-4.20 (m, 2H).
4.26.11 Synthesis of Intermediate 352 Scheme 71
[0700] ##STR116##
[0701] Compound 4 (1.0 g, 3.17 mmol) was dissolved in 12 mL of THF
and 2 mL of DMF. Triethylamine (844 .mu.L, 6 mmol) was added and
the mixture was cooled to 0.degree. C. using an ice-H.sub.2O bath.
The acid chloride (271) (545 .mu.L, 3.82 mmol) was added at
0.degree. C. and the reaction mixture was stirred at 0.degree. C.
to room temperature overnight. The reaction mixture was
concentrated under reduced pressure and the residue was purified by
liquid-liquid extraction using CHCl.sub.3 (10 mL) and H.sub.2O (4
mL.times.2). The organic layer was concentrated and dried over high
vacuum to give 1.54 g of crude product 350 with HPLC purity of 95%
by ELSD. LC-MS: m/e 450.4 [M+1].sup.+ (exact ms: 449.25). This
crude material was directly used in the next step.
[0702] Compound 350 (0.71 g, 1.59 mmol) was dissolved in 10 mL of
DMF and cooled down to 0.degree. C. using an ice-H.sub.2O bath. NaH
(60% dispersion in mineral oil, 153 mg, 3.82 mmol) was added at
0.degree. C. and stirred at 0.degree. C. for 1 hour. MeI (0.59 mL,
9.54 mmol) was added and the mixture was stirred at room
temperature for 17 hours. The solvent was evaporated under reduced
pressure and the residue was purified by liquid-liquid extraction
between EtOAc (6 mL) and H.sub.2O (4 mL.times.2). The organic layer
was concentrated under reduced pressure to give the desire product
3. LC-MS: m/e 478.3 [M+1].sup.+ (exact ms: 477.28).
[0703] Compound 351 (200 .mu.mol) was dissolved in 1 mL of THF. The
solution was degassed by alternately connecting with vacuum and
N.sub.2. Pd/C (10 wt %, 22 mg, 20 .mu.mol) was added under N.sub.2.
A H.sub.2 balloon was then attached and the reaction mixture was
stirred at room temperature overnight. LC-MS result indicated that
no product formed. Pd/C (40 mg, wet) and additional 2 mL of THF was
added. The reaction mixture was degassed the same way as before and
a H.sub.2 balloon was attached. The mixture was stirred at room
temperature overnight and the LC-MS result indicated 50% conversion
by ELSD. Additional Pd/C (10 wt %, wet, 100 mg) was added and the
mixture was degassed and a H.sub.2 balloon was attached. The
reaction mixture was continued to stir at room temperature
overnight. The LC-MS result confirmed 80% conversion by ELSD. The
inorganic solid was then filtered off through Celite, washed with
methanol (3 mL). The filtrate was concentrated and purified by
reverse-phase HPLC using a gradient of CH.sub.3CN and H.sub.2O to
give the desired product (352) (50.45 mg, 147 .mu.mol, 73.5%
isolated yield) with the HPLC purity of 100% by ELSD. LC-MS: m/e
344.3 [M+1].sup.+ (exact ms: 343.25).
4.26.12 Scheme 72 Describes the Synthesis of Intermediate 357.
[0704] ##STR117##
[0705] Compound 4 (0.5 g, 1.59 mmol), compound 353 (452.5 mg, 1.75
mmol), NaHCO.sub.3 (267.2 mg, 3.18 mmol) and 8 mL of THF were
mixed. The mixture was shaken at room temperature for 2 days. LC-MS
confirmed the completion of the reaction. The reaction mixture was
dried under reduced pressure to give the desired product (354).
LC-MS: m/e 538.3 [M+1].sup.+ (exact ms: 537.28).
[0706] The above compound 354 was dissolved in 6 mL of THF. HCl
(4.0 M in dioxane, 8 mL, 32 mmol) was added and the mixture was
shaken at room temperature for 68 hours. The mixture was dried
under reduced pressure to give the desired product (355) as the HCl
salt with HPLC purity of 90% by ELSD. LC-MS: m/e 338.2 [M+1].sup.+
(exact ms: 337.18). This crude product was directly used in the
next step.
[0707] The above compound 355 was dissolved in 12 mL of THF and 2
mL of DMF. .sup.iPr.sub.2NEt.sub.3 (1.0 M, 4.74 mL, 4.74 mmol) in
THF was added followed by tri-fluoroacetic anhydride (483 .mu.L,
3.48 mmol). The mixture was stirred at room temperature overnight
and concentrated under reduced pressure. The residue was purified
by liquid-liquid extraction work-up by using EtOAc (6 mL) and
H.sub.2O (4 mL.times.2). The organic layer was dried under reduced
pressure to give the desired product 356. LC-MS: m/e 530.2
[M+1].sup.+ (exact ms: 529.14).
[0708] Piperidine (2 mL) was added into a slurry of the above
compound 356 in 8 mL of THF, 1 mL of DMF and 1 mL of
CH.sub.2Cl.sub.2. The mixture was shaken at room temperature over a
weekend and was then concentrated under reduced pressure. The crude
product was purified by HPLC using a gradient of CH.sub.3CN and
H.sub.2O to give 76.7 mg (0.25 mmol, 15.8% isolated yield for 4
steps) of the desired product 357. LC-MS: m/e 308.2 [M+1].sup.+
(exact ms: 37.08).
4.26.13 Scheme 73 Describes the Synthesis of Intermediate 360.
[0709] ##STR118##
[0710] Compound 350 (1.58 .mu.mol) was dissolved in 6 mL of THF.
HCl (4.0 M in dioxane, 8 mL, 32 mmol) was added and the mixture was
shaken at room temperature for 68 hours. The mixture was dried
under reduced pressure to give the desired product (358) as the HCl
salt with HPLC purity of 100% by ELSD. LC-MS: m/e 250.2 [M+1].sup.+
(exact ms: 249.15).
[0711] The above compound 358 was dissolved in 12 mL of THF and 2
mL of DMF. .sup.iPr.sub.2NEt.sub.3 (1.0 M, 4.74 mL, 4.74 mmol) in
THF was added followed by acetic anhydride (326 .mu.L, 3.48 mmol).
The mixture was stirred at room temperature overnight and
concentrated under reduced pressure. The residue was purified by
liquid-liquid extraction work-up by using EtOAc (6 mL) and H.sub.2O
(4 mL.times.2). The organic layer was dried under reduced pressure
to give the desired product 359. LC-MS: m/e 334.2 [M+1].sup.+
(exact ms: 333.17).
[0712] The above compound 359 was dissolved in 1 mL of THF and 1 mL
of methanol. The solution was degassed by alternately connecting
with vacuum and N.sub.2. Pd/C (10 wt %, wet, 800 mg) was added
under N.sub.2. A H.sub.2 balloon was then attached and the reaction
mixture was stirred at room temperature under H.sub.2 atmosphere
for 2 days. The inorganic solid was then filtered off through
Celite. The filtrate was concentrated to give the desired product
(360) (59.6 mg, 178.9 .mu.mol, 11.3% isolated yield for 3 steps) as
a brown solid with the HPLC purity of 90% by ELSD. LC-MS: m/e 200.3
[M+1].sup.+ (exact ms: 199.13). This material was directly used
without further purification.
4.27 Synthesis of Intermediates: Aniline Derivatives
4.27.1 General Procedure to Synthesize .beta.-Keto-Amide
Substituted Anilines (368)
[0713] ##STR119##
[0714] R is optionally substituted alkyl, aryl, heteroaryl,
cycloalkyl, or heterocycloalkyl.
[0715] .beta.-ketone ester (500 mg, 2.11 mmol, 362) and an
equivalent mole amount of aniline (361) (2.11 mmol) were mixed and
heated at 180.degree. C. for 20 minutes with stirring (without
solvent). After cooling down the reaction mixture, 3 mL of EtOH was
added, sonicated and centrifuged. The top clear solution was
removed and the resulting solid was dried under vacuum to give
desired product (363). LC-MS and NMR was used to confirm the
identity of the desired products.
[0716] .beta.-ketoamide substituted nitro-aniline (150 .mu.mol,
364) was dissolved upon heating (or slurry) in 1.2 mL of EtOH (or a
mixture of EtOH and DMF if low solubility) and heated at 50.degree.
C. 50 .mu.L of neat NH.sub.2NH.sub.2 (98% anhydrous) was added
followed by immediately 300 .mu.L of Raney-Nickel (50% slurry in
H.sub.2O) at 50.degree. C. The reaction stopped bubbling 20 minutes
later after the addition. The TLC result showed the completion of
the reaction. The reaction mixture was then cooled down, filtered
through a plug of Celite, washed with small amount of MeOH and
concentrated under vacuum to give the desired product (364). LC-MS
and .sup.1H NMR were used to confirm the identity of the desired
products. This methodology can be used for the preparation of the
meta-analogs of compound 364.
4.27.2 EXAMPLE 28
Synthesis of 4-(.beta.-ketoamide) substituted anilines (368)
[0717] 500 mg of .beta.-ketone ester (362) (2.11 mmol) and same
equivalent of 3,4-dichloroaniline (367) (2.11 mmol) were mixed and
heated at 180.degree. C. for 20 minutes with stirring (without
solvent). After cooling down the reaction mixture, 3 mL of EtOH was
added, sonicated and centrifuged. The top clear solution was
removed and the resulting solid was dried under vacuum to give the
desired product (365). LC-MS and NMR were used to confirm the
identity of the desired product. LC-MS: MS m/e 353 [M+1] was found
(exact MS: 352.0); .sup.1H NMR (DMSO-d.sub.6): A mixture of the
isomers (1:1) as listed below 366 and 367) was identified. .sup.1H
NMR (DMSO-d.sub.6): .delta. 10.62 (s, 1H), 10.51 (s, 1H), 8.34 (t,
3H), 8.20 (d, 2H), 7.93-8.0 (m, 3H), 7.58 (dd, 2H), 7.49 (dd, 1H),
7.42 (dd, 1H), 6.08 (s, 1H), 4.26 (s, 2H). ##STR120##
[0718] 150 .mu.mol of above .beta.-ketoamide (365) was dissolved
upon heating in 1.2 mL of EtOH and then heated at 50.degree. C. 50
uL of neat NH.sub.2NH.sub.2 (98% anhydrous) was added and
immediately followed by 300 mL of Raney-Nickel (50% slurry in
H.sub.2O) at 50.degree. C. The reaction stopped bubbling 20 minutes
later after the addition. The TLC result showed the completion of
the reaction. The reaction mixture was then cooled down, filtered
through a plug of Celite, washed with small amount of MeOH and
dried under vacuum to give the desired product (368).
4.27.3 General Procedure to Synthesize 3-hydroxy-4-amide
substituted anilines (370 and 372)
[0719] ##STR121##
[0720] R.sup.9 and R.sup.10 refer to substitutents as defined for
substituted aryls.
[0721] Into 150 .mu.mol of acid chloride (neat) was added 600 mL of
CH.sub.2Cl.sub.2 followed by 600 .mu.L of a solution of 0.25 M
2-hydroxy-4-nitro-aniline (46) in anhydrous THF containing 150
.mu.mol of Et.sub.3N. The reaction mixture was shaken at room
temperature overnight (>16 h) or heated at 50.degree. C. for 2
hours. The resulting solution was concentrated under vacuum and
pre-purified by liquid-liquid extraction (CHCl.sub.3/H.sub.2O) and
the organic layer was dried under vacuum to give the desired
product (369). The nitro group was further reduced as described
below.
[0722] The nitro-compound (150 .mu.mol, 369) was dissolved upon
heating (or slurry, at 80.degree. C.) in 1.2 mL of EtOH (or a
mixture of EtOH and DMF if low solubility) and decreased the
temperature to 50.degree. C. 50 .mu.L of neat NH.sub.2NH.sub.2 (98%
anhydrous) was added followed immediately by 300 .mu.L of
Raney-Nickel (50% slurry in H.sub.2O) at 50.degree. C. The reaction
stopped bubbling 20 minutes later after the addition. The TLC
result showed the completion of the reaction. The reaction mixture
was then cooled down, filtered through a plug of Celite, washed
with small amount of MeOH and dried under vacuum to give the
desired product (370). LC-MS was used to confirm the identity of
the desired products.
4.27.4 EXAMPLE 29
Synthesis of 3-hydroxy-4-amide substituted aniline (374) where
R.sup.9=4-n-Butyl
[0723] Into 150 .mu.mol of 4-n-butylbenzoyl chloride (neat) was
added 600 .mu.L of CH.sub.2Cl.sub.2 followed immediately by 600
.mu.L of a solution of 0.25 M 2-hydroxy-4-nitro-aniline (46) in
anhydrous THF containing 150 .mu.mol of Et.sub.3N. The reaction
mixture was shaken at room temperature overnight (for at least 16
h). The resulting solution was concentrated under vacuum and
pre-purified by liquid-liquid extraction (CHCl.sub.3/H.sub.2O) and
the organic layer was dried under vacuum to give the desired
product (373). The nitro group was further reduced as described
below.
[0724] The above nitro-compound (150 .mu.mol, 373) was dissolved
upon heating (80.degree. C.) in 1.2 mL of EtOH and then decreased
to 50.degree. C. 50 .mu.L of neat NH.sub.2NH.sub.2 (98% anhydrous)
was added immediately followed by 300 mL of Raney Nickel (50%
slurry in H.sub.2O) at 50.degree. C. The reaction stopped bubbling
20 minutes later after the addition. The TLC result showed the
completion of the reaction. The reaction mixture was then cooled
down, filtered through a plug of Celite, washed with small amount
of MeOH and dried under vacuum to give the desired product (374).
LC-MS was used to confirm the identity of the desired products. MS
m/e 285.2 [M+1] (exact ms: 284.15). This crude product was directly
used in the next step without further purification.
4.27.5 General Procedure to synthesize 3-hydroxy-4-sulfonamide
substituted anilines (372)
[0725] Into 150 .mu.mol of sulfonyl chloride (neat) was added 600
.mu.L of CH.sub.2Cl.sub.2 followed immediately by 600 .mu.L of a
solution of 0.25 M 2-hydroxy-4-nitro-aniline (46) in anhydrous THF
containing 150 .mu.mol of Et.sub.3N. The reaction mixture was
shaken at room temperature overnight (>16 h) or heated at
50.degree. C. for 2 hours. The resulting solution was concentrated
under vacuum and pre-purified by liquid-liquid extraction
(CHCl.sub.3/H.sub.2O) and the organic layer was dried under vacuum
to give the desired product (371). The nitro group was further
reduced as described below.
[0726] The nitro-compound (150 .mu.mol, 371) was dissolved upon
heating (or slurry, at 80.degree. C.) in 1.2 mL of EtOH (or a
mixture of EtOH and DMF if low solubility) and heated at 50.degree.
C. 50 .mu.L of neat NH.sub.2NH.sub.2 (98% anhydrous) was added
followed immediately by 300 .mu.L of Raney Nickel (50% slurry in
H.sub.2O) at 50.degree. C. The reaction stopped bubbling 20 minutes
later after the addition. The TLC result showed the completion of
the reaction. The reaction mixture was then cooled down, filtered
through a plug of Celite, washed with small amount of MeOH and
dried under vacuum to give the desired product (372). LC-MS was
used to confirm the identity of the desired products.
4.27.6 EXAMPLE 30
Synthesis of
N-(4-amino-o-hydroxyphenyl)-2,4-dichloro-benzenesulfonamide
(376)
[0727] Into 150 .mu.mol of 2,4-di-chlorobenzenesulfonyl chloride
(neat) was added 600 .mu.L of CH.sub.2Cl.sub.2 followed immediately
by 600 .mu.L of a solution of 0.25 M 2-hydroxy-4-nitro-aniline (46)
in anhydrous THF containing 150 .mu.mol of Et.sub.3N. The reaction
mixture was shaken at room temperature overnight (> or =16 h).
The resulting solution was concentrated under vacuum and
pre-purified by liquid-liquid extraction (CHCl.sub.3/H.sub.2O) and
the organic layer was dried under vacuum to give the desired
product (375). The nitro group was further reduced as described
below.
[0728] 150 .mu.mol of the above nitro-compound 375 was dissolved
upon heating (80.degree. C.) in 1.2 mL of EtOH and then decreased
to 50.degree. C. 50 .mu.L of neat NH.sub.2NH.sub.2 (98% anhydrous)
was added followed immediately by 300 .mu.L of Raney Nickel (50%
slurry in H.sub.2O) at 50.degree. C. The reaction stopped bubbling
20 minutes after the addition. The TLC result showed the completion
of the reaction. The reaction mixture was then cooled down,
filtered through a plug of Celite, washed with small amount of MeOH
and dried under vacuum to give the desired product (376). LC-MS was
used to confirm the identity of the desired products. MS m/e 333.1
[M+1] (exact ms: 331.98). This crude product was directly used in
the next step without further purification.
4.27.7 General Procedure to Synthesize o-hydroxybenzamide
Substituted Anilines (380)
[0729] ##STR122##
[0730] R is optionally substituted alkyl, aryl, heteroaryl,
cycloalkyl, or heterocycloalkyl.
[0731] 10 g (85.3 mmol) of 2-hydroxy-4-aminobenzoic acid (377) was
dissolved in 140 mL of ethanol. Triethylamine (18.4 mL neat, 130.6
mmol) was added at room temperature followed by a solution of 28.5
g (130.6 mmol) of Boc.sub.2O in 200 mL of THF and the reaction
mixture was stirred at room temperature overnight. TLC result
showed the completion of the reaction.
[0732] The reaction mixture was dried down under vacuum to get the
crude product. 75 mL of 1M of NaOH solution was added into the
crude product and this aqueous solution was extracted with organic
solvent three times (40 mL hexane, 50 mL of hexane, 40 mL hexane
plus 20 mL diethyl ether) to remove impurity. The separated aqueous
layer was then cooled to 0.degree. C. and a solution of 1M HCl (60
mL) was added and the pH of resulting solution was 4. The white
precipitate was collected by filtration under vacuum, washed with
water and dried in a vacuum oven at 50.degree. C. The off-white
solid (13.97 g, 84.5% isolated yield) was obtained. LC-MS and
.sup.1H-NMR confirmed the identity of the desired product (378)
with HPLC purity of 94%. LC-MS: HPLC purity was 97.7%; MS m/e 254.1
[M+1]found (exact ms: 253.1).
[0733] 110 .mu.mol of the above Boc-protected 4-amino-2-hydroxy
benzoic acid (378) was dissolved in 220 .mu.L of DMF. A solution of
220 .mu.L of 0.5 M of amine solutions in THF containing 4
equivalent of Et.sub.3N was added followed by 440 .mu.L of 0.5 M of
HOBt in THF. The resulting reaction mixture was vortexed to mix
very well. 880 uL of 0.25 M EDCl solution in methylene chloride was
then added, vortexed and shaken at room temperature for 24 hours.
The reaction mixture was then dried down under vacuum and purified
by liquid-liquid extraction between CHCl.sub.3 (2 mL) and H.sub.2O
(1 mL.times.2). LC-MS of the organic layer confirmed the identity
of the desired product (379) and the organic layer was concentrated
under vacuum until very dry.
[0734] 2 mL of methanol was added into above compound (379) to
dissolve followed by 2 mL of 4 M HCl in 1,4-dioxane at room
temperature. The resulted solution was shaking at room temperature
overnight, concentrated under vacuum with heating (50-60.degree.
C.) to give the desired product (380) as solid. LC-MS confirmed the
identity of the product as HCl salt.
4.27.8 EXAMPLE 31
Synthesis of 4-amino-2-hydroxy-N-(4-methoxy-phenyl)-benzamide
(382)
[0735] 110 .mu.mol of the BOC-protected 4-amino-2-hydroxy benzoic
acid (378) was dissolved in 220 .mu.L of DMF. A solution of 220
.mu.L of 0.5 M of 4-methoxyaniline in THF containing 4 equivalent
of Et.sub.3N was added followed by 440 .mu.L of 0.5 M of HOBt in
THF. The resulting reaction mixture was vortexed to mix very well.
880 .mu.L of 0.25 M EDCl solution in methylene chloride was then
added, vortexed and shaken at room temperature for 24 hours. The
reaction mixture was then dried down under vacuum and purified by
liquid-liquid extraction between CHCl.sub.3 (2 mL) and H.sub.2O (1
mL.times.2). LC-MS of the organic layer confirmed the identity of
the desired product (381) and the organic layer was concentrated
under vacuum until very dry. MS m/e 359.2 [M+1] (exact MS:
358.15).
[0736] 2 mL of methanol was added into above compound (381) to
dissolve followed by 2 mL of 4 M HCl in 1,4-dioxane at room
temperature. The resulted solution was shaking at room temperature
overnight, concentrated under vacuum with heating (50-60.degree.
C.) to give the desired product (382) as solid. LC-MS confirmed the
identity of the product. MS m/e 259.1 [M+1] (exact MS 258.1).
4.27.9 Synthesis of 386
[0737] Scheme 77 describes the synthesis of compound 386.
##STR123##
[0738] A flask containing a stirred suspension of
2-hydroxy-naphthoic acid (142) (21.3 mmol) and 4-nitroaniline (384)
(21.3 mmol) in xylenes (160 mL) was fitted with a condenser and
heated to reflux (.about.130.degree. C.). Phosphorous tribromide
(PBr.sub.3, 8.5 mmol, 0.4 equiv) was carefully added to the
resulting solution. An immediate precipitate was observed, the top
of the condenser was left open to allow any HBr to vent and the
suspension was allowed to reflux for another 3 h, at which point it
was allowed to cool. At room temperature, THF (200 mL) and
saturated NaHCO.sub.3 (200 mL) were added. The organic phase was
collected on a separatory funnel and washed with 2 M NaHSO.sub.4
(2.times.150 mL), saturated NaHCO.sub.3 (150 mL), brine (150 mL),
dried (MgSO.sub.4) and concentrated. The resulting dark syrup was
dissolved in hot EtOH/MeOH (1:1, v/v, 100 mL) and allowed to stand
at room temperature overnight and filtered to yield
N-(4-nitrophenyl)-2-hydroxy-napthoanilide (385) (19.5 mmol, 91%
yield) as dark yellow crystals. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.=7.49 ppm (d, 1H, J=9 Hz), 7.58 (appeared td, 1H, J=1, 8
Hz), 7.68 (appeared td. 1H, J=1, 7 Hz), 7.91 (d, 1H, J=8 Hz), 8.06
(dt, 2H, J=2, 9 Hz), 8.10 (d, 1H, J=9 Hz), 8.26-8.32 (m, 3H), 10.82
(s, 1H).
[0739] To a stirred solution of 385 (8.11 mmol) in a mixture of THF
and MeOH (1:1, v/v, 100 mL) was added Raney nickel (2 mL, 50%
suspension in water). Hydrazine (N.sub.2H.sub.4, 32.0 mmol, 4
equiv) was added in portions over a period of 30 minutes. Once
effervescence had ceased, TLC analysis (15:2:0.1,
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) indicated complete conversion of
the starting material to a compound that had lower R.sub.f than the
starting material (stained spontaneously with PMA/Ce stain without
requiring heating). The suspension was diluted with THF (100 mL)
and filtered through a pad of Celite on a fritted funnel. The
supernatant was concentrated to yield 1-hydroxy-[2]naphthoic
acid-(4-amino-anilide) (111) (7.8 mmol, 96% yield) as a dark purple
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=5.06 ppm (br s,
2H), 6.57 (br d, 2H, J=9 Hz), 7.29 (br d, 2H, J=9 Hz), 7.39 (d, 1H,
J=9 Hz), 7.53 (app. td, 1H, J=1, 8 Hz), 7.62 (app. td, 1H, J=1, 7
Hz), 7.86 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=9 Hz), 8.26 (d, 1H, J=8
Hz), 10.13 (br s, 1H). LC-MS: m/e 279.2 [M+1].sup.+.
[0740] The aniline 111 (102 mg) was further purified by
reverse-phase MS-triggered HPLC using gradient of CH.sub.3CN and
H.sub.2O with 0.05% TFA to generate the TFA salt of 111 that was
further converted to the HCl salt by treating with HCl (2.0 M) to
give 70.4 mg of 111 as the HCl salt. LC-MS: m/e 279.2 [M+1].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=10.60 (s, 1H, CONH),
8.29 (d, J=7.6 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.90 (d, J=8 Hz,
1H), 7.78-7.83 (m, 2H), 7.63-7.68 (m, 1H), 7.54-7.60 (m, 1H), 7.45
(d, J=8.4 Hz, 1H), 7.32-7.37 (m, 2H). Elemental analysis calcd (%)
for C.sub.17H.sub.14N.sub.2O.sub.2.HCl (314.767): C, 64.87; H,
4.80; N, 8.90. found C, 64.75; H, 5.12; N, 9.13.
4.27.10 Synthesis of Aniline 391 (scheme 78)
[0741] ##STR124##
{3-Benzyloxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylam-
ino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (389)
[0742] 5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic
acid (388) (0.293 g, 1.2 mmol) and
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium
hexafluorophosphate (HBTU) (0.455 g, 1.2 mmol) were combined and
dissolved in DMA (24 mL). .sup.iPr.sub.2EtN (0.313 mL, 1.8 mmol)
was added and the mixture was shaken for 30 minutes at room
temperature. The (4-amino-3-benzyloxy-phenyl)-carbamic acid
9H-fluoren-9-ylmethyl ester (65) (0.25 g, 0.573 mmol) was added and
the mixture was shaken in a 40 mL I-Chem vial for 16 h. LC-MS
indicated complete coupling at this point. The mixture was poured
into ice-water and a very pale/purple powder precipitated.
Collection by filtration under reduced pressure followed by drying
under high vacuum for 16 h gave the desired product (389) as a
white/purple solid (0.28 g, 0.422 mmol, 73.7% yield). LC-MS (ESI):
(exact mass: 662.26) m/e=663.2 [M+1].sup.+ (100%).
{3-Hydroxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamin-
o]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (390)
[0743]
{3-Benzyloxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pent-
anoylamino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (389)
(0.28 g, 0.422 mmol) was dissolved in TFA (2 mL) and thioanisole
(0.4 mL) was added. The mixture was shaken at room temperature in a
Teflon septum capped 40 mL I-Chem vial for 3 h. LC-MS indicated
complete de-benzylation at this point. The mixture was diluted with
water (15 mL) and a pink/orange precipitate formed. Collection by
filtration under reduced pressure followed by rinsing with water
followed by drying under high vacuum for 16 h gave the desired
product (390) as a pink/orange powder (0.152 g, 0.266 mmol, 63%
yield). LC-MS (ESI): (exact mass: 572.21) m/e=573.1
[M+1].sup.+.
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid
(4-amino-2-hydroxyphenyl)-amide (391)
[0744]
{3-Hydroxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentan-
oylamino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (390)
(0.152 g, 0.266 mmol) was dissolved in a mixture of THF (10 mL) and
DMF (4 mL). Piperidine (0.53 mL, 5.3 mmol) was added. The mixture
was shaken at room temperature for 3 h. LC-MS indicated complete
de-protection at this point. The mixture was diluted with EtOAc
(100 mL), water (2.times.50 mL) and brine (2.times.50 mL) via
extraction, dried over MgSO.sub.4 and concentrated under reduced
pressure to give an oil. Purification by flash chromatography on
silica gel using a gradient of hexane and EtOAc (eluting with
15-100% EtOAc/hexane in 30 minutes) gave the desired product (391)
as a beige oil (0.076 g, 0.217 mmol, 81.6% yield). LC-MS (ESI):
(exact mass: 350.14) m/e=351.3 [M+1].sup.+ (100%), 701.3
[2M+1].sup.+ (15%).
4.27.11 Synthesis of 396 (Scheme 79)
[0745] ##STR125##
(2,4-Dimethoxy-phenyl)-(2-methoxy-4-nitro-phenyl)-methanone
(394)
[0746] 2-Methoxy-4-nitro-benzoyl chloride (392) (0.5 g, 2.32 mmol),
1,3-dimethoxybenzene (393) (0.962 g, 6.96 mmol) and zinc (II)
chloride (0.063 g, 0.46 mmol) were combined. The mixture was heated
to 150.degree. C. for 30 minutes. TLC indicated product formation.
The mixture was diluted with EtOAc (200 mL), washed with aqueous
HCl (100 mL, 1.0 M), NaHCO.sub.3 (aqueous saturated, 100 mL) and
brine (100 mL) via extraction, dried over MgSO.sub.4 and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel using a gradient of hexane and EtOAc
(eluting with 15-100% EtOAc/hexane in 30 minutes) gave the desired
product along with the corresponding o-acylated product (10:1 ratio
by NMR). Recrystallization from acetone followed by filtration
under reduced pressure gave the desired product (394) as yellow
cubic crystals (0.618 g, 2.0 mmol, >99% pure, 84% yield).
.sup.1H NMR (400 MHz, Acetone-d.sub.6): .delta. 3.53 (s, 3H), 3.78
(s, 3H), 3.85 (s, 3H), 6.58 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4
Hz, 2 Hz), 7.44 (d, 1H, J=8 Hz), 7.63 (d, 1H, J=9.2 Hz), 7.81 (d,
1H, J=2 Hz), 7.84 (dd, 1H, J=8.4 Hz, J.sub.2=2.4 Hz).
(2,4-Dihydroxy-phenyl)-(2-hydroxy-4-nitro-phenyl)-methanone
(395)
[0747] (2,4-Dimethoxy-phenyl)-(2-methoxy-4-nitro-phenyl)-methanone
(394) (0.4 g, 1.26 mmol) was dissolved in CH.sub.2Cl.sub.2 and
BBr.sub.3 was added. The mixture was heated to 40.degree. C. while
shaking in a sealed 40 mL I-Chem vial for 16 h. TLC (R.sub.f: 0.5
compared to R.sub.f: 0.65 for compound 394 in 1:1 hexane/EtOAc,
single spot) indicated the complete de-methylation at this point.
Purification by flash chromatography on silica gel using a gradient
of hexane and EtOAc (eluding with 15-100% EtOAc/hexane in 30
minutes) gave the desired product (395) as a yellow solid upon
concentration (0.255 g, 0.927 mmol, 73.5%). The product was used in
the next step without further characterization.
(4-Amino-2-hydroxy-phenyl)-(2,4-dihydroxy-phenyl)-methanone
(396)
[0748] (2,4-Dihydroxy-phenyl)-(2-hydroxy-4-nitro-phenyl)-methanone
(395) (0.255 g, 0.927 mmol) was dissolved in warm AcOH (10 mL) and
TiCl.sub.3 (2.0 M solution in aqueous 1M HCl, 5 mL) was added
portion wise over a period of 2 hours until the color of the
solution remained purple. TLC (R.sub.f: 0.5 compared to R.sub.f:
0.35 for compound 395 in 1:1 hexane/EtOAc, single spot) indicated
complete reaction at this point. The mixture was concentrated to
remove nearly all the AcOH. The mixture was diluted with EtOAc (100
mL), washed with NaHCO.sub.3 (aqueous sat., 500 mL) and brine (500
mL) via extraction, dried over MgSO.sub.4 and concentrated under
reduced pressure. Purification by flash chromatography on silica
gel using a gradient of hexane and EtOAc (eluding with 15-100%
EtOAc/hexane in 30 minutes) gave the desired product (396) as a
yellow/orange oil (0.067 g, 0.273 mmol, 29.4% yield). LC-MS (ESI):
(exact mass: 245.07) m/e=246.2 [M+1].sup.+.
4.27.12 Synthesis of Aniline 398 (Scheme 80)
[0749] ##STR126##
N-(3-Amino-phenyl)-4-chloro-2-hydroxy-benzamide (398)
[0750] 7-Chloro-benzo[1,3]dioxine-2,4-dione (91) (0.090 g, 0.455
mmol) and benzene-1,3-diamine (397) (0.17 g, 1.57 mmol) were
combined and dissolved in NMP (6 mL). The mixture was heated to
110.degree. C. for 2 h. TLC was inconclusive, it was later
determined that the desired product had same R.sub.f as the aniline
(397). LC-MS indicated complete reaction. The mixture was diluted
with MeOH (2 mL) and LiOH (aqueous, 2.0 M, 4 mL). The mixture was
stirred for 10 minutes. The solution was diluted with EtOAc (25
mL), washed with water (2.times.15 mL), saturated aqueous
NaHCO.sub.3 (2.times.15 mL) and brine (2.times.15 mL) via
extraction, dried over MgSO.sub.4 and concentrated to give a brown
oil. Purification by flash chromatography on silica gel using a
gradient of hexane and EtOAc (15-100% EtOAc in hexane) gave the
desired product (398) as an off-white solid upon concentration
(0.091 g, 0.347 mmol, 76% yield). LC-MS (ESI): (exact mass: 262.05)
m/e=263.0 [M+1].sup.+ (100%), 525.3 [2M+1].sup.+ (10%).
4.28 Synthesis of Intermediate: Triazine Substituted Aniline
Intermediates
4.28.1 Synthesis of Intermediate 402 (scheme 81)
[0751] ##STR127##
N-[2-Benzyloxy-4-(4,6-dichloro-[1, 3,
5]triazin-2-ylamino)-phenyl]-acetamide (400)
[0752] N-(4-Amino-2-benzyloxy-phenyl)-acetamide (399) (0.65 g, 2.54
mmol) and NaHCO.sub.3 (1.28 g, 15.24 mmol) were suspended in THF
(100 mL) and chilled on a dry-ice/acetone bath. The cyanuric
chloride (5) (0.465 g, 2.54 mmol) was dissolved in THF (4 mL) and
added to the chilled solution. The ice-bath was removed and the
mixture was stirred while warming to room temperature over a period
of 45 minutes. TLC (R.sub.f: 0.6 compared to R.sub.f: 0.1 for
compound 399 and R.sub.f: 0.95 for compound 400 in 1:1
hexane/EtOAc, single spot) indicated complete reaction at this
point. This reaction mixture was used directly in the next step
without further purification or characterization.
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-pipe-
ridin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (401)
[0753] (3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidine (4)
(1.68 g, 5.33 mmol) was suspended in DMF (20 mL), sonicated for 2
minutes and added to the crude reaction mixture containing
N-[2-benzyloxy-4-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamid-
e (400). The mixture was heated to 80.degree. C. for 8 h. LC-MS
indicated complete reaction at this point. The mixture was
concentrated to a volume of 50 mL and poured into ice-water. A
white solid precipitated immediately and was collected by
filtration under reduced pressure followed by drying under high
vacuum for 16 h to give the desired product (401) as a white powder
(2.32 g, 2.4 mmol, 95% total yield for two steps). LC-MS (ESI):
(exact mass: 961.54) m/e=962.7 [M+1].sup.+ (100%).
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperi-
din-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (402)
[0754]
N-[2-Benzyloxy-4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylami-
no)-piperidin-1-yl)-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide
(401) (2.32 g, 2.4 mmol) was dissolved in an mixture of MeOH and
dioxane (150 mL, 4:1). Hydrazine monohydrate (100 mL) was added and
the mixture was heated to reflux for 10 days. LC-MS indicated
complete de-protection at this point. Upon cooling, a white
precipitate formed. The mixture was poured into ice water, forcing
additional precipitate to form. The solid was collected by
filtration under reduced pressure, rinsed with water (100 mL), and
dried under high vacuum for 16 h to give the desired product (402)
as a white powder (1.48 g, 1.62 mmol, 68% yield). LC-MS (ESI):
(exact mass: 919.53) m/e=920.6 [M+1].sup.+ (100%).
4.28.2 Synthesis of Intermediate 406 (Scheme 82)
[0755] Scheme 82 describes the procedure for synthesis of
intermediate 406. ##STR128##
[0756] Cyanuric chloride (5) (500 mg, 2.711 mmol) in THF (5 ml) was
allowed to sit in the refrigerator for half an hour at -25.degree.
C. 4-Nitro-phenylamine (403) (374 mg, 2.711 mmol) in THF (10 ml)
with .sup.iPr.sub.2NEt (472 .mu.L, 2.711 mmol) was then added into
the above solution. The reaction mixture was allowed to sit in the
refrigerator overnight at -25.degree. C. The reaction mixture was
shaken at room temperature for 2 h to give compound 404. The
reaction was monitored by TLC. The reaction mixture was directly
used in next step.
[0757] (3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4)
(1.717 g, 5.423 mmol) and .sup.iPr.sub.2NEt (1.8 ml, 5.423 mmol)
were added into the previous reaction mixture. The mixture was
heated at 80.degree. C. overnight. The solvent was removed under
reduced pressure. Liquid-liquid extraction was performed with
CHCl.sub.3 and H.sub.2O. The organic layer was dried over
MgSO.sub.4. After filtration, the solvent was removed under reduced
pressure. The resulting solid was purified by flash chromatography
to give the intermediate 405 (1.66 g, 72.7% yield) as a solid.
LC-MS (ESI): m/e=844.6 [M+H].sup.+.
[0758] Compound 405 (1.660 g, 1.97 mmol) was dissolved in MeOH (50
ml) and THF (50 ml). Raney Nickel (50% slurry in water) (6 ml) was
added to the reaction mixture followed by anhydrous hydrazine (3
ml). The reaction mixture was stirred at room temperature for 45
minutes until stop bubbling. The solid was filtered off through
celite under nitrogen and washed with MeOH. The solvent was removed
under reduced pressure. Liquid-liquid extraction was performed
using CHCl.sub.3 (100 mL) and H.sub.2O (50 mL.times.3). The organic
layer was dried over MgSO.sub.4, filtered and concentrated to give
the compound 406 (1.48 g) as a solid in 92% yield. LC-MS (ESI):
m/e=814.6 [M+H].sup.+
4.28.3 Synthesis of Intermediate 410
[0759] Scheme 83 describes the procedure for synthesis of
intermediate 410. ##STR129##
[0760] Cyanuric chloride (5) (500 mg, 2.711 mmol) in THF (5 ml) was
allowed to sit in the refrigerator for half an hour at -25.degree.
C. 3-Chloro-4-nitro-phenylamine (407) (467 mg, 2.711 mmol) in THF
(10 ml) with .sup.iPr.sub.2NEt (472 .mu.L, 2.711 mmol) was then
added into the above solution. The reaction mixture was allowed to
sit in the refrigerator overnight at -25.degree. C. The reaction
mixture was shaken at room temperature for 2 h to give compound
408. The reaction was monitored by TLC. The reaction mixture was
directly used in next step.
[0761] (3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidine (1.717
g, 5.423 mmol) and .sup.iPr.sub.2NEt (1.8 ml, 5.423 mmol) were
added into the previous reaction mixture. The mixture was heated at
80.degree. C. overnight. The solvent was removed under reduced
pressure. Liquid-liquid extraction was performed using CHCl.sub.3
and H.sub.2O. The organic layer was dried over MgSO.sub.4. After
filtration, the solvent was removed under reduced pressure. The
resulting solid was purified by flash chromatography to give the
intermediate 409 (1.16 g, 48.7%) as a solid. LC-MS (ESI): m/e=878.8
[M+1].sup.+
[0762] Compound 409 (1.16 g, 1.32 mmol) was dissolved in MeOH (50
ml) and THF (50 ml). Raney Nickel (50% slurry in water) (6 ml) was
added to the reaction mixture followed by anhydrous hydrazine (3
ml). The reaction mixture was stirred at room temperature for 30
minutes until bubbling stopped. The solid was filtered off through
celite under nitrogen and washed with MeOH. The solvent was removed
under reduced pressure. Liquid-liquid extraction was performed
using CHCl.sub.3 (100 mL) and H.sub.2O (50 mL.times.3). The organic
layer was dried over MgSO.sub.4, filtered and concentrated to give
the compound 410 (850.5 mg) as a solid in yield 75.8%. LC-MS (ESI):
m/e=848.8 [M+1].sup.+
4.28.4 Synthesis of Intermediate 414 (Scheme 84)
[0763] ##STR130##
[0764] 3-Nitroaniline (411) (138 mg, 1 mmol) was dissolved in 12 mL
of THF. NaHCO.sub.3 (504.1 mg, 6 mmol) was added followed by 10
drops of water. The mixture was cooled to -78.degree. C. A solution
of cyanuric chloride (5) (184.4 mg, 1 mmol) in 8 mL of THF was
added with stirring. The mixture was shaken at -78.degree. C. to
room temperature for 15 hours.
[0765] A slurry of amine 4 (726 mg, 2.3 mmol) in 4.6 mL of THF was
added and the mixture was heated at 80.degree. C. overnight with
stirring. LC-MS result confirmed the completion of the reaction.
The solvent was evaporated under reduced pressure and the residue
was purified by liquid-liquid extraction using CHCl.sub.3 (10 mL)
and H.sub.2O (5 mL.times.2) to give a pale yellow solid. The
organic layer was concentrated to give the desired product 413.
LC-MS: m/e 844.6 [M+1].sup.+ (expect ms: 843.46).
[0766] Compound 413 was dissolved in 12 mL of THF and 8 mL of MeOH
with the help of heating at 55.degree. C. NH.sub.2NH.sub.2 (98%,
700 .mu.L) was added immediately followed by Raney Nickel (50%
slurry, 1.4 mL). The mixture was stirred at 55.degree. C. for 0.5
hours. LC-MS result showed the incompletion of the reaction.
Additional NH.sub.2NH.sub.2 (700 uL) and Raney Nickel (50% slurry,
1.4 mL) was added. After stirring for 0.5 hours, additional
NH.sub.2NH.sub.2 (98%, 700 .mu.L) was added immediately followed by
Raney Nickel (50% slurry, 1.4 mL). After 20 minutes stirring at
55.degree. C., the LC-MS result confirmed the completion of the
reaction. The inorganic solid was filtered off and the filtrate was
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel using a gradient of hexane
and EtOAc to give the desired product 414 (174.8 mg, 21.5% isolated
yield for 3 steps) as a pale yellow solid. This intermediate was
directly used without further characterization.
4.29 Synthesis of Intermediates: Other Intermediates
4.29.1 Synthesis of Intermediate 90 of benzo-dioxine-diones (Scheme
85)
[0767] ##STR131##
[0768] R.sup.5 refers to a substitutent as defined for substituted
aryls.
[0769] The salicylic acid derivative (27) (1 equiv.),
N,N'-disuccinimidyl carbonate (415) (1 equiv.) and NaHCO.sub.3 (1
equiv.) were combined. DMF (0.2M) was added and the mixture was
heated at 80.degree. C. with shaking in a 40 mL I-Chem vial for 1
h. Occasional venting may be needed. The reaction was monitored by
TLC (the benzo-dioxine-dione is generally less polar than the
corresponding salicylic-acid). Upon the complete cyclization, the
mixture was diluted with EtOAc, washed with water, saturated
aqueous NaHCO.sub.3 and brine via extraction, dried over MgSO.sub.4
and concentrated to give the desired product (90) in good yield.
The product was used in the next step without further
purification.
4.29.2 Synthesis of Intermediate 65 (Scheme 86)
[0770] ##STR132##
Acetic acid 2-acetylamino-5-nitro-phenyl ester (416)
[0771] 2-Amino-5-nitro-phenol (46) (20 g, 97.3 mmol) was suspended
in THF (125 mL) and Acetic-anhydride (75 mL) was added.
Di-methyl-amino-pyridine (DMAP) (300 mg, 2.45 mmol) was added and
the mixture was stirred for 16 h at room temperature. A solid
precipitated and was collected by filtration followed by rinsing
with 3:1 hexane/EtOAc (3.times.100 mL). The solid was dried under
high vacuum for 8 h to give the desired product (416) as a yellow
powder (21 g, 88.2 mmol, 90.7% yield). LC-MS (ESI): (exact mass:
238.06) m/e=239.2 [M+1].sup.+ (15%), 477.1 [2M+1].sup.+ (100
N-(2-Hydroxy-4-nitro-phenyl)-acetamide (417)
[0772] Acetic acid 2-acetylamino-5-nitro-phenyl ester (416) (21 g,
88.2 mmol) was suspended in MeOH (185 mL) and 2M aqueous LiOH (185
mL) was added. An instantaneous reaction occurred, the solution
turned red, everything dissolved and a slight exothermic reaction
was felt by the warmth of the flask. TLC (R.sub.f: 0.55 compared to
R.sub.f: 0.45 for compound 416 in EtOAc) after 10 minutes indicated
complete hydrolysis. Addition of 1.0 M aqueous HCl (500 mL) caused
the color to fade and a precipitate to form. Collection of the
precipitate via vacuum filtration followed by rinsing with water
(2.times.100 mL) and drying under high vacuum for 16 h gave the
desired product (417) as a yellow powder. (17.2 g, 87.8 mmol, 99.5%
yield). LC-MS was inconclusive. The product was used in the next
step without further characterization
N-(2-Benzyloxy-4-nitro-phenyl)-acetamide (418)
[0773] N-(2-Hydroxy-4-nitro-phenyl)-acetamide (417) (17 g, 86.7
mmol) was dissolved in a mixture of acetone (200 mL) and THF (200
mL). Potassium-carbonate (24 g, 173.4 mmol, 2 equiv.) was added as
a dry powder and the solution turned deep red. Benzyl-bromide (16.3
g, 95.37 mmol, 1.1 equiv.) was added and the mixture stirred at
room temperature for 20 h. TLC (R.sub.f: 0.5 compared to R.sub.f:
0.2-0.3 for compound 417 in 1:1 hexane/EtOAc) indicated complete
alkylation at this point. The mixture was poured into ice water
(.about.1000 mL) and a precipitate formed while stirring for 20
min. The precipitate was collected by filtration under reduced
pressure, washed with water (3.times.100 mL) and dried under high
vacuum for 16 h to give the desired product (418) as a faintly
yellow powder (13 g, 45.4 mmol, 51.7% yield). LC-MS was
inconclusive. The product was used in the next step without further
characterization
N-(4-Amino-2-benzyloxy-phenyl)-acetamide (419)
[0774] N-(2-Benzyloxy-4-nitro-phenyl)-acetamide (418) (5 g, 17.5
mmol) was dissolved in a mixture of EtOAc (25 mL) and EtOH (25 mL).
The solution was chilled on an ice bath. Raney Nickel (5 mL, 50%
slurry in water) followed immediately by anhydrous hydrazine (10
mL) were added. Violent bubbling was observed. The ice bath was
removed after 10 minutes and the slurry continued to stir until all
bubbling had ceased (.about.30 minutes). LC-MS and TLC (R.sub.f:
0.15 compared to R.sub.f: 0.5 for compound 418 in 1:1 hexane/EtOAc)
indicated complete reduction at this point. The reaction mixture
was passed through a plug of silica gel, concentrated, dissolved in
EtOAc (250 mL), washed with water (2.times.75 mL), brine
(2.times.75 mL), dried over MgSO.sub.4 and concentrated to give the
desired product (419) as a beige solid (3.82 g, 14.9 mmol, 85.3%
yield). LC-MS (ESI): (exact mass: 256.12) m/e=257.1 [M+1].sup.+
(100%), 513.2 [2M+1].sup.+ (15%).
(4-Acetylamino-3-benzyloxy-phenyl)-carbamic acid
9H-fluoren-9-ylmethyl ester (420)
[0775] N-(4-Amino-2-benzyloxy-phenyl)-acetamide (419) (3 g, 11.72
mmol) and Fmoc-Cl (3.1 g, 12 mmol) were combined and dissolved in
THF (60 mL). .sup.iPr.sub.2EtN (18 mmol, 1.2 equiv.) was added and
the mixture was heated to 80.degree. C. for 15 minutes while
stirring. TLC indicated complete reaction at this point. The
mixture was poured into ice-water (500 mL) and a white solid
precipitated. The solid was collected by filtration under reduced
pressure followed by drying under high vacuum to give the desired
product (420) as a white powder (3 g, 6.28 mmol, 54% yield). LC-MS
(ESI): (exact mass: 478.19) m/e=479.2 [M+1].sup.+ (70%), 957.6
[2M+1].sup.+ (100%).
(4-Amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl
ester (65)
[0776] (4-Acetylamino-3-benzyloxy-phenyl)-carbamic acid
9H-fluoren-9-ylmethyl ester (420) (3 g, 6.28 mmol) was dissolved in
a mixture of MeOH (15 mL) and NMP (10 mL). 4.0 M HCl in dioxane (20
mL) was added and the mixture was refluxed for 40 h. LC-MS
indicated complete de-protection at this point. The mixture was
diluted with EtOAc (200 mL), washed with saturated aqueous
NaHCO.sub.3 (3.times.300 mL), water (100 mL) and brine (100 mL) via
extraction, dried over MgSO.sub.4 and upon concentration under
reduced pressure, a precipitate formed. Collection by filtration
under reduced pressure followed by drying under high vacuum for 16
h gave the desired product (65) as a beige/pink powder (1.28 g,
2.93 mmol, 46.7% yield). LC-MS (ESI): (exact mass: 436.18)
m/e=437.2 [M+1].sup.+ (100%), 873.5 [2M+1].sup.+ (100%).
4.29.3 Synthesis of Intermediates 423 & 425 (Scheme 87)
[0777] ##STR133##
2-Benzyloxy-nicotinic acid (423)
[0778] 2-Chloro-nicotinic acid (421) (3 g, 19.04 mmol) was
dissolved in anhydrous THF (50 mL) and chilled to 0.degree. C. on
an ice bath. NaH (50 mmol, 60% suspension in mineral oil) was added
portion wise to the solution over a period of 5 minutes. The
resulting mixture was stirred at 0.degree. C. for 30 minutes.
Benzyl-alcohol (422) (2.27 g, 21 mmol) was added drop wise over a
period of 10 minutes. The ice bath was removed and the mixture was
warmed to room temperature over a period of 2 h. The mixture was
refluxed for 16 h. LC-MS and TLC (R.sub.f: 0.4-0.5 compared to
R.sub.f: 0.1 for compound 421 in 1:1 hexane/EtOAc, single spot)
indicated complete reaction at this point. The mixture was diluted
with water (300 mL) and the pH was adjusted to 6 by the addition of
HCl (aqueous, 1M) and the product was extracted with EtOAc
(3.times.200 mL). The combined organic layers were washed with
brine (100 mL) via extraction, dried over MgSO.sub.4 and
concentrated under reduced pressure to give a yellow oil.
Recrystallization from EtOAc/hexane gave the desired product (423)
as a white powder (2.8 g, 12.2 mmol, 64% yield). LC-MS (ESI):
(exact mass: 229.07) m/e=230.2 [M+1].sup.+ (100%), 459.3
[2M+1].sup.+ (90%).
{3-Benzyloxy-4-[(2-benzyloxy-pyridine-3-carbonyl)-amino]-phenyl}-carbamic
acid 9H-fluoren-9-ylmethyl ester (424)
[0779] 2-Benzyloxy-nicotinic acid (423) (0.157 g, 0.687 mmol) was
dissolved in DMF (4 mL),
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium
hexafluorophosphate (HBTU) (0.273 g, 0.721 mmol) was added followed
by .sup.iPr.sub.2EtN (0.143 mL, 0.824 mmol) and the mixture was
shaken in a Teflon septum capped 40 mL vial at room temperature for
25 minutes. (4-Amino-3-benzyloxy-phenyl)carbamic acid
9H-fluoren-9-ylmethyl ester (65) (0.3 g, 0.687 mmol) was added and
the mixture was shaken at room temperature for 16 h. LC-MS
indicated complete coupling at this point. The mixture was diluted
with EtOAc (25 mL), washed with water (15 mL), NaHCO.sub.3 (aqueous
saturated, 15 mL) and brine (15 mL) via extraction, dried over
MgSO.sub.4 and concentrated to give a brown oil. Purification by
flash chromatography (eluding with 15-100% EtOAc/hexane in 30
minutes) gave the desired product (424) as a yellow powder upon
concentration (0.436 g, 0.673 mmol, 98% yield). LC-MS (ESI): (exact
mass: 647.24) m/e=648.3 [M+1].sup.+ (100%).
N-(4-Amino-2-benzyloxy-phenyl)-2-benzyloxy-nicotinamide (425)
[0780]
{3-Benzyloxy-4-[(2-benzyloxy-pyridine-3-carbonyl)-amino]-phenyl}-c-
arbamic acid 9H-fluoren-9-ylmethyl ester (424) (0.430 g, 0.664
mmol) was dissolved in a mixture of THF (6 mL) and DMF (3 mL).
Piperidine (12.88 mmol) was added. The mixture was shaken at room
temperature for 1 h. LC-MS indicated complete de-protection at this
point. The mixture was concentrated under reduced pressure to give
a dark brown/purple oil. Purification by flash chromatography on
silica gel using a gradient of hexane and EtOAc (15-100%
EtOAc/hexane 25 minutes) gave the desired product (425) as an
orange oil upon concentration (0.229 g, 0.538 mmol, 81% yield).
LC-MS (ESI): (exact mass: 425.17) m/e=426.2 [M+1].sup.+ (100%).
4.29.4 Synthesis of Intermediate 428 (Scheme 88)
[0781] Scheme 88 describes the synthetic procedure for preparing
intermediate 428. ##STR134##
3,5-Dibromo-2-methoxy-pyridine (427)
[0782] 2-Methoxy-pyridine (426) (4.45 g, 40.8 mmol) was dissolved
in AcOH (20 mL). While stirring, NaOAc (6.56 g) was added portion
wise to form a homogeneous slurry. Bromine (7.17 mL) was added drop
wise over a period of 5 minutes. The mixture continued to stir at
room temperature for 16 h. TLC (R.sub.f: 0.8 compared to R.sub.f:
0.65 for compound 426 in 3:1 hexanes/EtOAc) and LC-MS indicated
complete reaction at this point. The mixture was concentrated under
reduced pressure to give an orange solid. The solid was dissolved
in a mixture of water (50 mL) and EtOAc (100 mL). The organic phase
washed with saturated aqueous NaHCO.sub.3 (2.times.20 mL) and brine
(2.times.20 mL) via extraction, dried over MgSO.sub.4 and
concentrated to give a yellow oil. Purification by flash column on
silica gel eluded with hexanes to give the desired product (427) as
a white powder upon concentration (3.1 g, 11.61 mmol, 28.5% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 3.99 (s, 3H), 7.92 (d,
1H, J=1.6 Hz), 8.13 (d, 1H, J=2 Hz).
3,5-Dibromo-2-chloro-pyridine (428)
[0783] 3,5-Dibromo-2-methoxy-pyridine (427) (1.5 g, 5.62 mmol) was
dissolved in anhydrous DMF (14 mL) and chilled to 0.degree. C.
While stirring, POCl.sub.3 (2.1 mL, 22.48 mmol) was added drop wise
over a period of 5 minutes. The mixture was stirred at 0.degree. C.
for 1 h. The mixture was then heated to 100.degree. C. under
N.sub.2, for 16 h. TLC indicated complete reaction at this point.
Ice-chips (10 g) were added to the cooled solution and the mixture
was stirred for 20 minutes. The mixture was diluted with EtOAc (200
mL), washed with saturated aqueous NaHCO.sub.3 (2.times.50 mL) and
brine (2.times.50 mL) via extraction, dried over MgSO.sub.4 and
concentrated to give a brown oil. Purification by column
chromatography gave the desired product (428) as an off white solid
upon concentration (1.01 g, 3.722 mmol, 66.2% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.07 (d, 1H, J=2 Hz), 8.38 (d, 1H,
J=1.6 Hz).
[0784] Compound 428 was synthesized according to the literature
method described in (1) Thomas M. Bargar, Jacqueline K. Dulworth,
Michael T. Kenny, Renee Massad, John K. Daniel, Thomas Wilson and
Roger N. Sargent, J. Med. Chem. 1986, 29, 1590-1595, and (2)
Min-Jen Shiao, Li-Ming Shyu and Kai-Yih Tarng, Synthetic
Communications, 1990, 20(19), 2971-2977.
4.30 General Methods for Purification of Formula I Compounds
[0785] The Formula I compounds and the Boc-protected precursors of
Formula I compounds were purified by one or more of the four
following methods:
[0786] Method A: Precipitation (trituration/recrystallization): In
some cases, the reaction product precipitated in the reaction
solution, then the solid was filtered and washed with a small
amount of a solvent in which the compound was sparingly soluble and
dried.
[0787] Method B: HPLC purification: The majority of the final
products compounds were purified by reverse-phase HPLC based on the
MS-triggered method using Waters purification system using solvent
mixture of TPLC grade of CH.sub.3CN and H.sub.2O containing 0.05%
TFA.
[0788] Method C: Preparative TLC purification: In some cases,
compounds were purified by preparative TLC plate using Merck 1000
mm TLC plates using developing solvent of ethyl acetate and
chloroform in the ratio of 4:1-1:1.
[0789] Method D: Flash column chromatography: Some of the compounds
of type B were purified by flash chromatography.
4.31 Biological Testing
[0790] The antibacterial activity of the Formula I compounds was
evaluated against standard bacterial strains by determining the
minimal inhibitory concentration (MIC) to block growth. Each drug
was assayed by the microdilution method in Mueller-Hinton medium,
as recommended by the National Committee for Clinical Laboratory
Standards. Approved Standard M7-A5: Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically 5th Ed. (National Committee for Clinical Laboratory
Standards, Wayne, Pa., 2000).
[0791] The tested bacterial strains included Escherichia coli
(American Type Collection ATCC25922), Staphylococcus aureus
(ATCC25923), and Pseudomonas aeruginosa (ATCC27853).
[0792] Two-fold serial dilutions of each compound ranging from 64
to 0.5 .mu.g/ml were tested in duplicate. The MIC was determined as
the lowest concentration of each compound that prevented bacterial
growth after 18 hours of incubation at 35.degree. C. The results
are summarized in Table 1, wherein ++ means MIC<16 .mu.g/ml in
E. coli or S. aureus, + means MIC<64 .mu.g/ml in E. coli or S.
aureus, and - means MIC>64 .mu.g/ml in E. coli or S. aureus. The
mass of each compound in the Table was confirmed by LC-MS.
TABLE-US-00001 Structure Name Potency ##STR135##
N-(4-nitro-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR136## N-(3-bromo-phenyl)-4,6-
Bis-((3R.5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
+ ##STR137## N-(3-trifluoromethyl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR138##
N-(3,4-dichloro-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR139##
N-(2-hydroxymethyl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl- [1,3,5]triazine-2-amine ##STR140##
N-(4-carbamoyl-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR141##
N-[4-(2,6-dimethyl- pyrimidin-4-ylsulfamoyl)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR142## N-phenyl-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR143##
N-(2-fluoro-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR144## N-(4-trifluoromethoxy-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR145## N-(4-methoxy-phenyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR146## N-(4-diethylamino-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR147##
N-{4-[ethyl-(2-hydroxy- ethyl)-amino]-phenyl}-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]tiiazine-2-amine
##STR148## N-(4-morpholin-4-yl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR149##
N-(3-hydroxymethyl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR150##
N-[4-(2-diethylamino- ethylcarbamoyl)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR151## N-(4-sulfamoyl-phenyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR152## N-[4-(pyridin-2- ylsulfamoyl)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR153## N-[4-(3,4-dimethyl- isoxazo-5-ylsulfamoyl)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR154## N-pyridin-4-yl-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR155## N-(2,4-dioxo-1,2,3,4- tetrahydro-pyrimidin-5-yl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR156## N-(5-amino-pyridin-3-yl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR157## N-(4-acetylamino-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR158## N-(2-hydroxy-phenyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR159## N-(4-bromo-phenyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR160##
N-(4-benzoylamino-5- chloro-2-methyl-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-pipertdin-1-yl)- [1,3,5]triazine-2-amine - ##STR161##
N-[4-(thiazol-2- ylsulfamoyl)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR162## N-(4-hydroxy-phenyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperadin-1-yl)- [1,3,5]triazine-2-amine - ##STR163##
N-piperidin-4-yl-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR164## N-(2-sulfamoyl-phenyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR165## N-(2-phenylcarbamoyl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR166##
N-furan-2-ylmethyl-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]tuiazine-2-amine - ##STR167## 2,4-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)-6- (3-methyl-4-p-tolyl- piperazin-1-yl)-
[1,3,5]triazine - ##STR168## 1-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-
piperidine-3-carboxylic acid diethylamide - ##STR169##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(2-propyl-piperidin-1-yl)- [1,3,5]triazine - ##STR170##
N-(2-hydroxy-3-piperazin- 1-yl-propyl)-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR171## N-(3-aminomethyl-benzyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR172##
N-piperidin-3-yl-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR173## N-pyrrolidin-3-yl-4,6-Bis-
((3R,5S)-3,5-amino- piperidin-1-yl)- [1,3,5]triazin-2-amine -
##STR174## N-(4,6-Bis-((3R,SS)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)- hydrazine ##STR175## N-benzo[1,3]dioxol-5-
ylmethyl-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR176## 1-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-piperidin- 3-ol -
##STR177## 2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(4-pyridin-2-yl-piperazin-1- yl)-[1,3,5]triazine - ##STR178##
2-Chloro-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine ##STR179## N-(2-allyloxy-4,5-dihydroxy-
6-hydroxymethyl- tetrahydro-pyran-3-yl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR180## N-(4-amino-phenyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR181##
N-(4-methoxy-biphenyl-3- yl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR182##
N-(2-morpholin-4-yl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR183##
N-(2,5-dimethoxy-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR184##
N-{4-[2-(2-chloro- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR185## N-(4-phenylamino-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR186## N-(3-trifluoromethoxy-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR187## N-[4-(5-methoxy-pyrimidin-
2-ylsulfamoyl)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR188##
N-(3-amino-propyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR189## N-(4- trifluoromethylsulfanyl-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR190## N-(4-guanidino-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR191## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'- Phenyl-hydrazine
- ##STR192## N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'- Chloro-phenyl)-hydrazine - ##STR193##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2- Fluoro-phenyl)-hydrazine - ##STR194##
N-(4-phenoxy-phenyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR195##
N-[4-(2,2,2-trifluoro- acetylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR196## N-[4-(4-methoxy- phenylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
+ ##STR197## N-[4-(1H-indazol-6- ylsulfamoyl)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR198## N-(8-hydroxy-quinolin-5-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR199##
N-pyridin-3-ylmethyl-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR200##
8-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-1- phenyl-1,3,8-triaza- spiro[4.5]decan-4-one
- ##STR201## N-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-((3S,5R)-
3,5-diamino-piperidin-1-yl)- [1,3,5]trlazin-2-yl]- hydroxylamine
##STR202## 2-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- benzoic acid methyl ester - ##STR203##
4-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- benzoic acid ethyl ester - ##STR204##
N-(5-acetylamino-2- methoxy-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR205##
N-[2-(3-methoxy-phenyl)- ethyl]-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR206##
4-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-3- hydroxy-benzoic acid methyl ester -
##STR207## [1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-piperidin- 2-yl]-methanol - ##STR208##
N-(5-dimethylsulfamoyl-2- methyl-phenyl)-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine -
##STR209## 4-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)- piperazin-2-one - ##STR210##
N-(3-carbamimidoyl- phenyl)-4,6-Bis-((3R,5S)-
3,4-diamino-pyrrolidin-1-yl)- [1,3,5]triazine-2-amine ##STR211##
N-[1,3,4]thiadiazol-2-yl-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR212##
N-(2-methoxy-4-morpholin- 4-yl-phenyl)-4,6-Bis- piperidin-1-yl)-
[1,3,5]triazine-2-amine
##STR213## 1,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
phthalazine ##STR214## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'-(4-
Methoxy-phenyl)- hydrazine ##STR215## N-{3-chloro-4-[(3-hydroxy-
quinoxaline-2-carbonyl)- amino]-phenyl}-4,6-Bis-
(cis-3,5-Diamino-piperidin- 1-yl)-[1,3,5]triazine-2- amine
##STR216## N-[3-hydroxy-4-(4- sulfamoyl- phenylcarbamoyl)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR217## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'-(3-
Chloro-phenyl)-hydrazine + ##STR218## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N-(3,5-
Dichloro-phenyl)- hydrazine + ##STR219## N-[4-(N-methyl-guanidino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR220## N-(3,4-dichloro-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR221## N-ethyl-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR222##
N-(3-chloro-2-methyl- benzyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR223##
N-(4-phenoxy-benzyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR224##
(S)-2-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3S,5R)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin
2-ylamino]-2-phenyl- ethanol ##STR225## N-biphenyl-4-ylmethyl-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
+ ##STR226## N-(carbamoyl-phenyl- methyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR227##
N-(2,5-dimethyl-benzyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR228##
N-(4-trifluoromethoxy- benzyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR229##
N-(2-methyl-allyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR230## N-(3-methyl-benzyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR231## N-(4-methyl-benzyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR232##
N-((S)-1-naphthalen-1-yl- ethyl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR233##
N-[2-(2,4-dichloro-phenyl)- ethyl]-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR234##
N-(2-methoxy-benzyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR235##
N-(1-phenyl-ethyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR236## N-(2-methoxy-1-methyl-
ethyl)-4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR237## N-[3-(2-oxo-pyrrolidin-1-yl)-
propyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR238## (1S,2R)-2-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-1,2-diphenyl- ethanol
##STR239## N-(2,6-dimethoxy-benzyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR240##
(1S,2R)-2-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3S,5R)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-1,2-diphenyl- ethanol ##STR241## N-(3-hydroxy-1-phenyl-
propyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR242## N-(1,2-diphenyl-ethyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR243## N-((1S,2R,5R)-6,6- dimethyl- bicyclo[3.1.1]hept-2-
ylmethyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR244## (4aR,8aS)-2-(4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-yl)-decahydro- isoquinoline ##STR245## 2-{[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-yl]-methyl-
amino}-ethanol ##STR246## 2-[1-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-piperidin-
2-yl]-ethanol ##STR247## 4-{[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]biazin-2-yl]-phenyl- amino)-phenol
- ##STR248## N-(4-carbazol-9-yl-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR249##
N-{4-[benzyl-(toluene-4- sulfonyl)-amino]-3-hydroxy-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR250## N-[4-(4-{2-[4-(1,1,3,3-
tetramethyl-butyl)- phenoxy]-ethoxy)- benzoylamino)-pheny]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR251## N-(2-chloro-benzyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR252##
N-(2-morpholin-4-yl-ethyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR253##
N-propyl-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-y)-
[1,3,5]triazine-2-amine ##STR254## N-[2-(1-methyl-pyrrolidin-2-
yl)-ethyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR255## N-(2,4-dimethoxy-benzyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR256## N-pyridin-3-ylmethyl-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR257## N-(2,3-dihydroxy-propyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR258##
N-(4-tert-butyl-cyclohexyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR259##
N-(1,2-dimethyl-propyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR260##
N-indan-1-yl-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR261## N-(1,3-dimethyl-butyl)-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR262## N-(4-methoxy-benzyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR263##
N-(4-chloro-benzyl)-4,6- Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR264## N-(3-amino-benzyl)-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR265## N-(3,4,5-trimethoxy- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR266##
N-(2-bromo-benzyl)-4,6- Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR267## N-[1-(4-fluoro-phenyl)-
ethyl]-4,6- Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR268## (R)-2-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-phenyl- ethanol
benzamide ##STR269## N-indan-2-yl-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR270##
N-(2,4-dichloro-benzyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR271##
N-(3-methyl-butyl)-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR272## N-(1-phenyl-propyl)-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR273## N-(2-methoxy-ethyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR274##
N-(3-methoxy-propyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR275##
N-allyl-4,6- Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR276##
N-naphthalen-1-ylmethyl-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR277##
N-(1-naphthalen-1-yl- ethyl-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR278##
N-(1,2,3,4-tetrahydro- naphthalen-1-yl)-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR279##
N-(3,5-bis-trifluoromethyl- benzyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR280##
N-((1R,2S,4R)-1,7,7- trimethyl- bicyclo[2.2.1]hept-2-yl)-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR281## N-[2-(5-nitro-pyridin-2- ylamino)-ethyl]-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine -
##STR282## 2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(3-methyl-piperidin-1-yl)- [1,3,5]triazine ##STR283##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)- decahydro-quinoline ##STR284##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6- morpholin-4-yl-
[1,3,5]triazine-2-amine ##STR285## 2-[4-(2,4-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- phenyl)-piperazine-1-yl]-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine
##STR286## N-allyl-N-methyl-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR287##
5-Bromo-1-(4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine- 2-yl)-2,3-dihydro-1H- indole ##STR288##
2-[1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)-piperidin- 3-yl]-ethylamine ##STR289##
N-isobutyl-N-methyl-4,6- Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR290## N-cyclohexyl-N-methyl-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR291## 2-(4-Benzyl-piperidin-1-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR292##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)- pyrrolidin-3-ol ##STR293## 4-(4-Chloro-3-
trifluoromethyl-phenyl)-1- (4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-yl)-piperidin- 4-ol
##STR294## N,N-Methyl-naphthalen-1- ylmethyl-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR295##
1-[1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-piperidin- 4-yl]-1,3-dihydro-
benzoimidazol-2-one ##STR296## [1-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-yl)-piperidin-
3-yl]-methanol ##STR297## 4-[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl]-
piperazine-1-carboxylic acid ethyl ester ##STR298##
2-[4-(4-Fluoro-phenyl)- piperazin-1-yl]-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR299##
2-(3,5-Dimethyl-piperidin-1- yl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine ##STR300##
N-(4-phenylcarbamoyl- phenyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine - ##STR301##
N-(4-methyl-thiazol-2-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR302##
N-[4-(3-oxo-3-phenyl- propionylamino)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR303## N-(2-phenylamino-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR304## N-[3-(2-ethyl-5-oxo-1-
phenyl-2,5-dihydro-1H- pyrazol-3-yl)-phenyl]-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR305##
N-[4-(4-methyl-pyrimidin-2- ylsulfamoyl)-phenyl]-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR306## 4-{[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl]-p-tolyl- amino}-phenol ##STR307##
N-(4-hydroxy-2-nitro- phenyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR308##
N-[4-(4-nitro- benzenesulfonyl)-phenyl]-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR309##
N-(2-methoxy- dibenzofuran-3-yl)-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR310##
N-(4-acetylamino-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR311##
N-naphthalen-2-yl-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR312## N-(4-sec-butyl-phenyl)-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR313## N-(9-ethyl-9H-carbazol-3- yl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR314##
N-[4-(4,5-dimethyl-oxazol- 2-ylsulfamoyl)-phenyl]-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR315## N-(3-iodo-phenyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR316##
N-(4-hexyloxy-phenyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR317##
N-(4-methylsulfanyl-benzyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR318##
N-[3-(2-methyl-piperidin-1- yl)-propyl]-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR319##
N-(4-trifluoromethyl- benzyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR320##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(2-methyl-piperidin-1-yl)- [1,3,5]triazine - ##STR321##
N-(2-methyl-benzyl)-4,6- Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR322## N-methyl-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR323##
N-(3-hydroxy-propyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR324##
N-benzhydryl-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR325## N,N-di-Methyl-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR326## N-(1-Benzyl-pyrrolidin-3- yl-N-methyl-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR327## 1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)- piperidine-3-carboxylic acid amide ##STR328##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)-2,3- dihydro-1H-indole ##STR329##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
[4-(4-nitro-phenyl)- piperazin-1-yl]- [1,3,5]triazine ##STR330##
[1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)- pyrrolidin-2-yl]-methanol ##STR331##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine
##STR332## N-(5-chloro-2-methyl- benzyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR333##
N,N-di-ethyl-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR334## N,N-di-isopropyl-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR335## 1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)- piperidine-4-carboxylic acid amide
##STR336## 2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(4-phenyl-piperazin-1-yl)- [1,3,5]triazine + ##STR337##
2-{[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]-methyl- amino}-1-phenyl-ethanol ##STR338##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-piperidin- 3-ylamine ##STR339##
2-(3,6-Dihydro-2H-pyridin- 1-yl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine - ##STR340##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)-piperidin- 4-ol ##STR341##
N-Methyl-N-prop-2-ynyl- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR342##
N-[1,3]Dioxolan-2-ylmethyl)- N-methyl-4,6-Bis-((3R,5S)- 3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR343##
N-Methyl-N-pentyl-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR344## N-Methyl-N-pyridin-2-yl-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR345## 2-[4-(3,4-Dimethyl-phenyl)-
piperazin-1-yl]-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine ##STR346## N-{4-[(1-hydroxy-
naphthalene-2-carbonyl)- amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR347##
N-[3-hydroxy-4-(4-methyl- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR348## N-{4-[4-(2,2-dimethyl- propionylamino)-
benzenesulfonylamino]-3- hydroxy-phenyl)-4,6- Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR349##
N-(1H-benzoimidazol-5-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR350##
N-(4-benzoylamino-2- methoxy-5-methyl-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR351## N-[4-(5-chloro-1,3-dioxo-
1,3-dihydro-isoindol-2-yl)- 3-methyl-phenyl]-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR352##
4-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-benzoic acid phenyl ester ++
##STR353## N-(2,4-dimethyl-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR354##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-piperidin- 4-ylamine - ##STR355##
N-(4-bromo-2-methyl- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR356##
N-(4-acetyl-phenyl)-4,6- Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR357## 9-[4-((3R,5S)-3,5-Diamino-
piperidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]-9H- carbazol-2-ol ##STR358##
N-(3-nitro-phenyl)-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR359## N-(9H-fluoren-2-yl)-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR360## N-(3-methyl-4-nitro- phenyl)-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR361##
N-pyren-1-yl-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR362## N-(2-pyrrol-1-yl-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR363## N-indan-5-yl-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine -
##STR364## N-pyridin-2-yl-4,6-Bis- ((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR365##
5-Bromo-1-(4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)- 1H-indole ##STR366## 4-[4,6-Bis-((3R,5S)-3,5
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]- benzoic acid
methyl ester - ##STR367## N-(4-methyl-2-oxo-2H-
chromen-7-yl]-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR368## N-(8-hydroxy-quinolin-2-yl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR369## N-(2-carbamoyl-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR370## 4-[4-(4,6-Bis((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-yl)-
piperazin-1-yl]-phenol + ##STR371## N-biphen-4-yl-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR372## N-(9-oxo-9H-fluoren-3-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR373##
N-(4-phenylazo-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR374##
N-(4-methoxy-2-nitro- phenyl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR375##
N-[4-(6-methyl- benzothiazol-2-yl)-phenyl]- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR376## N-(3-carbamoyl-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR377##
N-(2-piperidin-1-yl-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR378##
N-[4-(5-methyl-3-oxo-2,3- dihydro-pyrazol-1-yl)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-pipeiidin-1-yl)-
[1,3,5]triazine-2-amine ##STR379## N-(4-acetylamino-3,5-
dichloro-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR380## N-(3,4-dimethyl-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR381## N-(3-methylsulfanyl-
phenyl)-4,6-Bis- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR382## N-isoxazol-3-yl-4,6-Bis-
((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine -
##STR383## N-(5-methylsulfanyl- [1,3,4]thiadiazol-2-yl)-4,6-
Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR384## N-(5-methyl-isoxazol-3-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR385##
N-(Octahydro- cyclopenta[c]pyrrole-2-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR386##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2,5- Dichloro-phenyl)- hydrazine +
##STR387## N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2,4- Dinitro-phenyl)-hydrazine -
##STR388## N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2,5- Difluoro-phenyl)-hydrazine ##STR389##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(7- Methyl-thienol[3,2-
d]pyrimidin-4-yl)-hydrazine - ##STR390## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'-(4-
Trifluoromethyl-phenyl)- hydrazine ##STR391##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2- Trifluoromethyl-phenyl)- hydrazine
##STR392## N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(3- Chloro-5-trifluoromethyl-
pyridin-2-yl)-hydrazine ##STR393## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'-(6-
Chloro-pyridazin- 3-yl)-hydrazine ##STR394##
3-{N'-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- hydrazino}-6-methyl- [1,2,4]triazin-5-ol
##STR395## N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(3- Nitro-pyridin-2-yl)- hydrazine
##STR396## N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2- Chloro-4-methanesulfonyl-
phenyl)-hydrazine ##STR397## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'-(4-
Trifluoromethyl-pyrimidin-2- yl)-hydrazine ##STR398##
4-Hydroxy-benzoicacid N'- [4-((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- hydrazide ##STR399## 3-Bromo-benzoicacid
N'-[4- ((3R,5S)-3,5-diamino- piperidin-1-yl)-6-((3S,5R)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl]- hydrazide
##STR400## 3-Methoxy-benzoicacid N'- [4,6-bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl]- hydrazide ##STR401##
Furan-2-carboxylicacid N'- [4-((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- hydrazide ##STR402## 2-Methoxy-benzoicacid
N'- [4,6-bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- hydrazide ##STR403## N-(3-dimethylamino-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR404## 3-[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]- butyric acid
methyl ester ##STR405## 1-[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl]-
piperidine-4-carboxylic acid methyl ester ##STR406##
N-(1,2,3,4-tetrahydro- quinolin-2-ylmethyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR407## N-(4-chloro-2-methyl- benzyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR408##
N-(2,3-dichloro-benzyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR409##
N-biphenyl-2-ylmethyl-4,6- Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR410##
N-(3,4-dimethyl-benzyl)- 4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR411##
N-(3,5-dimethyl-benzyl)- 4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR412##
N-(2,4-difluoro-benzyl)-4,6- Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR413##
N-furan-2-ylmethyl-4,6-Bis- ((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR414## 2,4-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)-6- (4-methyl-piperidin-1-yl)-
[1,3,5]triazine ##STR415## 1-(4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-yl)-
pyrrolidin-3-ylamine ##STR416## 1-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-4-(3-
trifluoromethyl-phenyl)- piperidin-4-ol ##STR417##
1-[1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-4- phenyl-piperidin-4-yl]- ethanone ##STR418##
N-[3-(morpholine-4- sulfonyl)-4-morpholin-4-yl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR419## N-[4-(4-chloro-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR420##
N-(4-acetylamino-3-nitro- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR421##
N-[2-(toluene-4- sulfonylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR422## 2-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-3- methoxy-benzoic acid ##STR423##
N-(4-bromo-naphthalen-1- yl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR424##
N-(4-vinyl-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR425## 4-{[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl]-
naphthalen-2-yl-amino)- phenol ##STR426## N-(6-methyl-pyridin-2-
yl)-4,6-Bis-((3R,5S)- 3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR427## N-(2-sulfamoyl-phenyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR428## N-(4-thioureido- iminomethyl-phenyl)-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR429## N-benzothiazol-2-yl-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR430##
N-(3,5-dimethyl-phenyl)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR431##
N-[2-chloro-5-(2-cyano- ethylsulfamoyl)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR432## N-(Morpholino)-4,6-Bis-
((3R,5S)-3,5- diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR433## 4-{N'-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl}-6-
((3S,SR)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazine-
2-yl]-hydrazino}-3-nitro- benzanitrile - ##STR434##
N-(4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-yl)-N'- Pentafluorophenyl- hydrazine ##STR435##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(3,5- Dichloro-pyridin-4-yl)- hydrazine +
##STR436## N-(4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-yl)-N'- Pyridin-2-yl-hydrazine - ##STR437##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(2,6- Dimethyl-pyrimidin-4-yl)- hydrazine
##STR438## N-(3-methyl-thioureido)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR439##
2-Hydroxy-benzoicacid N'- [4-((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- hydrazide + ##STR440## N-(2,5-diethoxy-4-
morpholin-4-yl-phenyl)-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR441##
N-(5-carbamoyl-1H- imidazol-4-yl)-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR442##
N-[4-(ethyl-isopropyl- amino)-phenyl]-4,6-Bis- ((3R,5S)-3,5-
diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR443##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)-N'-(4- Chloro-phenyl)-hydrazine ##STR444##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(3- Fluoro-phenyl)-hydrazine - ##STR445##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-1H- benzoimidazole - ##STR446##
6-((3S,SR)-3,5-Diamino- piperidin-1-yl)-N-(3,4- dichloro-phenyl)-
[1,3,5]triazine-2,4-diamine - ##STR447## 4,6-Bis-((3R,5S)-3,5-
diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR448##
N-{4-[2-(2-chloro- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR449## N-pyrrolidin-3-ylmethyl-4,6-
Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR450## N-(2,4-dimethyl-benzyl)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR451##
N-(4-fluoro-benzyl)-4,6-Bis- ((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR452##
N-(2-pyridin-2-yl-ethyl)-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR453##
N-(3-imidazol-1-yl-propyl)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR454##
N-cyclooctyl-4,6-Bis- ((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine
##STR455## N-(2-cyano-ethyl)-4,6-Bis- ((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR456##
(2S,3S)-2-[4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine- 2-ylamino]-3-methyl- pentan-1-ol ##STR457##
N-(2-chloro-6-methyl- benzyl)-4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR458##
3-[1-(4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-yl)-piperidin-4-yl]-phenol - ##STR459##
2-(4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-yl)- decahydro-isoquinoline - ##STR460##
1-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- piperidine-2-carboxylic acid ethyl ester
##STR461## N-{3-hydroxy-4-[4-(3- methyl-butyrylamino)-
benzenesulfonylamino]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR462##
N-(2-methyl-4-nitro- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR463##
N-anthracen-2-yl-4,6-Bis- ((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR464## N-(9,10-dioxo-9,10-
dihydro-anthracen-2-yl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR465##
N-(3-ethynyl-phenyl)-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR466##
N-(benzenesulfonylamino)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR467##
4-Bromo-benzoicacid N'-[4- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- hydrazide ##STR468## N-(4-diethylamino-2-
methyl-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR469## N-(8-hydroxy-quinolin-5-yl)-
4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR470## N-(4-methanesulfonyl-
benzyl)-4,6-Bis-((3R,5S)- 3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR471## N-[2-(4-hydroxy-3-
methoxy-phenyl)-ethyl]-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR472##
N-[1-carbamoyl-2-(1H- indol-3-yl)-ethyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR473## (S)-2-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-ylamino]-4- methylsulfanyl-butyramide ##STR474##
N-(4-sulfamoyl-benzyl)-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR475##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)-N'- (1,4,5,6-tetrahydro-
pyrimidin-2-yl)-hydrazine - ##STR476## N-(4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-yl)-N'-o- Tolyl-hydrazine
+ ##STR477## N-cyclohexylmethyl-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR478##
N-cycloheptyl-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR479## N-cyclohexyl-4,6-Bis-
((3R,5S)-3,5- diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR480## N-(3,5-dimethoxy-benzyl)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR481##
2-(2-Ethyl-piperidin-1-yl)- 4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR482##
[1-(4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-yl)-piperidin- 4-yl]-methanol ##STR483##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(4-p-tolyl-piperizin-1-yl)- [1,3,5]triazine - ##STR484##
1-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-piperidin- 4-ylamine ##STR485##
8-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-1,4- dioxa-8-aza- spiro[4.5]decane. ##STR486##
N-{3-hydroxy-4-[4-(7- methyl-octanoylamino)- benzenesulfonylamino]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR487## N-(3-chloro-4-nitro-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR488## N-(4-benzenesulfonyl-
sulfamoyl-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR489## N-{4-(4-(2-hydroxy-ethyl)-3-
methyl-5-oxa-4,5-dihydro- pyrazol-1-yl]-phenyl}-4,6-
Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR490## N-(6-nitro-benzothiazol-2- yl)-4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR491##
N-(4-benzoyl-phenyl)-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR492##
N-isoquinolin-1-yl-4,6-Bis- ((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR493## N-(2-methyl-quinolin-4-yl)-
4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR494## N-(4-carbamoyl-2,3,5,6-
tetrafluoro-phenyl)-4,6-Bis ((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR495## N-(5-carbamoyl-pyridin-2-
yl)-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR496## N-(6-methanesulfonyl-
benzothiazal-2-yl)-4,6-Bis- ((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR497## N-(5-cyclopropyl-
[1,3,4]thiadiazol-2-yl)-4,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR498##
N-(3,5-bis-trifluoromethy)- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR499##
N-(4,6-dimethyl-pyrimidin- 2-yl)-4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR500##
N-(azepan-1-yl)-4,6-Bis- ((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR501## N-(4-hydroxy-naphthalen-
1-yl)-4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR502## N-carbamoylmethyl-4,6-
Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR503## (S)-2-(4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3S,5R)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-3-hydroxy- propionamide - ##STR504##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-6-
(4-pyrimidin-2-yl-piperazin- 1-yl)-[1,3,5]triazine ##STR505##
N-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl]-O,N- dimethyl-hydroxylamine ##STR506##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(3- Trifluoromethyl-phenyl)- hydrazine +
##STR507## N-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- benzamidine ##STR508##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-p- Tolyl-hydrazine + ##STR509##
N-(4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-yl)-N'-m- Tolyl-hydrazine + ##STR510##
N-(4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazin-2-yl)-N'-(4- Fluoro-phenyl)-hydrazine + ##STR511##
2-Benzyl-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)- pyrimidine
##STR512## (3,4-Dichloro-phenyl)-(2,6- Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- pyrimidin-4-yl)-amine ##STR513##
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)- pyrimidine
##STR514## N-(4- trifluoromethylsulfanyl-
phenyl)-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR515## 4-[4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-3-
(4-chloro-phenyl)- butyricacid methyl ester ##STR516##
N-[4-(1H-indazol-5- ylsulfamoyl)-phenyl]-4,6- Bis-((3R,5S)-3,5-
diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR517##
N-[4-(4-nitro- benzenesulfonyl)-phenyl]- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR518##
(3R,5S)-1-[4-(3-Amino- piperidin-1-yl)-6-(3,4-
dichloro-phenylamino)- [1,3,5]triazine-2-yl]-
piperidine-3,5-diamine + ##STR519## (3S,5R)-1-[4-(3,4-Dichloro-
phenylamino)-6-morpholin- 4-yl-[1,3,5]triazin-2-yl]-
piperidine-3,5-diamine ##STR520## (3R,5S)-1-[4-(4-Amino-
piperidin-1-yl)-6-(3,4- dichloro-phenylamino)-
[1,3,5]triazin-2-yl]- piperidine-3,5-diamine + ##STR521##
N-Benzo[1,3]dioxol-5- ylmethyl-6-((3S,5R)-3,5-
diamino-piperidin-1-yl)-N'- (3,4-dichloro-phenyl)-
[1,3,5]triazine-2,4-diamine ##STR522## 6-((3R,5S)-3,5-Diamino-
piperidin-1-yl}-N-(3,4- dichloro-phenyl)-N'-(4- methoxy-phenyl)-
[1,3,5]triazine-2,4-diamine ##STR523## N-{4-[2-(2-morpholin-4-yl-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR524##
N-(4-{2-[4-(4-methoxy- phenylamino)- phenylcarbamoyl]-acetyl}-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR525## N-(4-{3-oxo-3-[4-(2-oxo-
2,3-dihydro-benzoimidazol- 1-yl)-piperidin-1-yl]-
propionyl}-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR526## N-{4-[2-(4-methoxy-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR527##
N-{4-[2-(6-methyl-pyridin-2- ylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR528## N-{4-[2-(3-bromo-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + + ##STR529##
N-{4-[2-(biphenyl-4- ylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR530## N-{4-[2-(2-chloro-5-
trifluoromethyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR531## N-{4-[2-(4-chloro-2,5-
dimethoxy- phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR532##
N-{4-[2-(2,4-dichloro- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR533## N-{4-[2-(3-chloro-
phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR534## N-{4-[2-(4-fluoro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR535##
N-{4-[2-(2-trifluoromethyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR536## N-{4-[2-(2,5-dimethoxy-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR537##
N-{4-[2-(3,4,5-trimethoxy- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR538## N-{4-[2-(3-chloro-4-fluoro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR539##
N-{4-[2-(3-trifluoramethoxy- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR540## N-{4-[2-(3,4-difluoro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR541## N-{4-[2-(4-
trifluoromethylsulfanyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR542## N-{4-[2-(3-
trifluoromethylsulfanyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR543## N-{4-[2-(4-trifluoromethyl-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR544##
N-{4-[2-(2-fluoro- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)-3,5- diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR545## N-{4-[2-(3-amino-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-3,5- diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR546##
N-{4-[1-hydroxy-2-(2- trifluoromethyl- phenylcarbamoyl)-ethyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR547## N-{4-[2-(3,4-dichloro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl- [1,3,5]triazine-2-amine ##STR548##
(3R,5S)-1-[4-((3R,5S)-3,5- Bis-(aminomethyl)-
piperidin-1-yl)-6-(3,4- dichloro-phenylamino)-
[1,3,5]triazin-2-yl]- piperidine-3,5-diamine + ##STR549##
3-{4-[4-((3R,5S)-3,5-Bis- (aminomethyl)-piperidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-N-(2- chloro-phenyl)-3-oxo- propionamide +
##STR550## N-{4-[2-(isoxazol-3- ylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR551## N-{4-[2-(3-hydroxymethyl-
phenylcarbamoyl)-acetyl]- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR552##
N-(4-{2-[4-(2-diethylamino- ethylcarbamoyl)-
phenylcarbamoyl]-acetyl}- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR553##
N-{4-[2-(4-sulfamoyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR554## N-{4-[2-(2,2-difluoro-
benzo[1,3]dioxol-5- ylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR555##
N-{4-[2-(4-chloro- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR556## N-{4-[2-(4-chloro-2-fluoro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR557##
N-(4-{2-[4-(1H-indazol-6- ylsulfamoyl)- phenylcarbamoyl]-acetyl}-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR558## N-(4-{2-[(benzo[1,3]dioxol-
5-ylmethyl)-carbamoyl]- acetyl}-phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR559##
N-{4-[2-(4-aminomethyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR560## N-(2-Chloro-phenyl)-3-{4-
[4-((3S,5R)-3,5-diamino- piperidin-1-yl)-6-((R)-3-
hydroxy-piperidin-1-yl)- [1,3,5]triazine-2-amino]- phenyl}-3-oxo-
propionamide + ##STR561## N-Benzyl-N-{4-[4-((3R,5S)-
3,5-diamino-piperidin-1-yl)- 6-((R)-3-hydroxy-piperidin-
1-yl)-[1,3,5]triazin-2- ylamino]-3-hydroxy- phenyl}-4-methyl-
benzenesulfonamide + ##STR562## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-6-((R)-3- hydroxy-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-amide + ##STR563##
4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-((R)-3-hydroxy-piperidin- 1-yl)-[1,3,5]triazin-2-
ylamino]-2-hydroxy- phenyl}-benzamide + ##STR564##
N-{4-(4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((R)-3-hydroxy-piperidin-1- yl)-[1,3,5]triazin-2-ylamino]-
2-hydroxy-phenyl}-4- methyl-benzamide - ##STR565##
4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-((R)-3-
hydroxy-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-N-
(1H-indazol-6-yl)- benzenesulfonamide - ##STR566##
3-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-((R)-3-
hydroxy-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]- fluoren-9-one +
##STR567## N-[3-chloro-4-(2-hydroxy-6- methoxy-benzoylamino)-
phenyl]-4,6-Bis-(cis-3,5- Diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR568## N-{4-[(4-hydroxy-quinoline-
3-carbonyl)-amino]- phenyl}-4,6-Bis-(cis-3,5-
Diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR569##
N-[4-(2,2-difluoro- benzo[1,3]dioxol-5- ylcarbamoyl)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR570## N-[4-(3,5-dichloro-4-
hydroxy-phenylcarbamoyl)- 3-hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR571## N-[4-(4-cyano- phenylcarbamoyl)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR572## N-[4-(2-chloro-5-
trifluoromethyl- phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)- 3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR573## N-[4-(4-chloro-2,5- dimethoxy- phenylcarbamoyl)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR574## N-[4-(2,4-dichloro-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR575##
N-[4-(3-chloro- phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR576## N-[4-(4-fluoro- phenylcarbamoyl)-3-
hydroxy-phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR577## N-[4-(2,5-dimethoxy-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR578##
N-[3-hydroxy-4-(3,4,5- trimethoxy- phenylcarbamoyl)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR579## N-[4-(2,3-dichloro-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR580##
N-[4-(3-chloro-4-fluoro- phenylcarbamoyl)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR581## N-[4-(4-chloro-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR582##
N-[3-hydraxy-4-(3- trifluoromethoxy- phenylcarbamoyl)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR583## N-[4-(3,4-difluoro-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR584##
N-[4-(4-chloro-2-fluoro- phenylcarbamoyl)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR585## N-[4-(benzo[1,3]dioxol-5-
ylcarbamoyl)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR586##
N-[3-hydroxy-4-(3- trifluoromethylsulfanyl)-
phenylcarbamoyl)-phenyl]- 4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR587##
N-{3-hydroxy-4-[4-(1H- indazol-6-ylsulfamoyl)- phenylcarbamoyl]-
phenyl}- 4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR588## N-[3-hydroxy-4-(3-
trifluoromethyl)- phenylcarbamoyl)-phenyl]- 4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR589##
N-[4-(2-fluoro- phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)- 3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR590## N-{4-[(benzo[1,3]dioxal-5- ylmethyl)-carbamoyl]-3-
hydroxy-phenyl)-4,6-Bis- ((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR591## N-[4-(2-chloro-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR592## N-[4-(3,4-dichloro- phenylcarbamoyl)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR593## N-[3-hydroxy-4-(4-hydroxy-
phenylcarbamoyl)-phenyl]- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR594##
N-[4-(1H-benzoimidazol-5- ylcarbamoyl)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR595## N-[3-hydroxy-4-
(morpholine-4-carbonyl)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR596##
N-[3-hydroxy-4-(3-oxo- piperazine-1-carbonyl)-
phenyl]-4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR597## N-[3-hydroxy-4-(2-
methoxy-ethylcarbamoyl)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine -
##STR598## N-{4-[(furan-2-ylmethyl)- carbamoyl]-3-hydroxy-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR599## N-[3-hydroxy-4-(4-
trifluoromethylsulfanyl- phenylcarbamoyl)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR600## N-Benzyl-N-{4-[4-[bis-(2-
amino-ethyl)-amino]-6- ((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine- 2-ylamino]-3-hydroxy- phenyl)-4-methyl-
benzenesulfonamide + ##STR601## N-{4-[4-[Bis-(2-amino-
ethyl)-amino]-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-chloro- benzamide +
##STR602## 1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-[bis-(2-
amino-ethyl)-amino]-6- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl}-amide ++
##STR603## N-{4-[4-[Bis-(2-amino- ethyl)-amino]-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-methyl- benzamide + ##STR604##
4-[4-[Bis-(2-amino-ethyl)- amino]-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-N-
(1H-indazol-6-yl)- benzenesulfonamide - ##STR605##
3-[4-[Bis-(2-amino-ethyl)- amino]-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]- fluoren-9-one -
##STR606## 4-[4-[Bis-(2-amino-ethyl)- amino]-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- hydroxy-benzoicacid phenylester +
##STR607## 1-{4-[4-[Bis-(2-amino- ethyl)-amino]-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-
phenyl]-ethanone + ##STR608## 7-[4-[Bis-(2-amino-ethyl)-
amino]-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-4- methyl-chromen-2-one - ##STR609##
N-(2-Chloro-phenyl)-3-{4- [4-((3S,5R)-3,5-diamino-
piperidin-1-yl)-6-((3R,5R)- 3,5-dihydroxy- piperidin-1-
yl)-[1,3,5]triazin-2-ylamino]- phenyl)-3-oxo- propionamide +
##STR610## N-Benzyl-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-((3R,5R)-3,5-dihydroxy- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl)-4-methyl- benzenesulfonamide +
##STR611## 1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-
((3S,5R)-3,5-diamino- piperidin-1-yl)-6-((3R,5R)-
3,5-dihydroxy-piperidin-1- yl)-[1,3,5]triazin-2-ylamino]-
phenyl}-amide + ##STR612## 7-[4-((3R,5S)-3,5-Diamino-
piperidin-1-yl)-6-((3R,5R)- 3,5-dihydroxy-piperidin-1-
yl)-[1,3,5]triazin-2-ylamino]- 4-methyl-chromen-2-one - ##STR613##
N-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3R,5R)-3,5-dihydroxy- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-4-methyl- benzamide - ##STR614##
4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-((3R,5R)-
3,5-dihydroxy-piperidin-1- yl)-[1,3,5]triazin-2-ylamino]-
2-hydroxy-benzoicacid phenylester - ##STR615##
4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-((3R,5R)-
3,5-dihydroxy-piperidin-1- yl)-[1,3,5]triazin-2-ylamino]-
N-(1H-indazol-6-yl)- benzenesulfonamide - ##STR616##
1-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3R,5R)-3,5-dihydroxy- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}- ethanone - ##STR617##
4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-((3R,SR)-3,5-dihydroxy- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl56 -benzamide + ##STR618##
N-(2-Chloro-phenyl)-3-{4- [4-((3S,5R)-3,5-diamino-
piperidin-1-yl)-6-((3R,4S)- 3,4-dihydroxy-pyrrolidin-1-
yl)-[1,3,5]triazin- 2-ylamino]- phenyl}-3-oxo- propionamide +
##STR619## N-Benzyl-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-((3R,4S)-3,4-dihydroxy- pyrrolidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl-
benzenesulfonamide + ##STR620## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-6-((3R,4S)- 3,4-dihydroxy-pyrrolidin-1-
yl)-[1,3,5]triazin-2-ylamino]- phenyl}-amide + ##STR621##
7-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-((3R,4S)-
3,4-dihydroxy-pyrrolidin-1- yl)-[1,3,5]triazin-2-ylamino]-
4-methyl-chromen-2-one - ##STR622## N-{4-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- ((3R,4S)-3,4-dihydroxy-
pyrrolidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl)-4-methyl- benzamide - ##STR623##
3-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-((3R,4S)-
3,4-dihydroxy-pyrrolidin-1- yl)-[1,3,5]triazin-2-ylamino]-
fluoren-9-one - ##STR624## 4-[4-((3S,5R)-3,5-Diamino-
piperidin-1-yl)-6-((3R,4S)- 3,4-dihydroxy-pyrrolidin-1-
yl)-[1,3,5]triazin-2-ylamino]- 2-hydroxy-benzoicacid phenylester +
##STR625## 4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-((3R,4S)-
3,4-dihydroxy-pyrrolidin-1- yl)-[1,3,5]triazin-2-ylamino]-
N-(1H-indazol-6-yl)- benzenesulfonamide - ##STR626##
1-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3R,4S)-3,4-dihydroxy- pyrolidin-1-yl)- [1,3,5]triazin-2-ylamino]-
phenyl]-ethanone - ##STR627## 4-Chloro-N-{4-[4-((3S,5R)-
3,5-diamino-piperidin-1-yl)- 6-((3R,4S)-3,4-dihydroxy-
pyrrolidin-1-yl)- [1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-
benzamide + ##STR628## 3-{4-[4-((3S,5R)-3-Amino-
5-hydroxy-piperidin-1-yl)-6- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl}-N-(2-
chloro-phenyl)-3-oxo- propionamide ++ ##STR629##
N-{4-[4-((3S,5R)-3-Amino- 5-hydroxy-piperidin-1-yl)-6-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-N-benzyl-4-methyl)-
benzenesulfonamide + ##STR630## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((3S,5R)-3-amino-5-
hydroxy-piperidin-1-yl)-6- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl]-amide ++
##STR631## 7-[4-((3S,5R)-3-Amino-5- hydroxy-piperidin-1-yl)-6-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazin-
2-ylamino]-4-methyl- chromen-2-one - ##STR632##
N-{4-[4-((3S,5R)-3-Amino- 5-hydroxy-piperidin-1-yl)-6-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-4-methyl- benzamide + ##STR633##
3-[4-((3S,5R)-3-Amino-5- hydroxy-piperidin-1-yl)-6-
((3S,5R)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-fluoren-9-one ++ ##STR634## 4-[4-((3S,5R)-3-Amino-5-
hydroxy-piperidin-1-yl)-6- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-hydroxy- benzoicacid
phenylester ++ ##STR635## 4-[4-((3S,5R)-3-Amino-5-
hydroxy-piperidin-1-yl)-6- ((3S,5R)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-N-(1H-indazol-
6-yl)-benzenesulfonamide - ##STR636## 1-{4-[4-((3S,5R)-3-Amino-
5-hydroxy-piperidin-1-yl)-6- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl}- ethanone -
##STR637## N-{4-[4-((3S,5R)-3-Amino- 5-hydroxy-piperidin-1-yl)-6-
((3S,5R)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-4-chloro- benzamide ++ ##STR638##
N-(2-Chloro-phenyl)-3-{4- [4-((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3R,4S)- 3,4-diamino-pyrrolidin-1-
yl)-[1,3,5]triazin-2-ylamino]- phenyl}-3-oxo- propionamide +
##STR639## N-Benzyl-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-((3R,4S)-3,4-diamino- pyrrolidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl-
benzenesulfonamlde ++ ##STR640## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3R,4S)- 3,4-diamino-pyrrolidin-1-
yl)-[1,3,5]triazin-2-ylamino]- phenyl}-amide ++ ##STR641##
7-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-((3R,4S)-
3,4-diamino-pyrrolidin-1- yl)-[1,3,5]triazin-2-ylamino]-
4-methyl-chromen-2-one - ##STR642## N-{4-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- ((3R,4S)-3,4-dlamino- pyrrolidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl- benzamide +
##STR643## 3-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-((3R,4S)-
3,4-diamino-pyrrolidin-1- yl)-[1,3,5]triazin-2-ylamino]-
fluoren-9-one + ##STR644## 4-[4-((3R,5S)-3,5-Diamino-
piperidin-1-yl)-6-((3R,4S)- 3,4-diamino-pyrrolidin-1-
yl)-[1,3,5]triazin-2-ylamino]- 2-hydroxy-benzoicacid phenylester +
##STR645## 4-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-((3R,4S)-
3,4-diamino-pyrrolidin-1- yl)-[1,3,5-]triazin-2-ylamino]-
N-(1H-indazol-6-yl)- benzenesulfonamide - ##STR646##
1-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
((3R,4S)-3,4-diamino- pyrrolidin-1-yl)- [1,3,5]triazin-2-ylamino]-
phenyl]-ethanone - ##STR647## 4-Chloro-N-{4-[4-((3R,5S)-
3,5-diamino-piperidin-1-yl)- 6-((3R,4S)-3,4-diamino-
pyrrolidin-1-yl)- [1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-
benzamide + ##STR648## N-[4-(3,5-dichloro-2- hydroxy-
benzenesulfonylamino)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR649## N-[3-hydroxy-4-(2,4,6- trimethyl- benzenesulfonylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR650## N-[4-(3,5-dichloro-
benzenesulfonylamino)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR651## N-[4-(2,6-dichloro- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR652## N-[4-(4-ethoxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR653##
N-Benzyl-N-{4-[4-((3S,5R)- 3,5-bis-(aminomethyl)-
piperidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-3- hydroxy-phenyl)-4-methyl-
benzenesulfonamide + ##STR654## N-{4-[4-((3R,5S)-3,5-Bis-
(aminomethyl)-piperidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl}-4-chloro- benzamide ++ ##STR655## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((3R,5S)-3,5-bis- (aminomethyl)-piperidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-amide ++ ##STR656## N-{4-[4-((3S,5R)-3,5-Bis-
(aminomethyl)-piperidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yJ)-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl)-4-methyl- benzamide + ##STR657## 4-[4-((3R,5S)-3,5-Bis-
(aminomethyl)-piperidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-N-(1H-indazol-
6-yl)-benzenesulfonamide - ##STR658## 3-[4-((3R,5S)-3,5-Bis-
(aminomethyl)-piperidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin 2-ylamino]-fluoren-9-one +
##STR659## 4-[4-((3R,5S)-3,5-Bis- (aminomethyl)-piperidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- benzoicacid phenylester + ##STR660##
7-[4-((3S,5R)-3,5-Bis- (aminomethyl)-piperidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]-triazin-
2-ylamino]-4-methyl- chromen-2-one - ##STR661##
1-{4-[4-((3S,5R)-3,5-Bis- (aminomethyl)-piperidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}- ethanone - ##STR662## N-{4-[2-(3,4-difluoro-
phenylcarbamoyl)-acetyl]- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-amine ++ ##STR663##
N-{4-[2-(2,2-difluoro- benzo[1,3]dioxol-5- ylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR664## N-(3-hydroxy-4-
phenylmethanesulfanylami- no-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR665##
N-{3-hydroxy-4-[2-(2,2,2- trifluoro-acetyl)-1,2,3,4-
tetrahydro-isoquinoline-7- sulfonylamino]-phenyl}-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
- ##STR666## N-[4-(3,4-dimethoxy- benzenesulfonylamino)-3-
hydroxy-phenyl]-4,6-Bis- piperidin-1-yl)- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR667##
N-[4-(3-chloro-propane-1- sulfonylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR668## N-[3-hydroxy-4-(3- methoxy-
benzenesulfonylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR669##
N-(4-butyrylamino-3- hydroxy-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino-
[1,3,5]triazine-2-amine - ##STR670## N-[4-(3-bromo-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR671##
N-[3-hydroxy-4-(3-phenyl- acryloylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- [1,3,5]triazine-2-amine ++ ##STR672##
N-[4-(2-chloro- benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR673##
3-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-N-(2- chloro-phenyl)-3-oxo- propionamide +
##STR674## N-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- pipeuidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-N-benzyl-4-methyl)-
benzenesulfonamide + ##STR675## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((2S,4S)-4-amino-2- aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl)-amide ++ ##STR676## 7-[4-((2S,4S)-4-Amino-2-
aminomethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperdin-1-yl)-[1,3,5]triazin- 2-ylamino]-4-methyl- chromen-2-one -
##STR677## N-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl]-4-methyl- benzamide + ##STR678##
3-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl}-3-oxo- N-(4-
trifluoromethylsulfanyl- phenyl)-propionamide ++ ##STR679##
2-[4-((2S,4S)-4-Amino-2- aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-fluoren-9-one - ##STR680## 4-[4-((2S,4S)-4-Amino-2-
aminomethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-hydroxy- benzoicacid
phenylester ++ ##STR681## 4-[4-((2S,4S)-4-Amino-2-
aminomethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-N-(1H-indazol-
6-yl)-benzenesulfonamide - ##STR682## 1-{4-[4-((2S,4S)-4-Amino-
2-aminomethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl]- ethanone -
##STR683## N-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-4-chloro- benzamide ++ ##STR684##
3-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-N-(3,4- difluoro-phenyl)-3-oxo- propionamide +
##STR685## 3-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-N-(2,2- difluoro-benzo[1,3]dioxol-
yl)-3-oxo-propionamide ++ ##STR686## 3-{4-[4-((2S,4S)-4-Amino-
2-hydroxymethyl-pyrrolidin- 1-yl)-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-
phenyl}-N-(2-chloro- phenyl)-3-oxo- propionamide + ##STR687##
N-{4-[4-((2S,4S)-4-Amino- 2-hydroxymethyl-pyrrolidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-N-benzyl- 4-methyl-
benzenesulfonamide + ##STR688## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((2S,4S)-4-amino-2-
hydroxymethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl}-amide ++
##STR689## N-{4-[4-((2S,4S)-4-Amino- 2-hydroxymethyl-pyrrolidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl- benzamide +
##STR690## 3-{4-[4-((2S,4S)-4-Amino- 2-hydroxymethyl-pyrrolidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-3-oxo-N-(4-
tririuoromethylsulfanyl- phenyl)-propionamide ++ ##STR691##
2-[4-((2S,4S)-4-Amino-2- hydroxymethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-fluoren-9-one - ##STR692## 4-[4-((2S,4S)-4-Amino-2-
hydroxymethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-hydroxy- benzamide -
##STR693## 4-[4-((2S,4S)-4-Amino-2- hydroxymethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-N-(1H-indazol- 6-yl)-benzenesulfonamide - ##STR694##
1-{4-[4-((2S,4S)-4-Amino- 2-hydroxymethyl-pyrrolidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-ethanone - ##STR695##
N-{4-[4-((2S,4S)-4-Amino- 2-hydroxymethyl-pyrrolidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-chloro- benzamide +
##STR696## 3-{4-[4-((2S,4S)-4-Amino- 2-hydroxymethyl-pyrrolidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-N-(3,4-difluoro- phenyl)-3-oxo-
propionamide + ##STR697## 3-{4-[4-((2S,4S)-4-Amino-
2-hydroxymethyl-pyrrolidin- 1-yl)-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-
phenyl}-N-(2,2-difluoro- benzo[1,3]dioxol-5-yl)-3- oxo-propionamide
++ ##STR698## N-(2-Chloro-phenyl)-3-{4- [4-((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-methoxy- [1,3,5]triazin-2-ylamino]-
phenyl}-3-oxo- propionamide ++ ##STR699##
N-Benzyl-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-methoxy-[1,3,5]triazin-2- ylamino]-2-hydroxy- phenyl}-4-methyl-
benzenesulfonamide ++ ##STR700## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[4- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-methoxy- [1,3,5]triazin-2-ylamino]- phenyl}-amide
++ ##STR701## 7-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-methoxy-
[1,3,5]triazin-2-ylamino]-4- methyl-chromen-2-one - ##STR702##
N-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
methoxy-[1,3,5]triazin-2- ylamino]-2-hydroxy- phenyl}-4-methyl-
benzamide + ##STR703## 3-{4-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- methoxy-[1,3,5]triazin-2-
ylamino]phenyl}-3-oxo-N- (4-trifluoromethylsulfanyl-
phenyl)-propionamide ++ ##STR704## 2-[4-((3R,5S)-3,5-Diamino-
piperidin-1-yl)-6-methoxy- [1,3,5]triazin-2-ylamino]- fluoren-9-one
- ##STR705## 4-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-methoxy-
[1,3,5]triazin-2-ylamino]-2- hydroxy-benzoicacid phenylester ++
##STR706## 4-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-methoxy-
[1,3,5]triazin-2-ylamino]-N- (1H-indazol-6-yl)- benzenesulfonamide
- ##STR707## 1-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
methoxy-[1,3,5]triazin- ylamino]-phenyl}-ethanone - ##STR708##
4-Chloro-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
(6-methoxy-[1,3,5]triazin-2- ylamino]-2-hydroxy- phenyl)-benzamide
++ ##STR709## 3-55 4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
methoxy-[1,3,5]triazin-2- ylamino]-phenyl}-N-(3,4-
difluoro-phenyl)-3-oxo- propionamide ++ ##STR710##
3-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
methoxy-[1,3,5]triazin-2- ylamino]-phenyl}-N-(2,2-
difluoro-benzo[1,3]dioxol- 5-yl)-3-oxo- propionamide ++ ##STR711##
N-{4-[(adamantane-1- carbonyl)-amino]-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR712## (S)-4,7,7-Trimethyl-3-oxo- 2-oxo-
bicyclo[2.2.1]heptane-1- carboxylicacid {4-[4,6-bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-amide + ##STR713## N-[4-(3-chloro-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR714##
N-{4-[4-((3R.4S)-3- Aminomethyl-4-hydroxy-
piperidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-3- hydroxy-phenyl}-N-benzyl)- 4-methyl-
benzenesulfonamide + ##STR715## N-{4-[4-((3R,4S)-3-
Aminomethyl-4-hydroxy- piperidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-chloro- benzamide + ##STR716##
1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-
((3R,4S)-3-aminomethyl-4- hydroxy-piperidin-1-yl)-6-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-amide ++ ##STR717## 4-[4-((3R,4S)-3-
Aminomethyl-4-hydroxy- piperidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-N-
(1H-indazol-6-yl)- benzenesulfonamide - ##STR718## 3-[4-((3R,4S)-3-
Aminomethyl-4-hydroxy- piperidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-
fluoren-9-one - ##STR719## 4-[4-((3R,4S)-3- Aminomethyl-4-hydroxy-
piperidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-benzoicacid phenylester -
##STR720## 7-[4-((3R,4S)-3- Aminomethyl-4-hydroxy-
piperidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-4- methyl-chromen-2-one - ##STR721##
1-{4-[4-((3R,4S)-3- Aminomethyl-4-hydroxy-
piperidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-ethanone - ##STR722##
3-{4-[4-((2S,3S)-2- Aminomethyl-3-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-N-(2-chloro- phenyl)-3-oxo-
propionamide + ##STR723## N-{4-[4-((2S,3S)-2-
Aminomethyl-3-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1.3,5]triazin-2-ylamino]-3-
hydroxy-phenyl}-N-benzyl- 4-methyl-
benzenesulfonamide + ##STR724## N-{4-[4-((2S,3S)-2-
Aminomethyl-3-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-chloro- benzamide + ##STR725##
1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-
((2S,3S)-2-aminomethyl-3- hydroxy-pyrrolidin-1-yl)-6-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-amide ++ ##STR726## N-{4-[4-((2S,3S)-2-
Aminomethyl-3-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-methyl- benzamide ++ ##STR727## 4-[4-((2S,3S)-2-
Aminomethyl-3-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-N-
(1H-indazol-6-yl)- benzenesulfonamide - ##STR728## 3-[4-((2S,3S)-2-
Aminomethyl-3-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-
fluoren-9-one + ##STR729## 4-[4-((2S,3S)-2- Aminomethyl-3-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-benzoicacid phenylester -
##STR730## 7-[4-((2S,3S)-2- Aminomethyl-3-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-4- methyl-chromen-2-one - ##STR731##
1-{4-[4-((2S,3S)-2- Aminomethyl-3-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-ethanone - ##STR732##
N-{3-hydroxy-4-[2-(1H- indol-3-yl)-2-oxo- acetylamino]-phenyl}-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazin-2-amine
++ ##STR733## N-[3-hydroxy-4-(3-methyl- butyrylamino)-pheny]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
+ ##STR734## N-{3-hydroxy-4-[3-phenyl- 2-(toluene-4-
sulfonylamino)- propionylamino]-phenyl}- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-amine ++ ##STR735##
N-[4-(2,2-dimethyl- propionylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR736## N-[3-hydroxy-4-(4-
methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR737##
N-[4-(2,4-dimethoxy- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR738## N-[3-hydroxy-4-(2-
methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR739##
N-[4-(2,6-dimethoxy- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-amine + ##STR740## N-[4- (cyclohexanecarbonyl)-
amino)-3-hydroxy-phenyl]- 4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-amine + ##STR741##
N-{4-[4-(4-Acetyl-piperazin- 1-yl)-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-methyl- benzamide ##STR742##
4-[4-(4-Acetyl-piperazin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-N-(1H-indazol-
6-yl)-benzenesulfonamide - ##STR743## N-Benzyl-N-{4-[4-((3R,5S)-
3,5-diamino-piperidin-1-yl)- 6-(3-imidazol-1-yl-
propylamino)-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl}-4-methyl- benzenesulfonamide + ##STR744##
4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-(3-imidazol-1-yl- propylamino)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-benzamide + ##STR745##
4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-(3-
imidazol-1-yl-propylamino)- [1,3,5]triazin-2-ylamino]-N-
(1H-indazo1-6-yl)- benzenesulfonamide - ##STR746##
N-{4-[4-(3-Amino-azetidin- 1-yl)-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-N-benzyl- 4-methyl- benzenesulfonamide + ##STR747##
N-{4-[4-(3-Amino-azetidin- 1-yl)-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-methyl- benzamide + ##STR748##
4-Chloro-N-(4-{4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-[4-(2-morpholin-4-yl-2- oxo-ethyl)-piperazin-1-yl]-
[1,3,5]triazin-2-ylamino}-2- hydroxy-phenyl)- benzamide -
##STR749## N-Benzyl-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-(4-pyridin-4-yl-piperazin- 1-yl)-[1,3,5]triazin-2-
ylamino]-2-hydroxy- phenyl}-4-methyl- benzenesulfonamide ++
##STR750## 4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-(4-pyridin-4-yl-piperazin- 1-yl)-[1,3,5]triazin-2-
ylamino]-2-hydroxy- phenyl}-benzamide + ##STR751##
4-Chloro-N-(4-{4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-[2-(2-oxo-imidazolidin-1- yl)-ethylamino]-
[1,3,5]triazin-2-ylamino}-2- hydroxy-phenyl)- benzamide +
##STR752## 4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperdin-1-yl)-
6-(4-pyrrolidin-1-yl- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-benzamide + ##STR753##
4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-piperazin-1-yl- [1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-
benzamide ++ ##STR754## N-{4-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- (piperidin-4-ylamino)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl- benzamide ++
##STR755## 4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-(piperidin-4-ylamino)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}- benzamide ++ ##STR756## N-Benzyl-N-{4-[4-((3R,5S)-
3,5-diamino-piperidin-1-yl)- 6-(piperidin-3-ylamino)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl-
benzenesulfonamide + ##STR757## N-{4-[4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- (piperidin-3-ylamino)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl- benzamide +
##STR758## 4-Chloro-N-{4-[4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
6-(piperidin-3-ylamino)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}- benzamide ++ ##STR759## 4-[4-((3S,5R)-3,5-Diamino-
piperidin-1-yl)-6-(piperidin- 3-ylamino[1,3,5]triazin-2-
ylamino]-N-(IH-indazol-6- yl)-benzenesulfonamide - ##STR760##
2,4-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
quinoline-3-carboxylicacid methylester - ##STR761##
N-{4-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-2-
((1R,2S,5R)-2-isopropyl-5- methyl-cyclohexyloxy)- acetamide
##STR762## N-{4-[4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}- malonamic acid methyl
ester - ##STR763## N-(3-hydroxy-4- isobutyrylamino-phenyl)-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR764## N-{3-hydroxy-4-
[(naphthalene-2-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR765## N-(3-hydroxy-4- phenylacetylamino-
phenyl)-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR766## N-(3-hydroxy-4-
propionylamino-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR767##
N-{3-hydroxy-4- [(quinoxaline-2-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR768## N-[4-(2,2-dimethyl-
propionylamino)-3-hydroxy-phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR769##
N-[3-hydroxy-4-(4- methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR770##
N-{4-[4-(4-Acetyl-piperazin- 1-yl)-6-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-N-benzyl- 4-methyl- benzenesulfonamide ##STR771##
N-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6- (3-imidazol-1-yl-
propylamino)-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl}-4-methyl- benzamide ##STR772## 4-[4-(3-Amino-azetidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-N-(1H-indazol- 6-yl)-benzenesulfonamide - ##STR773##
N-Benzyl-N-(4-{4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-[4-(2-morpholin-4-yl-2- oxo-ethyl)-piperazin-1-yl]-
[1,3,5]triazin-2-ylamino)-2- hydroxy-phenyl)-4-methyl-
benzenesulfonamide ##STR774## N-(4-{4-((3R,5S)-3,5-
Diamino-piperidin-1-yl)-6- [4-(2-morpholin-4-yl-2-oxo-
ethyl)-piperazin-1-yl]- [1,3,5]triazin-2-ylamino}-2-
hydroxy-phenyl)-4-methyl- benzamide ##STR775##
4-{4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-[4-(2-
morpholin-4-yl-2-oxo- ethyl)-piperazin-1-yl]-
[1,3,5]triazin-2-ylamino}-N- (1H-indazol-6-yl)- benzenesulfonamide
##STR776## N-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
(4-pyridin-4-yl-piperazin-1- yl)-[1,3,5]triazin-2-ylamino}-
2-hydroxy-phenyl)-4- methyl-benzamide + ##STR777##
4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-(4-pyridin-
4-yl-piperazin-1-yl)- [1,3,5]triazin-2-ylamino]-N-
(1H-indazol-6-yl)- benzenesulfonamide + ##STR778##
N-(4-{4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
[2-(2-oxo-imidazolidin-1-yl)- ethylamino]-[1,3,5]triazin-2-
ylamino}-2-hydroxy- phenyl)-4-methyl- benzamide ##STR779##
4-{4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-[2-(2-oxo-
imidazolidin-1-yl)- piperidin-1-yl)-6-[2-(2-oxo-
ethylamino]-[1,3,5]triazin-2- ylamino}-N-(1H-indazol-6-
yl)-benzenesulfonamide ##STR780## N-Benzyl-N-{4-[4-((3R,5S)-
3,5-diamino-piperidin-1-yl)- 6-(4-piperidin-1-yl-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl}-4-methyl- benzenesulfonamide ##STR781##
N-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
(4-pyrrolidin-1-yl-piperidin- 1-yl)-[1,3,5]triazin-2-
ylamino]-2-hydroxy- phenyl}-4-methyl- benzamide + ##STR782##
4-[4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-(4-
pyrrolidin-1-yl-piperidin-1- yl)-[1,3,5]triazin-2-ylamino]-
N-(1H-indazol-6-yl)- benzenesulfonamide - ##STR783##
N-Benzyl-N-{4-[4-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
6-piperazin-1-yl- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-methyl- benzenesulfonamide + ##STR784##
4-(4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-piperazin-
1-yl-[1,3,5]triazin-2- ylamino]-N-(1H-indazol-6-
yl)-benzenesulfonamide - ##STR785## N-Benzyl-N-{4-[4-((3R,5S)-
3,5-diamino-piperidin-1-yl)- 6-(piperidin-4-ylamino)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-methyl-
benzenesulfonamide + ##STR786## 4-[4-((3S,5R)-3,5-Diamino-
piperidin-1-yl)-6-(piperidin- 4-ylamino)-[1,3,5]triazin-2-
ylamino]-N-(1H-indazol-6- yl)-benzenesulfonamlde -
##STR787## 1-[4-{4-[Benzyl-(toluene-4- sulfonyl)-amino]-3-hydroxy-
phenylamino}-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- piperidine-4-carboxylicacid amide ##STR788##
1-{4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-[3-
hydroxy-4-(4-methyl- benzoylamino)- phenylaminol-[1,3,5]triazin-
2-yl}-piperidine-4- carboxylicacid amide ##STR789##
1-[4-[4-(4-Chloro- benzoylamino)-3-hydroxy-
phenylamino]-6-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-yl]- piperidine-4-carboxylicacid amide ##STR790##
1-{4-((3S,5R)-3,5-Diamino- piperidin-1-yl)-6-[4-(1H-
indazol-6-ylsulfamoyl)- phenylamino[1,3,5]triazin-
2-yl)-piperidine-4- carboxylicacid amide ##STR791##
N-Benzyl-N-(4-{4-((3R,5S)- 3,5-diaminopiperidin-1-yl)-
yl)-ethylamino]- [1,3,5]triazin-2-ylamino}-2-
hydroxy-phenyl)-4-methyl- benzenesulfonamide ##STR792##
N-{4-[4-((3R,5S)-3,5- Diamino-piperidin-1-yl)-6-
piperazin-1-yl-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl)-4-methyl- benzamide ##STR793## N-{4-[4-(3-Amino-azetidin-
1-yl)-6-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-chloro- benzamide ++
##STR794## N-[4-(3,3-diphenyl-ureido)- 3-hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR795## N-[4-(4-acetylamino- benzenesulfonylamino)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR796## N-[4-(2,4-dichloro-
benzenesulfonylamino)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR797## N-[4-(4-chloro- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR798## 4-[4-((3S,5R)-3,5-Diamino-
piperidin-1-yl)-6-((R)-3- hydroxy-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-benzoicacid phenylester +
##STR799## 7-[4-((3R,5S)-3,5-Diamino- piperidin-1-yl)-6-((R)-3-
hydroxy-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-4-
methyl-chromen-2-one + ##STR800## 1-{4-[4-((3R,5S)-3,5-
Diamino-piperidin-yl)-6- ((R)-3-hydroxy-piperidin-1-
yl)-[1,3,5]triazin-2-ylamino]- phenyl}-ethanone - ##STR801##
N-{3-hydroxy-4-[4-(2-oxo- 2,3-dihydro- benzoimidazole-
1-yl)-piperidine-1- carbonyl]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR802## N-(4-{4-[benzyl-(toluene-4- sulfonyl)-amino]-3-hydroxy-
phenylcarbamoyl}-3- hydroxy-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR803##
N-[3-hydroxy-4-(isoxazol-3- ylcarbamoyl)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
+ ##STR804## N-[3-hydroxy-4-(4- methoxy- phenylcarbamoy)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR805## N-[3-hydroxy-4-(6-methyl-
pyridin-2-ylcarbamoyl)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR806##
N-[3-hydroxy-4-(4-methyl- 2-oxo-2H-chromen-7-
ylcarbamoyl)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR807##
N-[4-(5-bromo-2,3-dihydro- indole-1-carbonyl)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR808## N-[4-(biphenyl-4-
ylcarbamoyl)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidine-1-yl)- [1,3,5]triazine-2-amine ++ ##STR809##
N-[3-hydroxy-4-(3- hydroxymethyl- phenylcarbamoyl)-phenyl]-
4,6-Bis-((3R,5S)- 3,5-diamino-piperidine-1-yl)-
[1,3,5]triazine-2-amine + ##STR810## N-[4-(4-carbamoyl-
phenylcarbamoyl)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidine-1-yl)- [1,3,5]triazine-2-amine - ##STR811##
3-{4-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-N-(2-chloro- phenyl)-3-oxo-
propionamide + ##STR812## N-{4-[4-((2S,4R)-2-
Aminomethyl-4-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amino}-2-
hydroxy-phenyl}-N-benzyl- 4-methyl- benrenesulfanamide + ##STR813##
1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-
((2S,4R)-2-aminomethyl-4- hydroxy-pyrrolidin-1-yl)-6-
((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-amide + ##STR814## 7-[4-((2S,4R)-2-
Aminomethyl-4-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-4-
methyl-chromen-2-one - ##STR815## N-{4-[4-((2S,4R)-2-
Aminomethyl-4-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-4-methyl- benzamide - ##STR816##
3-{4-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl}-3-oxo-N-(4-
trifluoromethylsulfanyl- phenyl)-propionamide ++ ##STR817##
2-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- fluoren-9-one - ##STR818##
4-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-N- (1H-indazol-6-yl)- benzenesulfonamide
- ##STR819## 1-{4-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]- phenyl)-ethanone - ##STR820##
N-{4-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-4-chloro- benzamide +
##STR821## 3-{4-[4-((2S,4R)-2- Aminomethyl-4-hydroxy-
pyrrolidin-1-yl)-6-((3R,5S)- 3,5-diamino-piperidin-1-yl-
[1,3,5]triazin-2-ylamino]- phenyl}-N-(3,4-difluoro- phenyl)-3-oxo-
propionamide + ##STR822## 3-{4-[4-((2S,4R)-2-
Aminomethyl-4-hydroxy- pyrrolidin-1-yl)-6-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-
phenyl}-N-(2,2-difluoro- benzo[1,3]dioxol-5-yl)-3- oxo-propionamide
++ ##STR823## 1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-(2-
amino-ethylamino)-6- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-phenyl}-amide ++
##STR824## 3-[4-(2-Amino-ethylamino)- 6-((3R,5S)-3,5-diamino-
[1,3,5]triazin- 2-ylamino]-fluoren-9-one - ##STR825##
7-[4-(2-Amino-ethylamino)- 6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin 2-ylamino]-4-methyl- chromen-2-one -
##STR826## N-[3-chloro-4-(4- dimethylamino-2-hydroxy-
benzoylamino)-phenyl]-4,6- Bis-(cis-3,5-Diamino- piperidin-1-yl)-
[1,35]triazine-2-amine ##STR827## N-[3-(2-hydroxy-3-methyl-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR828##
N-[4-(2-hydroxy-3-methyl- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR829## N-[2-(2-hydroxy-3-methyl-
benzoylamino)-5-methoxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR830##
N-[3-hydroxy-4-(2-hydroxy- 3-methyl-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR831## N-[3-(4-chloro-2-hydroxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR832##
N-[2-(4-chloro-2-hydroxy- benzoylamino)-5-methoxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR833## N-[4-(4-chloro-2-hydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR834##
N-[4-(2,3-dihydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR835## N-[3-(2,3-dihydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR836## N-[4-(2,3-dihydroxy- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR837## N-[2-(2,3-dihydroxy-
benzoylamino)-5-methoxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidine-1-yl)- [1,3,5]triazine-2-amine - ##STR838##
N-[4-(2,3-dihydroxy- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR839## N-[4-(2-hydroxy-4-methyl-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR840##
N-[4-(2-hydroxy-4-methyl- benzoylamino)-2-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR841## N-[3-(2-hydroxy-4-methyl-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR842##
N-[4-(2-hydroxy-4-methyl- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR843## N-[2-(2-hydroxy-4-methyl-
benzoylamino)-5-methoxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR844##
N-[3-hydroxy-4-(2-hydroxy- 4-methyl-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR845## N-{4-[2-(3-chloro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR846##
N-[4-(2-phenylcarbamoyl- acetyl)-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR847## N-{4-[2-(4- trifluoromethylsulfanyl)-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR848##
N-{4-[2-(4- trifluoromethylsulfanyl- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR849## N-{4-[2-(4-chloro-
phenylcarbamoyl)-acetyl]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR850##
(3,5-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
phenyl)-(4-nitro-phenyl)- amine - ##STR851## (3,5-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- phenyl)-bis-(4-nitro- phenyl)-amine +
##STR852## N-{4-[2-(3-chloro- phenylcarbamoyl)-acetyl]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR853## N-[4-(2-hydroxy-3-nitro-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR854##
N-[4-(2-hydroxy-3-nitro- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR855## N-[3-(2-hydroxy-3-nitro-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR856##
N-[4-(2-hydroxy-3-nitro- benzoylamino)-2-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR857## N-[2-(2-hydroxy-3-nitro-
benzoylamino)-4-methoxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR858##
N-[2-hydroxy-4-(2-hydroxy- 3-nitro-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR859## N-[4-(2,4-dihydroxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR860##
N-[4-(2,4-dihydroxy- benzoylamino)-2-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR861## N-[3-(2,4-dihydroxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR862##
N-[4-(2,4-dihydroxy- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR863## N-[4-(2,4-dihydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR864##
N-[2-(2,4-dihydroxy- benzoylamino)-5-methoxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR865## N-{3-chloro-4-[(5-chloro-2-
hydroxy-pyridine-3- carbonyl)-amino]phenyl}-
4,6-Bis-(cis-3,5-Diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR866## N-[3-chloro-4-(2-hydroxy- 3,5-diisopropyl-
benzoylamino)-phenyl]-4,6- Bis-(cis-3,5-Diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR867## 1-Hydroxy-naphthalene-2-
carboxylicacid {4-[3- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-5-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
phenylamino]-phenyl}- amide ++ ##STR868## N-{4-[4-((2S,4S)-4-Amino-
2-aminomethyl-pyrrolidin-1- yl)-6-((3R,5S)-3,5-diamino-
piperidin-1-yl)-[1,3,5]triazin- 2-ylamino]-2-hydroxy-
phenyl)-2-(1H-indol-3-yl)-2- oxo-acetamide ++ ##STR869##
N-[3-hydroxy-4-(2-hydroxy- acetylamino)-phenyl]-4,6-
Bis-(cis-3,5-Diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR870## N-{3-fluoro-4-[(2-hydroxy- pyridine-3-carbonyl)-
amino]-phenyl}-4,6-Bis- (cis-3,5-Diamino-piperidin-
1-yl)-[1,3,5]triazine-2- amine ##STR871## N-[4-(2,4-dihydroxy-
benzoyl)-3-hydroxy- phenyl]-4,6-Bis-(cis-3,5-
Diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR872##
N-{3-chloro-4-[(2-hydroxy- 6-methyl-pyridine-3-
carbonyl)-amino]-phenyl}- 4,6-Bis-(cis-3,5-Diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR873##
1-Benzyloxy-naphthalene- 2-carboxylicacid {4-[3-
((3R,5S)-3,5-diamino- piperidin-1-yl)-5-((3S,5R)-
3,5-diamino-piperidin-1-yl)- phenylamino]-phenyl}- amide ++
##STR874## N-[3-Chloro-4-(2-hydroxy- acetylamino)-phenyl]-4,6-
Bis-(cis-3,5-Diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR875## N-{4-[(3,5-dihydroxy- naphthalene-2-carbonyl)-
amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR876## N-{4-[(3,5-dihydroxy-
naphthalene-2-carbonyl)- amino]-3-methyl-phenyl}-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR877## N-{4-[(3,5-dihydroxy-
naphthalene-2-carbonyl)- amino]-2-methyl-phenyl}-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR878## N-{3-[(3,5-dihydroxy-
naphthalene-2-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR879## 5-((3aR,4S,6aS)-2-Oxo- hexahydro-thieno[3,4-
d]imidazol-4-yl)- pentanoicacid {4-[4- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-6-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl)-amide - ##STR880##
N-(4-acetylamino-3- hydroxy-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR881##
N-(4-amina-3-benzyloxy- phenyl)-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR882##
N-[4-(2-hydroxy-5- methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR883##
N-[4-(2-hydroxy-4- methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR884##
N-(3-hydroxy-4- propionylamino-phenyl)- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR885##
N-(4-hexanoylamino-3- hydroxy-phenyl)-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR886## N-[3-hydroxy-4-(7-methyl- octanoylamino)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR887## N-[4-(2-ethyl-
heptanoylamino)-3- hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR888##
N-(4-decanoylamino-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR889## N-(4-benzoylamino-3- hydroxy-phenyl)-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR890## N-[4-(4-amino- benzenesulfonylamino)-3-
hydroxy-phenyl]-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR891## N-[3-hydroxy-4-(4-
pentanoylamino- benzenesulfonylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR892##
N-{4-[4-(2-ethyl- heptanoylamino)- benzenesulfonylamino]-3-
hydroxy-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR893## N-[4-(4-decanoylamino-
benzenesulfonylamino)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR894## N-(4- benzenesulfonylamino-3- hydroxy-phenyl)-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR895## 1-Hydroxy-naphthalene-2- carboxylicacid {4-[4-
((3S,5R)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-phenyl}-amide ++ ##STR896## N-{4-[4-[Bis-(2-amino-
ethyl)-amino]-6-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazin-2-ylamino]-2- hydroxy-phenyl}-2-(1H-
indol-3-yl)-2-oxo- acetamide ++ ##STR897## N-{4-[(1-hydroxy-
naphthalene-2-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR898## N-[4-(4-chloro-2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR899## N-[4-(4-chloro-2-hydroxy- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR900## N-[3-chloro-4-(4-chloro-2-
hydroxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR901##
N-[3,5-dichloro-4-(4-chloro- 2-hydroxy-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-pipeuidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR902## N-[3-bromo-4-(4-chloro-2-
hydroxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR903##
N-[4-(4-chloro-2-hydroxy- benzoylamino)-3-fluoro-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR904## N-[4-(4-chloro-2-hydroxy-
benzoylamino)-3- trifluoromethyl-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR905## N-[4-(4-chloro-2-hydroxy- benzoylamino)-3-
phenylcarbamoyl-phenyl]- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR906##
N-[4-(4-chloro-2-hydroxy- benzoylamino)-3-methoxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR907## N-{4-[(1-hydroxy-
naphthalene-2-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR908## N-{4-[(1-hydroxy- naphthalene-2-carbonyl)-
amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR909## N-[3-chloro-4-(4-chloro-2-
hydroxy-benzoylamino)-5- methyl-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR910## N-[4-(4-fluoro-2-hydroxy- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR911## N-[4-(3,4-difluoro-2-
hydroxy-benzoylamino)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine +
##STR912## N-{4-[4-(1,3-dihydro- isoindol-2-yl)-2-hydroxy-
benzoylamino]-3-hydroxy- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR913##
N-{3-hydroxy-4-[(2- hydroxy-6-trifluoromethyl-
pyridine-3-carbonyl)- amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR914##
N-[3-hydroxy-4-(2-hydroxy- 5-trifluoromethoxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR915##
N-[3-chloro-4-(4-fluoro-2- hydroxy-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine - ##STR916## N-[3-chloro-4-(3,4-difluoro-
2-hydroxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR917##
N-{3-chloro-4-(4-[1,3- dihydro-isoindol-2-yl)-2-
hydroxy-benzoylamino]- phenyl}-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR918## N-{3-chloro-4-[(2-hydroxy- naphthalene-1-carbonyl)-
amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino-
[1,3,5]triazine-2-amine ++ ##STR919## N-{3-chloro-4-[(2-hydroxy-
6-trifluoromethyl-pyridine- 3-carbonyl)-amino]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR920## N-[4-(4-fluoro-2-hydroxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR921##
N-[4-(3,4-difluoro-2- hydroxy-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR922## N-{4-[4-(1,3-dihydro-
isoindol-2-yl)-2-hydroxy- benzoylamino]-phenyl}-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR923## N-{4-[(2-hydroxy-6- trifluoromethyl-pyridine-3-
carbonyl)-amino]-phenyl}- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR924##
N-[4-(2-hydroxy-3,5- diisopropyl-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR925## N-[4-(4-dimethylamino-2-
hydroxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR926##
N-{4-[(3-hydroxy-pyridine- 2-carbonyl)-amino]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR927## N-{4-[(5-chloro-2-hydroxy-
pyridine-3-carbonyl)- amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR928##
N-[4-(5-bromo-2-hydroxy- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR929## N-[3-hydroxy-4-(2-hydroxy-
3,5-diisopropy)- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR930## N-[3-hydroxy-4-(2-hydroxy- 3,4-dimethoxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR931##
N-{3-hydroxy-4-[(2- hydroxy-6-methyl-pyridine- 3-carbonyl)-amino]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine + ##STR932## N-[4-(4-dimethylamino-2-
hydroxy-benzoylamino)-3- hydroxy-phenyl]-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR933## N-[4-(5-chloro-2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR934## N-[4-(5-bromo-2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR935## N-[3-hydroxy-4-(2-hydroxy- 4-methoxy-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR936## N-[3-hydroxy-4-(2-hydroxy-
5-methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR937##
N-[3-hydroxy-4-(2-hydroxy- 4-methyl-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR938## N-[4-(4-chloro-2-hydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidln-1-yl)- [1,3,5]triazine-2-amine ++ ##STR939##
N-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-4-chloro-2- hydroxy-benzamide ++
##STR940## N-[3-(4-chloro-2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR941## 1-Hydroxy-naphthalene-2- carboxylic acid [4-(3,5-
dichloro-2,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
pyridin-4-ylamino)-phenyl]- amide ++ ##STR942##
5-((S)-2-Oxo-hexahydro- thieno[3,4-d]imidazol-4-yl)- pentanoicacid
{4-[4- ((3S,5S)-3-amino-5-azido- piperidin-1-yl)-6-((3S,SR)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazin-2-ylamino]-2-
hydroxy-phenyl}-amide - ##STR943## 1-Hydroxy-naphthalene-2-
carboxylicacid [4-((3S,5R)- 3,5-diamino-piperidin-1-yl)-
phenyl]-amide - ##STR944## N-[3-(2,4-dihydroxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR945##
N-[4-(2,4-dihydroxy- benzoylamino)-3-methyl-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR946## N-[4-(2,4-dihydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1- yl)-[1,3,5]triazine-2-amine ++ ##STR947##
1-Hydroxy-naphthalene-2- carboxylicacid {4-[6-
((3R,5S)-3,5-diamino- piperidin-1-yl)-8-((3S,5R)-
3,5-diamino-piperidin-1-yl)- 7H-purin-2-ylamino]- phenyl}-amide ++
##STR948## 1-Hydroxy-naphthalene-2- carboxylicacid {4-[2-
((3R,5S)-3,5-diamino- piperidin-1-yl)-6-((3S,5R)-
3,5-diamino-piperidin-1- yl)-pyrimidin-4-ylamino]- phenyl}-amide ++
##STR949## N-{3-hydroxy-4-[(2- hydroxy-naphthalene-1-
carbonyl)-amino]-phenyl}- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR950##
N-{4-[(2-hydroxy- naphthalene-1-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine ++
##STR951## N-{4-[(8-hydroxy-quinoline- 7-carbonyl)-amino]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR952## N-[3-hydroxy-4-(2-hydroxy-
3-methoxy-benzoylamino)- phenyl]-4,6-Bis((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ++ ##STR953##
N-[3-chloro-4-(2-hydroxy-3- methoxybenzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR954## N-[4-(2-hydroxy-3-
methoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine + ##STR955##
N-[4-(2-hydroxy-5- trifluoromethoxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
++ ##STR956## N-[4-(2,4-dihydroxy-3,6- dimethyl-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR957## N-[4-(2-hydroxy-
acetylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine - ##STR958##
N-[3-hydroxy-4-(2-1H-indol- 3-yl-acetylamino)-phenyl]-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR959## 1-Hydroxy-naphthalene-2-
carboxylic acid (4-(2,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)-pyridin-4- ylamino)-phenyl]-amide ++ ##STR960##
1-Hydroxy-naphthalene-2- carboxylic acid [4-(4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)-pyridin-2-
ylamino)-phenyl]-amide ++ ##STR961## N-[4-(2-hydroxy-
benzoylamino)-phenyl]-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR962##
N-[4-(5-fluoro-2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR963## N-[4-(3-chloro-2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR964## N-[4-(2-hydroxy-3,5- dimethyl-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR965## N-{4-[(2-hydroxy-6-methyl-
pyridine-3-carbonyl)- amino]-phenyl}-4,6-Bis- ((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR966##
N-[3-hydroxy-4-(2-hydroxy- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR967## N-[4-(5-fluoro-2-hydroxy- benzoylamino)-3-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR968## N-[4-(5-chloro-2-hydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR969##
N-{3-hydroxy-4-[(3- hydroxy-pyridine-2- carbonyl)-amino]-phenyl}-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR970## N-{4-[(3-hydroxy-
quinoxaline-2-carbonyl)- amino]-phenyl}-4,6-Bis-
((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR971## N-[4-(2-hydroxy-5-methyl- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR972## N-{4-[(2-hydroxy-pyridine- 3-carbonyl)-amino]-
phenyl}-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR973## N-[4-(2-hydroxy-3,4-
dimethoxy-benzoylamino)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR974##
N-[4-(2-hydroxy-3-methyl- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR975## N-[3-(4.chloro-2-hydroxy- benzoylamino)-4-hydroxy-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR976## N-[4-(3-chloro-2-hydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR977##
N-{4-[(5-chloro-2-hydroxy- pyridine-3-carbonyl)-
amino]-3-hydroxy-phenyl}- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR978##
N-{3-chloro-4-[(2-hydroxy- pyridine-3-carbonyl)-
amino]-phenyl)-4,6-Bis- ((3R,5S)-3,5-diamino- piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR979## N-[4-(2-hydroxy-4-
propionylamino- benzoylamino)-phenyl]-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR980## N-{4-[2-hydroxy-4-(3- methyl-butyrylamino)-
benzoylamino]-phenyl}-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR981##
N-[4-(4-hexanoylamino-2- hydroxy-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR982## N-{4-[4-(2-ethyl-
hexanoylamino)-2-hydroxy- benzoylamino]-phenyl}-4,6-
Bis-((3R,5S)-3,5-diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR983## N-{4-[2-hydroxy-4-(7- methyl-octanoylamino)-
benzoylamino]-phenyl}-4,6- Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR984##
N-[4-(4-decanoylamino-2- hydroxy-benzoylamino)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR985## N-[4-(2-hydroxy-4-
propionylamino- phenylcarbamoyl)-phenyl]- 4,6-Bis-((3R,5S)-3,5-
diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR986##
N-{4-[2-hydroxy-4-(3- methyl-butyrylamino)-
phenylcarbamoyl]-phenyl}- 4,6-Bis-((3R,5S)-3,5-diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR987##
N-[4-(4-hexanoylamino-2- hydroxy-phenylcarbamoyl)-
phenyl]-4,6-Bis-((3R,5S)- 3,5-diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR988## N-{4-[4-(2-ethyl-
hexanoylamino)-2-hydroxy- phenylcarbamoyl]-phenyl}-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR989## N-{4-[2-hydroxy-4-(7-
methyl-octanoylamino)- phenylcarbamoyl]-phenyl}-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR990## N-[4-(4-decanoylamino-2-
hydroxy-phenylcarbamoyl)- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR991##
N-{3-hydroxy-4-[(2- hydroxy-pyridine-3- carbonyl)-amino]-phenyl}-
4,6-Bis-((3R,5S)-3,5- diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ++ ##STR992## N-[4-(5-bromo-2-hydroxy-
benzoylamino)-3-hydroxy- phenyl]-4,6-Bis-((3R,5S)-
3,5-diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR993##
N-{4-[4-((2S,4S)-4-Amino- 2-aminomethyl-pyrrolidin-1-
yl)-6-((3R,5S)-3,5-diamino- piperidin-1-yl)-[1,3,5]triazin-
2-ylamino]-2-hydroxy- phenyl}-2,4-dihydroxy- benzamide ++
##STR994## N-{3-hydroxy-4-[(8- hydroxy-quinoline-7-
carbonyl)-amino]-phenyl}- 4,6-Bis-(cis-3,5-Diamino-
piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR995##
N-{3-hydroxy-4-[(4- hydroxy-quinoline-3- carbonyl)-amino]-phenyl}-
4,6-Bis-(cis-3,5-Diamino- piperidin-1-yl)- [1,3,5]triazine-2-amine
##STR996## N-[4-[-(2,4-dihydroxy-3- methyl-benzoylamino)-
phenyl]-4,6-Bis-(cis-3,5- Diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine ##STR997## N-[4-(2-hydroxy-6-
methoxy-benzoylamino)- phenyl]-4,6-Bis-(cis-3,5-
Diamino-piperidin-1-yl)- [1,3,5]triazine-2-amine ##STR998##
N-{3-chloro-4-[(4-hydroxy- quinoline-3-carbonyl)-
amino]-phenyl}-4,6-Bis- (cis-3,5-Diamino-piperidin-
1-yl)-[1,3,5]triazine-2- amine ##STR999## N-[4-(2,4-dihydroxy-3-
methyl-benzoylamino)-3- hydroxy-phenyl]-4,6-Bis-
(cis-3,5-Diamino-piperidin- 1-yl)-[1,3,5]triazine-2- amine
##STR1000## N-{3-chloro-4-[(8-hydroxy- quinoline-7-carbonyl)-
amino]-phenyl}-4,6-Bis- (cis-3,5-Diamino-piperidin-
1-yl)-[1,3,5]triazine-2- amine ##STR1001##
N-[3-hydroxy-4-(2-hydroxy- 6-methoxy-benzoylamino)-
phenyl]-4,6-Bis-(cis-3,5- Diamino-piperidin-1-yl)-
[1,3,5]triazine-2-amine
* * * * *