Indian Patents
Title of Invention

"INDOLE COMPOUNDS OF FORMULA (I)"
Abstract An isomer, enantiomer, diastereoisomer or tautomer of a compound represented by formula I: Wherein R2, R3, M1, M2, M3, M4, A, B, Z, L, Y°, Y1 are as herein described.
Full Text The present invention relates to indole compounds of formula (I).
TECHNICAL FIELD OF THE INVENTION
The invention relates to inhibitors of RNA dependent RNA polymerases, particularly those viral polymerases within the Flaviviridae family, more particularly to HCV polymerase.
BACKGROUND OF THE INVENTION
About 30,000 new cases of hepatitis C virus (HCV) infection are estimated to, occur in the United States each year (Kolykhalov, A.A.; Mihalik, K.; Feinstone, S.M.; Rice, CM.; 2000; J. Virol. 74: 2046-2051). HCV is not easily cleared by the hosts' immunological defences; as many as 85% of the people infected with HCV become chronically infected. Many of thes^ persistent infections result in chronic liver disease, including cirrhosis and hepatocellular carcinoma (Hoofnagle, J.H.; 1997; Hepatology 26; 15S-20S*). There are an estimated 170 million HCV carriers world-wide, and HCV-associated end-stage liver disease is now the leading cause of liver transplantation. In the United States alone, hepatitis C is responsible for 8,000 to 10,000 deaths annually. Without effective intervention, the number is expected to triple in the next 10 to 20 years. There is no vaccine to prevent HCV infection. Prolonged treatment of chronically infected patients with interferon or interferon and ribavirin is the only currently approved therapy, but it achieves a sustained response in fewer than 50% of cases (Lindsay, K.L.; 1997; Hepatology 26: 71S-77S*, and Reichard, O.; Schvarcz, R.; Weiland, O.; 1997 Hepatology 26:108S-111S*).
HCV belongs to the family Flaviviridae, genus hepacivirus, which comprises three genera of small enveloped positive-strand RNA viruses (Rice, CM.; 1996; "Flaviviridae: the viruses and their replication"; pp. 931-960 in Fields Virology, Fields, B.N.; Knipe, D.M.; Howley, P.M. (eds.); Lippincott-Raven Publishers, Philadelphia Pa. *). The 9.6 kb genome of HCV consists of a long open reading frame (ORF) flanked by 5' and 3' non-translated regions (NTR's). The HCV 5' NTR is 341 nucleotides in length and functions as an internal ribosome entry site for cap-independent translation initiation (Lemon, S.H.; Honda, M.; 1997; Semin. Virol. 8: 274-288). The HCV polyprotein is cleaved co- and post-translationally into at least 10 individual polypeptides (Reed, K.E.; Rice, CM.; 1999; Curr. Top. Microbiol. Immunol. 242: 55-84*). The structural proteins result from signal peptidases in the N-
terminal portion of the polyprotein. Two viral proteases mediate downstream
cleavages to produce non-structural (NS) proteins that function as components of
the HCV RNA replicase. The NS2-3 protease spans the C-terminal half of the NS2
and the N-terminal one-third of NS3 and catalyses cis cleavage of the NS2/3 site.
The same portion of NS3 also encodes the catalytic domain of the NS3-4A serine
protease that cleaves at four downstream sites. The C-terminal two-thirds of NS3 is
highly conserved amongst HCV isolates, with RNA-binding, RNA-stimulated
NTPase, and RNA unwinding activities. Although NS4B and the NS5A
phosphoprotein are also likely components of the replicase, their specific roles are
unknown. The C-terminal polyprotein cleavage product, NS5B, is the elongation
subunit of the HCV replicase possessing RNA-dependent RNA polymerase (RdRp)
activity (Behrens, S.E.; Tomei, L; DeFrancesco, R.; 1996; EMBOJ. 15:12-22*; and
Lohmann, V.; Korner, F.; Herian, U.; Bartenschlager, R.; 1997; J. Virol. 71: 8416-
8428*). It has been recently demonstrated that mutations destroying NS5B activity
abolish infectivity of RNA in a chimp model (Kolykhalov, A.A.; Mihalik, K.; Feinstone,
S.M.; Rice, C.M.; 2000; J. Virol. 74: 2046-2051*).
The development of new and specific anti-HCV treatments is a high priority, and
virus-specific functions essential for replication are the most attractive targets for
drug development. The absence of RNA dependent RNA polymerases in mammals,
and the fact that this enzyme appears to be essential to viral replication, would
suggest that the NS5B polymerase is an ideal target for anti-HCV therapeutics.
WO 00/06529, WO 00/13708, WO 00/10573, WO 00/18231, WO 01/47883,
WO 01/85172 and WO 02/04425 report inhibitors of NS5B proposed for treatment of
HCV.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a novel series of compounds
having good to very good inhibitory activity against HCV polymerase.
Further objects of this invention arise for the one skilled in the art from the following
description and the examples.
In a first aspect of the invention, there is provided an isomer, enantiomer,
diastereoisomer or tautomer of a compound, represented by formula I:
(Figure Removed) wherein:
either A or B is N and the other B or A is C, wherein — between two C-atoms
represents a double bond and — between a C-atom and a N-atom represents a
single bond,
the group -C(=Y1)-Z is covalently linked to either M2 or M3,
M1 is CR4a,
M2 or M3, when not linked to -C(=Y1)-Z, is CR5,
M4 is CR4b,
and in addition one or two of the groups selected from M1, M2, M3 and M4 may also
be N, with the proviso that the group M2 or M3 to which -C(=Y1)-Z is linked is an Catom,
Sp is a spacer group selected from -(CR51R52)ki~, wherein
R51, R52are independently H, (d.6)alkyl, (C3.7)cycloalkyl or (d.3)alkyl-
(C3.7)cycloalkyl, or
R51 and R52are covalently bonded together and to the carbon-atom to which
they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6 or 7-
membered unsaturated cyclic system whereby the 5, 6 or 7-membered
saturated or unsaturated cyclic system optionally contains 1 to 3 heteroatoms
selected from N, O or S;
said alkyl, cycloalkyl, alkyl-cycloalkyl or cyclic system being optionally
substituted by halogen, hydroxy, (d-e)alkoxy, cyano, amino, -NH(d.4-alkyl)
and/or -N(d.4-alkyl)2;
Y° is O, S, NR11 or CR12R13, wherein
R11, R12, R13are each independently defined as R°;
R13 may also be COOR° or S02RC;
wherein Rc and each R° is optionally substituted with R150;
or both R12 and R13 are covalently bonded together and to the carbon-atom to
which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6
or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered
saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms
selected from N, O or S; said cyclic systems being optionally substituted with
R150;
L is d.6alkyl, (C3.6)cycloalkyl, d.6alkyl-(C3.6)cycloalkyl, (C2-6)alkenyl, aryl,
(d-6alkyl)aryl, Het, (d.6)alkyl-Het, all of which being optionally substituted
with R60;
or Y° and L are covalently bonded to form a 5, 6, 7 or 8-membered mono- or a 8, 9,
10 or 11-membered bicyclic group which is optionally unsaturated or aromatic
and which optionally contains 1, 2 or 3 heteroatoms selected from N, O and
S, wherein the mono- or bicyclic group is optionally substituted with R60;
or if Y° is CR12R13, then L may also be H;
or if Y° is O, then L may also be ORC,
wherein Rc is optionally substituted with R60;
or if Y° is O, S or NR11, then L may also be N(RN2)RN1, NRN3-N(RN2)RN1,
NRN3-NRN2-CO-RC, NRN4-NRN3-CO-N(RN2)RN1, NRN2-SO2-RC,
NRN2-CO-RC, NRN3-CO-N(RN2)RN1 or N(RN1)OR°;
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2
and/or RN3, and Rc and R° being optionally substituted with R60;
or if Y° is O or S, then L may also be OR6a or N(R5a)R6a, wherein R5a is defined as
RN2,
and wherein R6a is:
(Figure Removed) wherein R7aand R8aare each independently defined as R°, COOR° or
CON(RN2)RN1, wherein said R° is optionally substituted with R60; or
R7a and R8a are covalently bonded together to form a (C3.7)cycloalkyl or a 4,
5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from
O, N, and S; and when L is N(R5a)R6a, either of R7a or R8a may be covalently
bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle,
wherein said cycloalkyl or heterocycle being optionally substituted by R150;
and
W1 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
(Figure Removed) wherein the alkylene and alkenylene groups according to b), c) and d) may
be substituted with (d.3)alkyl;
Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or
R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered
heterocycle;
Q1 is aryl, Het, (d.6)alkyl-aryl, (d.6)alkyl-Het, (d.6)alkyl-CONH-aryl or (d-e)
alkyl-CONH-Het, all of which being optionally substituted with R60;
Y1 is O, S or NR14, wherein R14 is H or (Cm) alkyl;
Z is defined as
(Figure Removed) wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2,
and/or RN3, being optionally substituted with R60;
or Z is OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
(Figure Removed) wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1 respectively;
and
Q2 is aryl, Met, (Ci.6)alkyl-aryl, (d.6)alkyl-Het, (d-6)alkyl-CONH-aryl or (d-e)
alkyl-CONH-Het, all of which being optionally substituted with R60
or Q2 is R160
or Q2 is selected from the group consisting of O-Ci.4-alkyl, S-Ci.4-alkyl, d-4-
alkyl, C2-4-alkenyl and C2-4-alkynyl, all of which being optionally substituted
with R160; and
R2 is selected from: halogen or R21, wherein R21 is aryl or Met, said R21 is optionally
substituted with R150;
R3 is selected from (d-e)alkyl, (C3.7)cycloalkyl, (Ci.3)alkyl-(C3.7)cycloalkyl,
(C5.7)cycloalkenyl, (d-3)alkyl-(C5.7)cycloalkenyl, (C6-io)bicycloalkyl, (d.3)alkyl-
(C6-io)bicycloalkyl, (C6-io)bicycloalkenyl, (d-3)alkyl-(C6-io)bicycloalkenyl, HCy
or (d.3)alkyl-HCy,
wherein HCy is a saturated or unsaturated 4 to 7-membered heterocyclic
group with 1 to 3 heteroatoms selected from O, S and N;
said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, HCy and
alkyl-HCy being optionally substituted with from 1 to 4 substituents selected
from: a) halogen;
b) (d-e)alkyl optionally substituted with:
-1 to 3 substituents selected from halogen;
- OR31 or SR31 wherein R31 is H, (d.6alkyl), (C3.7)cycloalkyl or
(d.3)alkyl-(C3.7)cycloalkyl; or
- N(R32)2 wherein each R32 is independently H, (d.6)alkyl,
(C3-7)cycloalkyl or (d-3)alkyl-(C3.7)cycloalkyl; or both R32 are
covalently bonded together and to the nitrogen to which they
are attached to form a 5, 6 or 7-membered saturated
heterocycle;
c) OR33 or SR33 wherein R33 is H, (Ci.6)alkyl, (C3.7)cycloalkyl or
(Ci .3)alkyl-(C3.7)cycloalkyl;
d) N(R35)2 wherein each R35 is independently H, (d.6)alkyl,
(C3.7)cycloalkyl or (d-3)alkyl-(C3.7)cycloalkyl; or both R35 are covalently
bonded together and to the nitrogen to which they are attached to
form a 5, 6 or 7-membered saturated heterocycle;
R4a, R4b, R5 each are independently H or defined as R150;
R60 is each defined as 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: OPO3H, NO2, cyano, azido,
C(=NH)NH2> C(=NH)NH(d.6)alkyl orC(=NH)NHCO(d.6)alkyl, SO3H; and
-1 to 3 substituents selected from:
a) (d-6) alkyl, (C3.7)cycloalkyl, C3.7 spirocycloalkyl optionally containing 1 or 2
heteroatoms selected from N, O and S; (C2.6)alkenyl, (C2.8)alkynyl,
(d.6)alkyl-(C3.7)cycloalkyl, all of which optionally being substituted with
R150;
b) OR0;
c) OC(O)R°;
d) SR°, SO2RC, SO2N(RN2)RN1, SO2N(RN2)C(O)RC, CONRN3SO2N(RN2)RN1,
or CONRN2SO2RC;
e) N(RN2)RN1, N(RN2)COORC, N(RN2)SO2RC or N(RN1)R°;
f) N(RN2)CORC;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORC, N(RN3)COCOOR°orN(RN3)COCON(RN2)RN1;
i) COR°;
j) COOR°;
k) CON(RN2)RN1;
I) aryl, Met, (d.4alkyl)aryl or (d.4alkyl)Het, all of which optionally being
substituted with R150;
wherein said RN1, R° and R° are each independently optionally substituted
with R150as defined,
I150 is each defined as 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: OPO3H, NO2, cyano, azido,
C(=NH)NH2, C(=NH)NH(d.6)alkyl or C(=NH)NHCO(d-6)alkyl; and
-1 to 3 substituents selected from:
a) (d-e) alkyl, (C3.7)cycloalkyl, C3.7 spirocycloalkyl optionally containing 1 or 2
heteroatoms selected from N, O and S; (C2.6)alkenyl, (C2-8)alkynyl,
(Ci-3)alkyl-(C3.7)cycloalkyl, all of which optionally substituted with R160;
b) OR0;
c) OC(O)R°;
d) SR°, SO2RC, SO2N(RN2)RN1, SO2N(RN2)C(O)RC or CON(RN2)SO2RC;
e) N(RN2)RN1, N(RN2)COORC, N(RN2)SO2RC, or N(RN1)R°;
f) N(RN2)CORC;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORC, N(RN3)COCOOR°, N(RN3)COCON(RN2)OH,
N(RN3)COCON(RN2)OC1.4-alkyl or N(RN3)COCON(RN2)RN1;
i) COR°;
j) COOR°;
k) tetrazole, triazole, CONRN3-SO2N(RN2)RN1; or CON(RN2)RN1;
wherein said RN1, Rc and/or R° are optionally substituted with R160 as
defined;
I160 is each defined as 1, 2 or 3 substituents independently selected from:
-1, 2 or 3 fluorine substituents; and
- one of each substituent selected from tetrazole, triazole, chlorine, bromine,
iodine, CN, nitro, d^alkyl, CF3, COOR161, SO3H, SR161, SCF3, SO2R163,
OR161, OCF3, N(R162)2, S02N(R162)2, NR162SO2RC, NR162COR162, CON(R162)2,
-NR161-CO-COOR161, -NR161-CO-CO(NR162)2, -CONR161SO2RC, CONR161-
SO2N(R162)2 or -SO2-NR161-CORC, wherein R161, R163and each R162is
independently (d.4)alkyl, (C3.7)cycloalkyl or (d_3)alkyl-(C3.7)cycloalkyl; and
R161 and each R162 may each independently also be H; or both R162 are
covalently bonded together and to the nitrogen to which they are attached to
form a 5, 6 or 7-membered saturated heterocycle;
R°, Rcare independently defined as (d-e)alkyl, (C3.6)cycloalkyl, (d.4)alkyl-
(C3.6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (Ci.4)alkyl-aryl and (d-4)alkyl-Het; and
R° may also be H;
RN1 is independently selected from H, (d^alkyl, (C3.7)cycloalkyl, (d-4)alkyl-
(C3.6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1.4)alkyl-aryl, (d-4)alkyl-Het; or
RN2 RN3( RN4 are independently H] CH3, (C2.6)alkyl, (C3.6)cycloalkyl, (d.4)alkyl-
(C3.6)cycloalkyl; wherein said alkyl, cycloalkyl or alkylcycloalkyl is optionally
substituted with hydroxy, halogen, carboxy, d.6-alkoxycarbonyl, d.6-alkyl,
d-e-alkoxy, amino, -NH(d-4-alkyl) and/or -N(d.4-alkyl)2; and wherein said
CH3 is optionally substituted with halogen, carboxy or d.6-alkoxycarbonyl;
and
in the case
a) of a group N(RN2)RN1 the substituents RN2 and RN1; or
b) of a group NRN3-N(RN2)RN1 the substituents RN3 and RN1, or RN2 and RN1;
may be covalently bonded together to form a 4-, 5-, 6- or 7-membered
saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11-
membered N-containing heterobicycle each may have additionally from 1 to 3
heteroatoms selected from O, N, and S;
wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4
heteroatoms selected from O, N and S, or a 8-, 9-, 10- or 11-membered
heterobicycle having 1 to 5 heteroatoms selected from O, N and S;
or a salt thereof.
Included within the scope of this invention are compounds of the formula (I) as
described hereinbefore, to which a "detectable label", "affinity tag" or "photoreactive
group" is linked.
The compounds according to this invention generally show a good to very good
inhibitory activity against HCV polymerase. In particular compounds according to this
invention inhibit RNA synthesis by the RNA dependent RNA polymerase of HCV,
especially of the enzyme NS5B encoded by HCV. A further advantage of compounds
provided by this invention is their low to very low or even non-significant activity
against other polymerases.
In a second aspect of the invention, there is provided a use of a compound of
formula I according to this invention, or a pharmaceutically acceptable salt thereof,
as an HCV polymerase inhibitor.
In a third aspect of the invention, there is provided a use of a compound of .the
formula I according to this invention, or a pharmaceutically acceptable salt thereof,
as an inhibitor of RNA dependent RNA polymerase activity of the enzyme NS5B,
encoded by HCV.
In a fourth aspect of the invention, there is provided a use of a compound of the
formula I according to this invention, or a pharmaceutically acceptable salt thereof,
as an inhibitor of HCV replication.
In a fifth aspect of the invention, there is provided a method of treating or preventing
HCV infection in a mammal, comprising administering to the mammal an effective
amount of a compound of formula I according to this invention, or a pharmaceutically
acceptable salt thereof.
In a sixth aspect of the invention, there is provided a method of treating or preventing
HCV infection in a mammal, comprising administering to the mammal an effective
amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in
combination with another antiviral agent.
In a seventh aspect of the invention, there is provided a pharmaceutical composition
for the treatment or prevention of HCV infection, comprising an effective amount of a
compound of formula I according to this invention, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
According to a specific embodiment, the pharmaceutical compositions of this
invention comprise a therapeutically effective amount of one or more antiviral agents.
Examples of antiviral agents include, ribavirin and amantadine.
According to a further specific embodiment, the pharmaceutical compositions of this
invention comprise an other anti-HCV agent as an antiviral agent.
According to a more specific embodiment, the pharmaceutical compositions of this
invention comprise an additional immunomodulatory agent as an other anti-HCV
agent. Examples of additional immunomodulatory agents include but are not limited
to, a-, P-, 5- Y-, tau- and w-interferons.
According to another more specific embodiment, the pharmaceutical compositions of
this invention comprise another inhibitor of HCV polymerase as an other anti-HCV
agent.
According to another more specific embodiment, the pharmaceutical compositions of
this invention comprise an inhibitor of HCV NS3 protease as an other anti-HCV
agent.
According to yet another more specific embodiment, the pharmaceutical
compositions of this invention comprise an inhibitor of another target in the HCV life
cycle as an other anti-HCV agent. Examples of such other targets are HCV helicase,
HCV NS2/3 protease or HCV IRES.
In an eighth aspect of the invention, there is provided a use of a compound of
formula I according to this invention, or of a pharmaceutically acceptable salt thereof,
for the manufacture of a medicament for the treatment and/or the prevention of a
Flaviviridae viral infection, preferably an HCV infection.
In a ninth aspect of the invention, there is provided an intermediate compound
represented by the formula 2(v) and 2'(v)
(Figure Removed) wherein Y°, L, Sp, R° and R3 are defined as hereinbefore; and
X isCI, Brorl.
Furthermore in a tenth aspect of this invention an intermediate compound
represented by the formula
HOOC
and/or
wherein Y , Z, R , R , R , R and R are defined as hereinbefore;
not including compounds P1, P2, P3 and P4 of the following formula
HOOC.
Nwherein
(Figure Removed) In a eleventh aspect of the invention, there is provided a use of the intermediate
compounds as defined above for the manufacture of compounds according to this
invention.
A twelfth aspect of this invention is related to a process for producing compounds of
formula 1.1
COOFT
wherein Y°, L, Sp, R°, R2 and R3 are defined as before,
comprising the reaction of an indole derivative of the formula 2(iv)
COOFT 2(iv)
wherein R° and R3 are defined as hereinbefore and X is Cl, Br or I; according to one
of the following methods a), b), c) or d):
1.) cross-coupling of the indole derivative of the formula 2(iv) with an
organometallic species such as, but not limited to
i) a stannane derivative of the formula R2-SnR'3, wherein R2 is
defined as hereinbefore and R' is a C^-alky! or aryl group; or
ii) a boronic acid derivative R2-B(OH)2 and R2-B(OR')2, wherein R2
and R' are defined as hereinbefore;
under transition metal catalysis to yield an indole derivative of the
formula 2(vii)
COOFT
wherein R°, R2 and R3 are defined as hereinbefore;
2.) the indole derivative of the formula 2(vii) is further processed by Nalkylation
using the electrophilic reagent X-Sp-C(=Y°)-L, wherein X is
a leaving group, like e.g. Cl, Br, I, mesylate, triflate, tosylate; and Sp,
Y° and L are as defined hereinbefore, in the presence of a strong
base, yielding the product of the formula 1.1; or
b) 1.) halogen-metal exchange of the indole derivative of the formula 2(iv)
using an alkyllithium reagent or lithium metal; and
2.) trans-metallation of the reaction product yielded by the previous step
using:
i) a trialkyl tin halide;
ii) a trialkyl borate; or
iii) zinc chloride; and
3.) cross-coupling of the reaction product yielded by the previous step
using R2-X, wherein R2 is defined as hereinbefore and X is F, Cl, Br, I
or triflate, under transition metal catalysis to yield an indole derivative
of the formula 2(vii) as defined hereinbefore; and
4.) the indole derivative of the formula 2(vii) is further processed by Nalkylation
using the electrophilic reagent X-Sp-C(=Y°)-L, wherein X is
a leaving group, like e.g. Cl, Br, I, mesylate, triflate, tosylate; and Sp,
Y° and L are as defined hereinbefore, in the presence of a strong
base, yielding the product of the formula 1.1; or
c) 1.) N-alkylation of the indole derivative of the formula 2(iv) using the
electrophilic reagent X-Sp-C(=Y°)-L, wherein X is a leaving group, like
e.g. Cl, Br, I, mesylate, triflate, tosylate; and Sp, Y° and L are as
defined hereinbefore, in the presence of a strong base, yielding the
indole derivative of the formula 2(v)
2(v)
COOFT
2.) 1.) halogen-metal exchange of the derivative of the formula 2(v)
using an alkyllithium reagent or lithium metal; and
2.) trans-metallation of the reaction product according to the
previous step using:
i) a trialkyl tin halide;
ii) alkyl borate; or
iii) zinc chloride; and
3.) cross-coupling of the reaction product according to the
previous step using R2-X, wherein R2 is defined as
hereinbefore and X is F, Cl, Br, I or triflate, under transition
metal catalysis yielding the product of the formula 1.1; or
d) 1.) N-alkylation of the indole derivative of the formula 2(iv) using the
electrophilic reagent X-Sp-C(=Y°)-L, wherein X is a leaving group, like
e.g. Cl, Br, I, mesylate, triflate, tosylate; and Sp, Y° and L are as
defined hereinbefore, in the presence of a strong base, yielding the
indole derivative of the formula 2(v) as defined hereinbefore; and
2.) cross-coupling of the indole derivative of the formula 2(v) with an
organometallic species such as, but not limited to
i) a stannane derivative of the formula R2-SnR'3, wherein R2 is
efined as hereinbefore and R' is a Ci.8-alkyl or aryl group; or
ii) a boronic acid derivative R2-B(OH)2 and R2-B(OR')2, wherein R2
and R' are defined as hereinbefore;
under transition metal catalysis yielding the product of the formula 1.1.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The following definitions apply unless otherwise noted:
As used herein, the term (Ci.n) alkyl or d.n-alkyl, wherein n is an integer, either alone
or in combination with another radical, are intended to mean acyclic straight or
branched chain alkyl radicals containing 1 to n carbon atoms respectively. Examples
of such radicals include methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, 1-
methylpropyl, 2-methylpropyl, 1,1-dimethylethyl (tert.-butyl), n-pentyl, etc.. In the
following the term Me denotes a methyl group.
If an alkyl group is substituted by halogen, it is preferably mono-, di- or trisubstituted
with fluorine or monosubstituted by chlorine or bromine. Preferred alkyl-groups which
are trisubstituted with fluorine have a terminal CF3 group.
As used herein, the term (C2.n) alkenyl, wherein n is an integer, either alone or in
combination with another radical, is intended to mean an unsaturated, acyclic
straight chain radical containing two to n carbon atoms, at least two of which are
bonded to each other by a double bond. Examples of such radicals are ethenyl
(vinyl), 1-propenyl, 2-propenyl, 1-butenyl, etc..
As used herein, the term (C2.n) alkynyl, wherein n is an integer, either alone or in
combination with another group, is intended to mean an unsaturated, acyclic straight
chain radical containing 2 to n carbon atoms, at least two of which are bonded to
each other by a triple bond. Examples of such radicals are ethynyl, 1-propynyl, 2-
propynyl, etc.
As used herein, the term (C3.n)cycloalkyl, wherein n is an integer, either alone or in
combination with another radical, means a cycloalkyl radical containing from three to
n carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
As used herein, the term (C5.n)cycloalkenyl, wherein n is an integer, either alone or in
combination with another radical, means an unsaturated cyclic radical containing five
to n carbon atoms. Examples are cyclopentenyl and cyclohexenyl.
As used herein the term (Ci.n)alkyl-(C3.m)cycloalkyl, wherein n and m are integers,
either alone or in combination with another radical, means a branched or straight
chain alkyl radical having 1 to n C-atoms to which a cycloalkyl radical containing from
three to m C-atoms is covalently bonded. Preferably the alkyl radical is a straight
chain and the cycloalkyl radical is linked to its terminal C-atom. Examples of
(d-sJalkyKCa^cycloalkyl include cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl,
2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl,
3-cyclopentylpropyl, 3-cyclohexylpropyl, etc..
As used herein, the terms alkyl-aryl, alkyl-HCy, alkyl-Hetaryl, alkyl-Het, etc. mean an
alkyl radical to which an aryl, HCy, Hetaryl, Met group is bonded, respectively.
Examples of (Ci_3)alkyl-aryl are benzyl (phenylmethyl), phenylethyl and phenylpropyl.
As used herein, the term "carboxy protecting group" (CPG) defines protecting
groups that can be used during synthetic transformation and are listed in Greene,
"Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and
"The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York
(1981), the disclosures of which are hereby incorporated by reference.
A-carboxyl group is usually protected as an ester that can be cleaved to give the
carboxylic acid. Protecting groups that can be used include: 1) alkyl esters such as
methyl, trimethylsilylethyl and f-butyl, 2) aralkyl esters such as benzyl and substituted
benzyl, or 3) esters that can be cleaved by mild base treatment or mild reductive
means such as trichloroethyl and phenacyl esters.
As used herein, the term "aryl" either alone or in combination with another radical
means a 6- or 10-membered aryl, i.e. an aromatic radical containing six or ten
carbon atoms, for example phenyl, 1-naphthyl or 2-naphthyl. The most preferred
meaning of aryl is phenyl.
As used herein the term heteroatom means O, S or N.
As used herein, the term "heterocycle", either alone or in combination with another
radical, means a monovalent radical derived by removal of a hydrogen from a four-,
five-, six-, or seven-membered saturated or unsaturated (including aromatic)
heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen
and sulfur. Examples of such heterocycles include, but are not limited to, azetidine,
pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, hydantoin, diazepine,
1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine,
homopiperazine, 1 ,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-Noxide
or pyrimidine, or the following heterocycles:
N-N
As used herein, the term "9- or 10-membered heterobicycle" or "heterobicycle" either
alone or in combination with another radical, means a heterocycle as defined above
fused to one or more other cycle, be it a heterocycle or any other cycle. Examples of
such heterobicycles include, but are not limited to, indole, benzimidazole,
thiazolo[4,5-b]-pyridine, quinoline, orcoumarin, or the following:
, or
As used herein, the term "Met" defines a 4-, 5-, 6- or 7-membered heterocycle
having 1 to 4 heteroatoms selected from O, N and S, which may be saturated,
unsaturated or aromatic, or a 8-, 9-, 10- or 11-membered heterobicycle having 1 to 5
heteroatoms wherever possible, selected from O, N and S, which may be saturated,
unsaturated or aromatic, unless specified otherwise.
As used herein, the term "HCy" defines a saturated or unsaturated 4-, 5-, 6- or 7-
membered monocyclic heterocycle having 1 to 3 heteroatoms selected from O, N
and S, unless specified otherwise.
As used herein, the term "Hetaryl" defines an aromatic 5- or 6-membered
monocyclic heterocycle having 1 or 2 heteroatoms selected from O, N and S, or a 9-
or 10-membered aromatic heterobicycle having 1 to 4 heteroatoms selected from O,
N, and S, unless specified otherwise.
As used herein, the term "halo" means a halogen atom and includes fluorine,
chlorine, bromine and iodine.
As used herein, the term "OH" refers to a hydroxyl group. It is well known to one
skilled in the art that hydroxyl groups may be substituted by functional group
equivalents. Examples of such functional group equivalents that are contemplated
by this invention include, but are not limited to, ethers, sulfhydryls, and primary,
secondary or tertiary amines.
As used herein, the term "SH" refers to a sulfhydryl group. It is intended within the
scope of the present invention that, whenever a "SH" or "SR" group is present, it
can also be substituted by any other appropriate oxidation state such as SOR, S02R,
orSO3R.
It is intended that the term "substituted" when applied in conjunction with a radical
having more than one moiety such as Ci.6alkyl-aryl, or Ci.6alkyl-Het, sucn
substitution applies to both moieties i.e. both the alkyl and aryl or Het moieties can
be substituted with the defined substituents.
As used herein, the term "COOH" refers to a carboxylic acid group. It is well known
to one skilled in the art that carboxylic acid groups may be substituted by functional
group equivalents. Examples of such functional group equivalents that are
contemplated by this invention include, but are not limited to, esters, amides, imides,
boronic acids, tetrazoles, triazoles, N-acylsulfonyldiamides (RCONHSO2NR2), and Nacylsulfonamides
(RCONHSO2R).
As used herein, the term "functional group equivalent" is intended to mean an
element or a substituted derivative thereof, that is replaceable by another element
that has similar electronic, hybridization or bonding properties.
As used herein, the term "metal catalyst" is intended to mean a metal such as
palladium (0) or palladium (2) for use in a cross-coupling reaction. Examples of such
palladium catalysts include, but are not limited to, Pd(Ph3)4, Pd/C, Pd(OAc)2, PdCI2,
and the like. Alternative metals that can catalyze cross-coupling reactions include,
but are not limited to, complexes of Ni, Rh, Ru and Ir, like for example: Ni(acac)2,
Ni(OAc)2, or NiCI2.
The term "detectable label" refers to any group that may be linked to the polymerase
or to a compound of the present invention such that when the compound is
associated with the polymerase target, such label allows recognition either directly or
indirectly of the compound such that it can be detected, measured and quantified.
Examples of such "labels" are intended to include, but are not limited to, fluorescent
labels, chemiluminescent labels, colorimetric labels, enzymatic markers, radioactive
isotopes and affinity tags such as biotin. Such labels are attached to the compound
or to the polymerase by well known methods.
The term "affinity tag" means a ligand (that is linked to the polymerase or to a
compound of the present invention) whose strong affinity for a receptor can be used
to extract from a solution the entity to which the ligand is attached. Examples of
such ligands include biotin or a derivative thereof, a histidine polypeptide, a
polyarginine, an amylose sugar moiety or a defined epitope recognizable by a
specific antibody. Such affinity tags are attached to the compound or to the
polymerase by well-known methods.
The term "photoreactive group" means a group that is transformed, upon activation
by light, from an inert group to a reactive species, such as a free radical. Examples
of such groups include, but are not limited to, benzophenones, azides, and the like.
The term "salt thereof" means any acid and/or base addition salt of a compound
according to the invention; preferably a pharmaceutically acceptable salt thereof.
The term "pharmaceutically acceptable salt" means a salt of a compound of formula
(I) which is, within the scope of sound medical judgment, suitable for use in contact
with the tissues of humans and lower animals without undue toxicity, irritation,
allergic response, and the like, commensurate with a reasonable benefit/risk ratio,
generally water or oil-soluble or dispersible, and effective for their intended use. The
term includes pharmaceutically-acceptable acid addition salts and pharmaceuticallyacceptable
base addition salts. Lists of suitable salts are found in, e.g., S.M. Birge
et al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated by reference
in its entirety.
The term "pharmaceutically-acceptable acid addition salt" means those salts which
retain the biological effectiveness and properties of the free bases and which are not
biologically or otherwise undesirable, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid,
phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic
acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,
butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid,
digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric
acid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic
acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic
acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic
acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,
pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid,
pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, ptoluenesulfonic
acid, undecanoic acid, and the like.
The term "pharmaceutically-acceptable base addition salt" means those salts which
retain the biological effectiveness and properties of the free acids and which are not
biologically or otherwise undesirable, formed with inorganic bases such as ammonia
or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as
sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese,
aluminum, and the like. Particularly preferred are the ammonium, potassium,
sodium, calcium, and magnesium salts. Salts derived from pharmaceuticallyacceptable
organic nontoxic bases include salts of primary, secondary, and tertiary
amines, quaternary amine compounds, substituted amines including naturally
occurring substituted amines, cyclic amines and basic ion-exchange resins, such as
methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine,
triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine,
diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,
lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, Nethylpiperidine,
tetramethylammonium compounds, tetraethylammonium
compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine,
N,N'-dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred
organic nontoxic bases are isopropylamine, diethylamine, ethanolamine,
trimethylamine, dicyclohexylamine, choline, and caffeine.
The term "antiviral agent" as used herein means an agent (compound or biological) that
is effective to inhibit the formation and/or replication of a virus in a mammal. This
includes agents that interfere with either host or viral mechanisms necessary for the
formation and/or replication of a virus in a mammal. Antiviral agents include, for
example, ribavirin, amantadine, VX-497 (merimepodib, Vertex Pharmaceuticals), VX-
498 (Vertex Pharmaceuticals), Levovirin, Viramidine, Ceplene (maxamine), XTL-001
and XTL-002 (XTL Biopharmaceuticals).
The term "other anti-HCV agent" as used herein means those agents that are
effective for diminishing or preventing the progression of hepatitis C related
symptoms of disease. Such agents can be selected from: immunomodulatory
agents, inhibitors of HCV NS3 protease, other inhibitors of HCV polymerase or
inhibitors of another target in the HCV life cycle.
The term "immunomodulatory agent" as used herein means those agents (compounds
or biologicals) that are effective to enhance or potentiate the immune system response
in a mammal. Immunomodulatory agents include, for example, class I interferons (such
as a-, (3-, 5- and omega interferons, tau-interferons, consensus interferons and asialointerferons),
class II interferons (such as y-interferons) and pegylated interferons.
The term "inhibitor of HCV NS3 protease" as used herein means an agent (compound
or biological) that is effective to inhibit the function of HCV NS3 protease in a mammal.
Inhibitors of HCV NS3 protease include, for example, those compounds described in
WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929 or WO
02/060926, the Boehringer Ingelheim clinical candidate identified as BILN 2061 and the
Vertex pre-development candidate identified as VX-950. Particularly, compounds #2,3,
5, 6, 8, 10, 11, 18, 19, 29, 30, 31, 32, 33, 37, 38, 55, 59, 71, 91, 103, 104, 105, 112,
113, 114, 115, 116, 120, 122, 123, 124, 125, 126 and 127 disclosed in the table of
pages 224-226 in WO 02/060926, can be used in combination with the compounds of
the present invention .
The term "other inhibitor of HCV polymerase" as used herein means an agent
(compound or biological) that is effective to inhibit the function of HCV polymerase in a
mammal, whereby this agent has a structure different from the compounds according to
this invention and preferably binds to a site of the HCV polymerase different from the
site targeted by the compounds according to this invention. Other inhibitors of HCV
polymerase include non-nucleosides, for example, those compounds described in : WO
03/040112 (Rigel), WO 02/100846 A1 (Shire), WO 02/100851 A2 (Shire), WO 01/85172
A1 (GSK), WO 02/098424 A1 (GSK), WO 00/06529 (Merck), WO 02/06246 A1 (Merck),
EP 1 256 628 A2 (Agouron). Furthermore other inhibitors of HCV polymerase also
include nucleoside analogs, for example, those compounds described in: WO
01/90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), WO
02/057287 A2 (Merck/lsis) and WO 02/057425 A2 (Merck/lsis).
The term "inhibitor of another target in the HCV life cycle" as used herein means an
agent (compound or biological) that is effective to inhibit the formation and/or
replication of HCV in a mammal other than by inhibiting the RNA dependent RNA
polymerase of HCV. This includes agents that interfere with either host or HCV viral
mechanisms necessary for the formation and/or replication of HCV in a mammal.
Inhibitors of another target in the HCV life cycle include, for example, agents that
inhibit a target selected from a HCV helicase, HCV NS2/3 protease and HCV IRES.
Specific examples of inhibitors of another target in the HCV life cycle include ISIS-
14803 (ISIS Pharmaceuticals).
The term "HIV inhibitor" as used herein means an agent (compound or biological) that is
effective to inhibit the formation and/or replication of HIV in a mammal. This includes
agents that interfere with either host or viral mechanisms necessary for the formation
and/or replication of HIV in a mammal. HIV inhibitors include, for example, nucleosidic
inhibitors, non-nucleosidic inhibitors, protease inhibitors, fusion inhibitors and integrase
inhibitors.
The term "HAV inhibitor" as used herein means an agent (compound or biological) that
is effective to inhibit the formation and/or replication of HAV in a mammal. This includes
and/or replication of HAV in a mammal. HAV inhibitors include Hepatitis A vaccines, for
example, Havrix® (GlaxoSmithKline), VAQTA® (Merck) and Avaxim®(Aventis Pasteur).
The term "HBV inhibitor" as used herein means an agent (compound or biological) that
is effective to inhibit the formation and/or replication of HBV in a mammal. This includes
agents that interfere with either host or viral mechanisms necessary for the formation
and/or replication of HBV in a mammal. HBV inhibitors include, for example, agents that
inhibit HBV viral DMA polymerase or HBV vaccines. Specific examples of HBV
inhibitors include Lamivudine (Epivir-HBV®), Adefovir Dipivoxil, Entecavir, FTC
(Coviracil®), DAPD (DXG), L-FMAU (Clevudine®), AM365 (Amrad), Ldt (Telbivudine),
monoval-LdC (Valtorcitabine), ACH-126,443 (L-Fd4C) (Achillion), MCC478 (Eli Lilly),
Racivir (RCV), Fluoro-L and D nucleosides, Robustaflavone, ICN 2001-3 (ICN), Bam
205 (Novelos), XTL-001 (XTL), Imino-Sugars (Nonyl-DNJ) (Synergy), HepBzyme; and
immunomodulator products such as: interferon alpha 2b, HE2000 (Hollis-Eden),
Theradigm (Epimmune), EHT899 (Enzo Biochem), Thymosin alpha-1 (Zadaxin®), HBV
DNA vaccine (PowderJect), HBV DMA vaccine (Jefferon Center), HBV antigen
(OraGen), BayHep B® (Bayer), Nabi-HB® (Nabi) and Anti-hepatitis B (Cangene); and
HBV vaccine products such as the following: Engerix B, Recombivax HB, GenHevac B,
Hepacare, Bio-Hep B, TwinRix, Comvax, Hexavac.
The term "class I interferon" as used herein means an interferon selected from a
group of interferons that all bind to receptor type I. This includes both naturally and
synthetically produced class I interferons. Examples of class I interferons include a-,
(3-, omega interferons, tau-interferons, consensus interferons, asialo-interferons.
5
The term "class II interferon" as used herein means an interferon selected from a group
of interferons that all bind to receptor type II. Examples of class II interferons include yinterferons.
Specific preferred examples of some of these agents are listed below:
• antiviral agents: ribavirin and amantadine;
• immunomodulatory agents: class I interferons, class II interferons and pegylated
10 interferons;
• HCV NS3 protease inhibitors;
• other inhibitors of the HCV polymerase: nucleosidic and non-nucleosidic
inhibitors;
• inhibitor of another target in the HCV life cycle that inhibits a target selected from:
HCV NS2/3 protease or internal ribosome entry site (IRES);
• HIV inhibitors: nucleosidic inhibitors, non-nucleosidic inhibitors, protease
inhibitors, fusion inhibitors and integrase inhibitors; or
• HBV inhibitors: agents that inhibit viral DNA polymerase or is an HBV vaccine.
As discussed above, combination therapy is contemplated wherein a compound of
formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with at
least one additional agent selected from: an antiviral agent, an immunomodulatory
agent, an inhibitor of HCV NS3 protease, another inhibitor of HCV polymerase, an
inhibitor of another target in the HCV life cycle, an HIV inhibitor, an HAV inhibitor and an
HBV inhibitor. Examples of such agents are provided in the Definitions section above.
These additional agents may be combined with the compounds of this invention to
create a single pharmaceutical dosage form. Alternatively these additional agents may
be separately administered to the patient as part of a multiple dosage form, for example,
using a kit. Such additional agents may be administered to the patient prior to,
concurrently with, or following the administration of wherein a compound of formula (I),
or a pharmaceutically acceptable salt thereof.
As used herein, the term "treatment" means the administration of a compound or
composition according to the present invention to alleviate or eliminate symptoms of
the hepatitis C disease and/or to reduce viral load in a patient.
As used herein, the term "prevention" means the administration of a compound or
composition according to the present invention post-exposure of the individual to the
virus but before the appearance of symptoms of the disease, and/or prior to the
detection of the virus in the blood.
The following signs and /Wv*~ are used interchangeably in subformulas to
indicate the bond, or in the case of a spirocyclic group the atom, which is bonded to
the rest of the molecule as defined.
As used herein, the designation whereby a bond to a substituent R is drawn as
emanating from the center of a ring, such as, for example,
,or
means that the substituent R may be attached to any free position on the ring that
would otherwise be substituted by a hydrogen atom, unless specified otherwise.
Preferred embodiments
As long as not stated otherwise, all groups, substituents and indices, like e.g. R1,
R162, R163, R170, R°, Rc, RL, RN1, RN2, RN3, RN4, RQ, A, B, L, M1, M2, M3, M4, Q1, Q1a,
Q1b, Q1c, Q2, Q2a, Q2b, Q2c, W1, W2, Y°, Y1, Y2, Y3, X, Z, Sp, Met, HCy, Hetaryl, k,, q,
qa, and qb, have the meanings as defined hereinbefore and hereinafter. In the
following the preferred embodiments, groups, substituents and indices according to
this invention are described.
In a preferred embodiment of the first aspect of the invention, there is provided an
isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by
formula I:
(Figure Removed) wherein:
either A or B is N and the other B or A is C, wherein between two C-atoms
represents a double bond and between a C-atom and a N-atom represents a
single bond,
the group -C(=Y1)-Z is covalently linked to either M2 or M3,
and in addition one or two of the groups selected from M1, M2, M3 and M4 may also
be N, with the proviso that the group M2 or M3 to which -C(=Y1)-Z is linked is an Catom,
Sp is a spacer group selected from -(CR51R52)ki-, wherein
k1 is 1,2 or 3;
R51, R52are independently H, (d-6)alkyl, (C3.7)cycloalkyl or (d-a)alkyl-
(C3.7)cycloalkyl, or
R51 and R52are covalently bonded together and to the carbon-atom to which
they are attached to form a (C3-6)cycloalkyl group,
said alkyl, cycloalkyls or alkyl-cycloalkyl being optionally substituted by
halogen, hydroxy, (Ci.6)alkoxy, cyano, amino, -NH(d.4-alkyl) and/or -N(d-4-
alkyl)2;
Y° is O, S, NR11 or CR12R13, wherein
R11, R12, R13are each independently defined as R°;
R13 may also be COOR° or SO2RC;
wherein Rc and each R° is optionally substituted with R150;
or both R12 and R13 are covalently bonded together and to the carbon-atom to
which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6
or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered
saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms
selected from N, O or S; said cyclic systems being optionally substituted with
R150;
L is Ci-6alkyl, (C3.6)cycloalkyl, Ci-6alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl,
(Ci.6alkyl)aryl, Met, (d-e)alkyl-Het, all of which being optionally substituted
with R60;
or if Y° is CR12R13, then L may also be H;
or if Y° is O, then L may also be ORC,
wherein R° is optionally substituted with R60;
or if Y° is O, S or NR11, then L may also be N(RN2)RN1, NRN3-N(RN2)RN1,
NRN3-NRN2-CO-RC, NRN4-NRN3-CO-N(RN2)RN1, NRN2-S02-RC,
NRN2-CO-RC, NRN3-CO-N(RN2)RN1 or N(RN1)OR°;
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2
and/or RN3, and Rc and R° being optionally substituted with R60;
or if Y° is O or S, then L may also be OR6a or N(R5a)R6a, wherein R5a is defined as
RN2,
(Figure Removed) wherein R7aand R8aare each independently defined as R°, wherein said R°
is optionally substituted with R60; or
R7a and R8a are covalently bonded together to form a (C3.7)cycloalkyl or a 4,
5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from
0, N, and S; and when L is N(R5a)R6a, either of R7a or R8a may be covalently
bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle,
wherein said cycloalkyl or heterocycle being optionally substituted by R150;
and
Y2isOorS;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or
R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered
heterocycle;
Q1 is aryl, Het, (Cm) alkyl-aryl, (Cm) alkyl-Het, (Cm)alkyl-CONH-aryl or (Cm)
alkyl-CONH-Het, all of which being optionally substituted with R60;
Y1 is O, S or NR14, wherein R14 is H or (Cm) alkyl;
Z is defined as
a) OR0;
b) SO2RC;
c) N(RN2)RN1;
d) NRN3-N(RN2)RN1;
e) NRN3-NRN2-CO-RC;
f) NRN4-NRN3-CO-N(RN2)RN1;
g) NRN2-SO2-RC or
h) NRN2-CO-RC;
i) COOR°;
j) N(RN1)OR°;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2,
and/or RN3, being optionally substituted with R60;
or Z is OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
wherein R7b, R8b, Y3, R9b, Q2, are defined as R7a, R8a, Y2, R9a, Q1,
respectively;
R2 is selected from: halogen or R21, wherein R21 is aryl or Het, said R21 is optionally
substituted with R150;
R3 is selected from (d.6)alkyl, (C3.7)cycloalkyl, (d-3)alkyl-(C3.7)cycloalkyl,
(C5.7)cycloalkenyl, (d.3)alkyl-(C5.7)cycloalkenyl, (C6-io)bicycloalkyl, (d-s)alkyl-
33-
(C6-io)bicycloalkyl, (C6-io)bicycloalkenyl, (C1.3)alkyl-(C6.io)bicycloalkenyl, HCy
or (Ci.3)alkyl-HCy,
wherein HCy is a saturated or unsaturated 4 to 7-membered heterocyclic
group with 1 to 3 heteroatoms selected from O, S and N;
said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, HCy and
alkyl-HCy being optionally substituted with from 1 to 4 substituents selected
from: a) halogen;
b) (Ci.6)alkyl optionally substituted with:
- OR31 or SR31 wherein R31 is H, (d-ealkyl), (C3-7)cycloalkyl or
(Ci-3)alkyl-(C3.7)cycloalkyl; or
- N(R32)2 wherein each R32 is independently H, (d-e)alkyl,
(C3-7)cycloalkyl or (C1.3)alkyl-(C3.7)cycloalkyl; or both R32 are
covalently bonded together and to the nitrogen to which they
are attached to form a 5, 6 or 7-membered saturated
heterocycle;
c) OR33 or SR33 wherein R33 is H, (d-e)alkyl, (C3.7)cycloalkyl or
(d.3)alkyl-(C3-7)cycloalkyl;
d) N(R35)2 wherein each R35 is independently H, (d.6)alkyl,
(C3.7)cycloalkyl or (d.3)alkyl-(C3.7)cycloalkyl; or both R35 are covalently
bonded together and to the nitrogen to which they are attached to
form a 5, 6 or 7-membered saturated heterocycle;
R4a, R4b, R5 each are independently H or defined as R150;
R60 is each defined as 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: OPO3H, NO2, cyano, azido,
C(=NH)NH2, C(=NH)NH(d-e)alkyl or C(=NH)NHCO(d.6)alkyl, SO3H; and
-1 to 3 substituents selected from:
a) (d-e) alkyl, (C3.7)cycloalkyl, C3.7 spirocycloalkyl optionally containing 1 or 2
heteroatoms selected from N, O and S; (C2-6)alkenyl, (C2.8)alkynyl,
(d.6)alkyl-(C3.7)cycloalkyl, all of which optionally being substituted with
R150;
b) OR0;
c) OC(0)R°;
d) SR°, SO2RC, S02N(RN2)RN1, SO2N(RN2)C(O)RC or CONRN2SO2RC;
e) N(RN2)RN1, N(RN2)COORC, or N(RN2)SO2RC;
f) N(RN2)CORC;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORC, N(RN3)COCOOR° or N(RN3)COCON(RN2)RN1;
i) COR°;
j) COOR°;
k) CON(RN2)RN1;
I) aryl, Met, (Ci.4alkyl)aryl or (d.4alkyl)Het, all of which optionally being
substituted with R150;
wherein said RN1, Rc and R° are each independently optionally substituted
with R150as defined,
I150 is each defined as 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: OPO3H, NO2, cyano, azido,
C(=NH)NH2, C(=NH)NH(Ci.6)alkyl or C(=NH)NHCO(d.6)alkyl; and
-1 to 3 substituents selected from:
a) (d.6) alkyl, (C3-7)cycloalkyl, C3.7 spirocycloalkyl optionally containing 1 or 2
heteroatoms selected from N, O and S; (C2.6)alkenyl, (C2.8)alkynyl,
(d.3)alkyl-(C3.7)cycloalkyl, all of which optionally substituted with R160;
b) OR0;
c) OC(O)R°;
d) SR°, SO2RC, SO2N(RN2)RN1, SO2N(RN2)C(O)RC or CON(RN2)SO2RC;
e) N(RN2)RN1, N(RN2)COORC, or N(RN2)SO2RC;
f) N(RN2)CORC;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORC, N(RN3)COCOOR°orN(RN3)COCON(RN2)RN1;
wherein RN1 is as defined or OH, O-d-4-alkyl;
i) COR°;
j) COOR°;
k) tetrazole or CON(RN2)RN1;
wherein said RN1, Rc and/or R° are optionally substituted with R160 as
defined;
R160 is each defined as 1, 2 or 3 substituents independently selected from:
-1, 2 or 3 fluorine substituents; and
- one of each substituent selected from tetrazole, chlorine, bromine, iodine,
CN, nitro, d-4alkyl, CF3, COOR161, S03H, SR161, SO2R163, OR161, N(R162)2,
S02N(R162)2, S02NR162COR162, NR162SO2R163, NR162COR162, or CON(R162)2,
wherein R161, R163and each R162is independently (d.4)alkyl, (C3.7)cycloalkyl
or (Ci-3)alkyl-(C3-7)cycloalkyl; and R161 and each R162 may each independently
also be H; or both R162 are covalently bonded together and to the nitrogen to
which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
R°, Rcare independently defined as (d.6)alkyl, (C3.6)cycloalkyl, (d.4)alkyl-
(C3.6)cycloalkyl, (C2.6)alkenyl, aryl, Met, (d.4)alkyl-aryl and (C1.4)alkyl-Het; and
R° may also be H;
RN1 is independently selected from H, (d.6)alkyl, (C3.7)cycloalkyl, (d.4)alkyl-
(C3.6)cycloalkyl, (C2-6)alkenyl, aryl, Met, (C1.4)alkyl-aryl, (d-4)alkyl-Het; or
RN2 RN3_ RN4 are independently H, CH3, (C2.6alkyl), (C3.6)cycloalkyl, (d.4)alkyl-
(C3-e)cycloalkyl; wherein said alkyl, cycloalkyl or alkylcycloalkyl is optionally
substituted with hydroxy, halogen, carboxy, d.6-alkoxycarbonyl, d-e-alkyl,
d-e-alkoxy, amino, -NH(Ci-4-alkyl) and/or -N(d-4-alkyl)2; and wherein said
CH3 is optionally substituted with halogen, carboxy or d.6-alkoxycarbonyl;
and
in the case
a) of a group N(RN2)RN1 the substituents RN2 and RN1; or
b) of a group NRN3-N(RN2)RN1 the substituents RN3 and RN1, or RN2 and RN1;
may be covalently bonded together to form a 4-, 5-, 6- or 7-membered
saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11-
membered N-containing heterobicycle each may have additionally from 1 to 3
heteroatoms selected from O, N, and S;
wherein Met is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4
heteroatoms selected from O, N and S, or a 8-, 9-, 10- or 11-membered
heterobicycle having 1 to 5 heteroatoms selected from O, N and S;
or a salt thereof.
Core:
This invention comprises compounds of the formulas la and Ib
wherein the compounds of the formula la are preferred.
Furthermore this invention comprises compounds according to the formulas Ic and Id
(Figure Removed) wherein the compounds of the formula Ic are preferred.
wherein R1 denotes the group -Sp-C(=Y°)-L.
Also explicitly, this invention further comprises compounds of the following formulas:
wherein R1 denotes the group -Sp-C(=Y°)-L.
Preferably the groups M1 and M4 are CR4a and CR4b, respectively.
The group M2 or M3 to which the group -C(=Y1)-Z is covalently linked is C and the
other group M3 or M2 is preferably CR5.
Therefore those compounds are preferred which are described by the following
group of formulas 1.1 to 1.4
A group of most preferred compounds is described by the formula 1.1
Another group of preferred compounds is described by the formula 1.4 as given
above.
The preferred meaning of the spacer group Sp is a group selected from
-(CR51R52)ki-, wherein k1 is 1, 2 or 3; and R51, R52are independently H or (d.3)alkyl,
in particular H or methyl; and/or
R51, R52are covalently bonded together and to the carbon-atom to which they are
attached to form a cyclopropyl, cyclobutyl or cyclopentyl group.
More preferably Sp is a spacer group selected from -CH2-, -CH(CH3)-, -C(CH3)2-,
-CH2-CH2- and Most preferably Sp is -CH2-.
According to a first preferred embodiment of this invention Y° is O or S, most
preferably O.
According to a second preferred embodiment of this invention Y° and L are
covalently bonded to form a 5, 6, 7 or 8-membered mono- or a 8, 9, 10 or 11 -
membered bicyclic group which may contain 1, 2 or 3 heteroatoms selected from N,
O and S, wherein the mono- or bicyclic group is optionally substituted with R60.
In this second embodiment those compounds are preferred, wherein Y° and L are
covalently bonded to form an unsaturated 5 or 6-membered monocyclic group which
may contain 1 or 2 heteroatoms selected from N, O and S, wherein the monocyclic
group is optionally substituted with R60. Most preferably said monocyclic group is a
monocyclic aromatic or heteroaromatic group. Preferred examples of such
(hetero)aromatic groups are phenyl, pyridine and thiazole, being optionally
substituted as described.
Therefore preferred groups of the subformula " are
Beside said preferred first and second embodiment, Y°may also be NR11 or CR12R13
wherein R11, R12, R13 are defined as hereinbefore. Preferred meanings of R11, R12,
R13 are independently H or Chalky!; most preferably H or methyl.
L:
According to a first embodiment the group L has one of the following meanings:
a) Ci-6alkyl, (C3.6)cycloalkyl, Ci.6alkyl-(C3.6)cycloalkyl, (C2-6)alkenyl, all of which being
optionally substituted with R60; or
b) if Y° is CR12R13, then L may also be H; or
c) if Y° is O, then L may also be ORC,
wherein Rc is optionally substituted with R60,
wherein R12, R13, R60 and Rc are as defined hereinbefore.
According to a preferred second embodiment, wherein Y° is O, S or NR11, the group
L has one of the following meanings:
a) L is N(RN2)RN1, NRN3-N(RN2)RN1, NRN3-NRN2-CO-RC, NRN4-NRN3-CO-N(RN2)RN1,
NRN2-S02-RC or N(RN2)OR°
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2 and/or
RN3, and Rc being optionally substituted with R60; or
b) L is N(R5a)R6a wherein R5a is defined as RN2 and R6a is:
or R6a is:
wherein R7aand R8aare each independently defined as R°, wherein said R°
is optionally substituted with R60; or
R7a and R8a are covalently bonded together to form a second (Ca^cycloalkyl
or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected
from O, N, and S; and either of R7a or R8a may be covalently bonded to R5a to
form a nitrogen-containing 5-or 6-membered heterocycle, wherein said
cycloalkyl or heterocycle being optionally substituted by R150; and
W1 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or
R9a is covalently bonded to either of R7a or R88 to form a 5- or 6-membered
heterocycle;
Q1 is aryl, Met, (d.6)alkyl-aryl, (d.6)alkyl-Het, (d.6)alkyl-CONH-aryl or (Cm)
alkyl-CONH-Het, all of which being optionally substituted with R,60
The group Y1 is defined as 0, S or NR14, wherein R14 is H or (Ci-e)alkyl; most
preferably Y1 is O.
Z:
Preferably the group Z is selected from the group of definitions:
a) OR0;
c) N(RN2)RN1;
g) NRN2-SO2-RC;
h) NRN3-SO2-N(RN2)RN1; or
i) NRN2-CO-RC;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2, being
optionally substituted with R60;
or Z is OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1 respectively; and
Q2 is aryl, Met, (Ci.6)alkyl-aryl, (Ci.6)alkyl-Het, (CveOalkyl-CONH-aryl or (d.6) alkyl-
CONH-Het, all of which being optionally substituted with R60
or Q2 is R160
or Q2 is selected from the group consisting of O-C^-alkyl, S-Ci-4-alkyl, Ci.4-alkyl, C2.
4-alkenyl and C2.4-alkynyl, all of which being optionally substituted with R160;.
In the case Z being defined as OR0, SO2RC, COOR° or OR6b, wherein R6b is defined
as above, then Y1 is preferably O.
SP. Y°. L. Y1 and Z:
Those compounds according to this invention are preferred, wherein :
Sp is a spacer group selected from -CH2-, -CH(CH3)-, -C(CH3)2-,
-CH2-CH2- and \—*\^, ; most preferably Sp is -CH2-; and
Y° is O or S; most preferably O;
L is N(RN2)RN1, NRN3-N(RN2)RN1, NRN3-NRN2-CO-RC,
NRN4-NRN3-CO-N(RN2)RN1, NRN2-SO2-RC or N(RN1)OR°;
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2
and/or RN3, and Rc being optionally substituted with R60; or
(Figure Removed) wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2,
being optionally substituted with R60; or
Z is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1
respectively; and
Q2 is aryl, Net, (Cm) alkyl-aryl, (Cm) alkyl-Het, (Cm)alkyl-CONH-aryl or (Cm)
alkyl-CONH-Het, all of which being optionally substituted with R60
or Q2 is R160
or Q2 is selected from the group consisting of O-Ci.4-alkyl, S-Ci.4-alkyl, Ci-4-
alkyl, C2-4-alkenyl and C2.4-alkynyl, all of which being optionally substituted
with R160;.
In the following, preferred groups of compounds according to this invention are
described more specifically.
A first group of preferred compounds according to this invention is defined by
wherein RN1, including any heterocycle formed by RN1 and RN2, is optionally
substituted with R60; and
Z is defined as
a) OR0;
c) N(RN2)RN1;or
g) NRN2-S02-RC;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2,
being optionally substituted with R60; or
Z is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
«9b
or R6b is:
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1
respectively; and
Q2 is aryl, Het, (d^alkyl-aryl, (d.6)alkyl-Het, (d.6)alkyl-CONH-aryl or (d.6)
alkyl-CONH-Het, all of which being optionally substituted with R60
or Q2 is R160
or Q2 is selected from the group consisting of O-C1.4-alkyl, S-d.4-alkyl, d.4-
alkyl, C2-4-alkenyl and C2-4-alkynyl, all of which being optionally substituted
with R160;.
A second group of preferred compounds according to this invention is defined by
formula l.1b
wherein R7a, R8a, Y2, R9a, Q1, W1 are defined as hereinbefore;
is defined as
a) OR0;
c) N(RN2)RN1;or
g) NRN2-SO2-RC;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1
and RN2, being optionally substituted with R60; or
Z is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1
respectively; and
Q2 is aryl, Met, (d.6)alkyl-aryl, (d-6)alkyl-Het, (d.6)alkyl-CONH-aryl
or (Ci-6) alkyl-CONH-Het, all of which being optionally substituted with
R80
or Q2 is R160
or Q2 is selected from the group consisting of O-Ci-4-alkyl, S-d-4-
alkyl, d-4-alkyl, C2.4-alkenyl and C2-4-alkynyl, all of which being
optionally substituted with R160;.
A third group of preferred compounds according to this invention is defined by
formula l.1c
O R
wherein R is optionally substituted with R 6 0;. and
is defined as
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by R
and RN2, being optionally substituted with R60; or
is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1
respectively; and
Q2 is aryl, Met, (d.6)alkyl-aryl, (d.6)alkyl-Het, (d.6)alkyl-CONH-aryl
or (Ci-e) alkyl-CONH-Het, all of which being optionally substituted with
R60
or Q2 is R160
or Q2 is selected from the group consisting of O-d-4-alkyl, S-d.4-
alkyl, Ci-4-alkyl, C2-4-alkenyl and C2-4-alkynyl, all of which being
optionally substituted with R160;.
A fourth group of preferred compounds according to this invention is defined by
formula l.1d
wherein
is selected from ORC, NRN3-N(RN2)RN1, NRN3-NRN2-CO-RC,
NRN4-NRN3-CO-N(RN2)RN1 or N(RN1)OR°;
said RN1, including any heterocycle or heterobicycle formed by RN1,
RN2 and/or RN3, and Rc being optionally substituted with R60;
is defined as
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1
and RN2, being optionally substituted with R60; or
is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1 respectively;
and
Q2 is aryl, Met, (d-6)alkyl-aryl, (d.6)alkyl-Het, (d.6)alkyl-CONH-aryl or (d.6)
alkyl-CONH-Het, all of which being optionally substituted with R60
or Q2 is R160
or Q2 is selected from the group consisting of O-d-4-alkyl, S-d.4-alkyl, d-r
alkyl, C2-4-alkenyl and C2-4-alkynyl, all of which being optionally substituted
with R160:.
In the following, those preferred definitions of the groups L and Z which were
described as preferred hereinbefore are formulated in more detail.
In the case Y° is 0, S or NR11, L is more preferably
N(RN2)RN1, NRN3-N(RN2)RN1, NRN3-NRN2-CO-RC, NRN4-NRN3-CO-N(RN2)RN1,
NRN2-SO2-RC or N(RN1)OR°; wherein
RN2, RN3, RN4 are each independently H, methyl, (C2.4)alkyl, (C3.6)cycloalkyl or
(d-3)alkyl-(d;-6)cycloalkyl, all of which being optionally substituted with d.3-alkyl,
halogen, carboxy or (d.4)alkoxycarbonyl; and/or wherein said alkyl, cycloalkyl or
alkyl-cycloalkyl, but preferably not the C-atom thereof directly bonded to the N-atom,
is optionally substituted with hydroxy, amino, -NH(d.4-alkyl), -N(d.4-alkyl)2 and/or -
0-(d.4-alkyl);
RN1 is H, methyl, (C2.6)alkyl, (C3.6)cycloalkyl, (C1.3)alkyl-(C3.6)cycloalkyl, benzyl,
(C2.4)alkyl-phenyl, phenyl, Met or (d_4)alkyl-Het;
wherein all of said methyl, alkyl, and cycloalkyl groups are optionally substituted with
halogen, d_3-alkyl, carboxy or (d_4)alkoxycarbonyl, CONH2, CONH(d.4-alkyl),
CON(d.4-alkyl)2; and/or
wherein all of said alkyl, and cycloalkyl groups, but preferably not the C-atom thereof
directly bonded to the N-atom, are optionally substituted with hydroxy, amino,
-NH(d-4-alkyl), -N(Ci.4-alkyl)2 and/or-O-(Ci.4-alkyl); and
in the case
a) of a group N(RN2)RN1 the substituents RN1 and RN2 or
b) of a group NRN3-N(RN2)RN1 the substituents RN1 and RN3 or RN1 and RN2
may be covalently bonded together to form a 5-, 6- or 7-membered saturated or
unsaturated heterocycle which may have additionally 1 or 2 heteroatoms or a 8-, 9-,
10- or 11-membered saturated or unsaturated heterobicycle which may have
additionally from 1, 2 or 3 heteroatoms, whereby the heteroatoms are selected from
O, N, and S; and
wherein Met is a 4-, 5-, 6- or 7-membered, preferably 5- or 6-membered, monocyclic
group which contains 1 or 2 heteroatoms selected from N, O and S, wherein a
benzene ring may be fused to the monocyclic group; and
wherein said phenyl group, heterocycle, heterobicycle or Het is optionally substituted
by 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
-1 to 3 substituents selected from: (Ci.4)alkyl, hydroxy, O-(d-4)alkyl, amino, -COOH,
-COO(C1.4)alkyl, CONH2, CONH(d.4-alkyl), CON(d-4-alkyl)2, -NH(d.4-alkyl), -N(d-4-
alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl,
-(d.4)alkyl-OH, -(d.4)alkyl-O-(d.4)alkyl, -(d.4)alkyl-COOH, -(d.4)alkyl-
COO(d.4)alkyl, -(d.4)alkyl-CONH2, -(C1.4)alkyl-CONH(C1.4-alkyl), -(d.4)alkyl-
CON(d.4-alkyl)2, -(d.4)alkyl-amino, -(d.4)alkyl-NH(d.4-alkyl), -(C1.4)alkyl-N(C1.4-
alkyl)2,
wherein the alkyl-groups may be substituted with halogen; and
wherein the N-piperazinyl-group may be N-substituted with d-4-alkyl, (C3.6)cycloalkyl
or (d.3)alkyl-(ds.6)cycloalkyl.
In the above described preferred case, wherein Y° is O, S or NR11 and L is
N(RN2)RN1 the substituents have most preferably the following meanings:
N2 is H, methyl, (C2-4)alkyl, (C3.6)cycloalkyl or (C1.3)alkyl-(C3.6)cycloalkyl, all of
which being optionally substituted with Ci-a-alkyI, halogen, carboxy or
(d.4)alkoxycarbonyl; and/or wherein said alkyl, cycloalkyi or alkyl-cycloalkyl,
but preferably not the C-atom thereof directly bonded to the N-atom, is
optionally substituted with hydroxy, amino, -NH(d-4-alkyl), -N(d.4-alkyl)2
and/or -O-(Ci.4-alkyl);
?N1 is methyl, (C2.6)alkyl, (C3-7)cycloalkyl, (Ci.3)alkyl-(C3-7)cycloalkyl, benzyl,
(C2.4)alkyl-phenyl, Met and (Ci_4)alkyl-Het; wherein the methyl and alkyl
groups are optionally substituted with Ci.3-alkyl, halogen, carboxy or
(d.4)alkoxycarbonyl, CONH2, CONH(d.4-alkyl), CON(d.4-alkyl)2; and/or
wherein said alkyl, but preferably not the C-atom thereof directly bonded to
the N-atom, is optionally substituted with hydroxy, amino, -NH(d.4-alkyl),
-N(d_4-alkyl)2 and/or-O-(d-4-alkyl); and
wherein Met is a saturated or unsaturated 4-, 5-, 6- or 7-membered,
preferably 5- or 6-membered, monocyclic group which contains 1 or 2
heteroatoms selected from N, O and S, wherein a benzene ring may be
fused to the monocyclic group; and
wherein said phenyl group, heterocycle, heterobicycle or Met is optionally
substituted by 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
-1 to 3 substituents selected from: (d.4)alkyl, hydroxy, O-(d.4)alkyl, amino,
-COOH, -COO(Ci.4)alkyl, CONH2, CONH(Ci.4-alkyl), CON(d.4-alkyl)2,
-NH(d.4-alkyl), -N(d.4-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl,
N-thiomorpholinyl, N-piperazinyl, -(d.4)alkyl-OH, -(C1.4)alkyl-O-(C1.4)alkyl,
-(d.4)alkyl-COOH, -(d.4)alkyl-COO(d.4)alkyl, -(d.4)alkyl-CONH2, -(d.4)alkyl-
CONH(d.4-alkyl), -(Ci.4)alkyl-CON(d.4-alkyl)2, -(d.4)alkyl-amino, -(Ci.4)alkyl-
NH(d.4-alkyl),-(d.4)alkyl-N(d.4-alkyl)2,
wherein the alkyl-groups may be substituted with halogen; and
wherein the N-piperazinyl-group may be N-substituted with Ci.4-alkyl,
(C3-6)cycloalkyl or (d.3)alkyl-(C3.6)cycloalkyl.
Both RN2 and RN1 may also be H, so that L is -NH2.
According to the latter embodiment very preferred meanings for RN2 are selected
from H, methyl, ethyl, n-propyl, i-propyl, cyclopropyl and cyclopropylmethyl; in
particular H and methyl; and
RN1 is selected from methyl, ethyl, n-propyl, i-propyl, 1-methylpropyl, 2-
methylpropyl, (C4.7)cycloalkyl, (C^cycloalkylmethyl-, (C4.7)cycloalkylethyl-,
(C4.7)cycloalkenyl, (C4-7)cycloalkenylmethyl-, (C4.7)cycloalkenylethyl-, HCy-,
HCy-methyl-, HCy-ethyl-, benzyl-, phenylethyl-, Hetaryl-methyl- and Hetarylethyl-,
wherein
Hetaryl is an aromatic 5 or 6-membered monocyclic group which contains 1
or 2 heteroatoms selected from N, 0 and S; to which a benzene ring may be
fused; and
HCy is a 4-, 5-, 6- or 7-membered saturated or mono-unsaturated
heterocyclic group which contains 1 or 2 heteroatoms selected from N, O, S;
and
wherein all (C4.7)cycloalkyl, (C4.7)cycloalkenyl, phenyl groups, Hetaryl and
HCy are optionally substituted by 1 to 3 substituents independently selected
from:
-1 to 3 substituents selected from fluorine;
- one of each substituent selected from: chlorine, bromine, NO2> cyano; and
-1 to 3 substituents selected from: methyl, ethyl, n-propyl, i-propyl,
cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, d-3-alkoxy, -COOH,
-COO(Ci.3)alkyl, CONH2, CONH(d.3-alkyl), CON(Ci.3-alkyl)2, amino,
-NH(d-3-alkyl), -N(d.3-alkyl)2; and
the C-atom in a-position to the N-atom (of the group N(RN2)RN1) is optionally
substituted with methyl, CH2OH, CH2NH2, CH2NH(d-3-alkyl), CH2N(d.3-
alkyl)2, carboxy, (d^alkoxycarbonyl, CONH2, CONH(d-3-alkyl), CON(d-3-
alkyl)2; and/or, preferably or,
any C-atom in (3-position to the N-atom (of the group N(RN2)RN1) is optionally
substituted with hydroxy, d.3-alkoxy, amino, -NH(d.3-alkyl) or -N(d-3-alkyl)2.
wherein each R is independently H, methyl, ethyl, n-propyl, i-propyl or cyclopropyl;
most preferably H or methyl.
In the above described preferred case, wherein Y° is O, S or NR11 and L is
N(RN2)RN1 wherein RN2 and RN1 are covalently bonded together to form a heterocycle,
the following meanings are most preferred:
RN2 and RN1 are covalently bonded together to form a heterocycle selected from
azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,
homopiperidine and homopiperazine;
wherein said piperazine and homopiperazine may be N-substituted with
Ci.4alkyl, (Ca-eJcycloalkyl or d^alkyHCs-eJcycloalkyl; and
wherein said heterocycles are optionally monosubstituted by (C3.6)cycloalkyl,
(Ci.3)alkyl-(C3-6)cycloalkyl, HCy or d-aalkyl-HCy , wherein HCy is selected
from azetidine, pyrrolidine, piperidine, piperazine, morpholine,
thiomorpholine, homopiperidine and homopiperazine; and
wherein said heterocycles, including an optional alkyl-, cycloalkyl- or
alkylcycloalkyl-group and/or HCy or d-aalkyl-HCy group, are optionally
substituted by 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen and (d-4)alkyl;
- one of each substituent selected from: NO2, cyano, azido; and
-1 or 2 substituents selected from:
hydroxy, O-(Ci-4)alkyl, amino, -COOH, -COO(Ci.4)alkyl, CONH2, CONH(d-4-
alkyl), CON(Ci.4-alkyl)2, -NH(Ci.6-alkyl), -N(d.6-alkyl)2, -(d.4)alkyl-OH,
-(d.4)alkyl-O-(d.4)alkyl,-(d.4)alkyl-COOH,-(Ci.4)alkyl-COO(Ci.4)alkyl,
-(d.4)alkyl-CONH2,-(Ci.4)alkyl-CONH(d.4-alkyl),-(d.4)alkyl-CON(d.4-alkyl)2,
-(d.4)alkyl-amino,-(Ci.4)alkyl-NH(d.4-alkyl),-(d^alkyl-NCd^-alkyl)^
wherein said alkyl-groups may be substituted with halogen.
According to this preferred embodiment preferred examples of the group L are:
COOR \N'^V%VCONR2
Description (Complete)3wherein each R is independently H, methyl, ethyl, n-propyl, i-propyl or cyclopropyl;
most preferably H or methyl.
According to another preferred embodiment wherein Y° is O and L is OR6a, or
wherein Y° is O or S and L is N(R5a)R6a, wherein R5a is defined as RN2, and
R is defined according to the following subformula:
R8a
wherein
R7a is defined as H, COOH, CONH2, (C1.6)alkyl, (C3-6)cycloalkyl, (d-4)alkyl-
(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Met, (d-^alkyl-aryl, (d.4)alkyl-Het; all of
which are optionally substituted with R60; and
,8a is H or(Ci-4)alkyl; or
R7a and R8a are covalently bonded together to form a (C3.7)cycloalkyl or a 4, 5- or 6-
membered heterocycle having from 1 to 3 heteroatom selected from O, N,
and S; and
when L is N(R5a)R6a, either of R7a or R8a may be covalently bonded to R5a to
form a nitrogen-containing 5-or 6-membered heterocycle, wherein said
cycloalkyl or heterocycle being optionally substituted by R150; and
W1 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
wherein the alkylene and alkenylene groups according to b), c) and d) may
be substituted with (d-a) alkyl;
Q1 is a group of the subformula Ilia
- R1q Mia
wherein
Q1a is aryl, Hetaryl, (d-3) alkyl-aryl or (d.3)alkyl-Hetaryl;
Q1b is phenyl or Hetaryl;
Q1c is a bond, O-Ci.4-alkyl, S-C1.4-alkyl, Ci.4-alkyl, C2-4-alkenyl or C2.4-
alkynyl; and
R1q is selected from H, CN, COOR161, CON(R162)2, SO2N(R162)2, -N(R162)2,
OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2l
NHSO2RC, CONHS02RC, SO2NHCORC, tetrazole, triazole and
CONHSO2N(R162)2;
q isOoM;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is
optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2
heteroatoms selected from O, N, and S, or a 8-, 9- or 10-membered aromatic
heterobicycle having 1 to 4 heteroatoms selected from O, N, and S.
In another above described preferred case, wherein Y° is O and L is OR6a, or
wherein Y° is O or S and L is N(R5a)R6a wherein R5a is defined as RN2, and
R6a is defined as:
the substituents have most preferably one of the following meanings:
R7aand R8aare each independently defined as R°, wherein said R° is optionally
substituted with R60; or
R7a and R8a are covalently bonded together to form a second (C3.7)cycloalkyl or a 4,
5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from
0, N, and S; and when L is N(R5a)R6a, either of R7a or R8a may be covalently
bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle,
wherein said cycloalkyl or heterocycle being optionally substituted by R1SO;
and
Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or
R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered
heterocycle;
wherein
Q1a is aryl, Hetaryl, (Ci-3) alkyl-aryl or (d.3)alkyl-Hetaryl;
Q1b is phenyl or Hetaryl;
Q1c is a bond, O-Ci.4-alkyl, S-Cv^alkyl, C^-alkyl, C2.4-alkenyl or C2.4-
alkynyl; and
R1q is selected from H, CN, COOR161, CON(R162)2, SO2N(R162)2, -N(R162)2,
OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2,
NHSO2RC, CONHSO2RC, S02NHCORC, tetrazole, triazole and
CONHSO2N(R162)2;
q isOorl;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is optionally
substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2
heteroatoms selected from O, N, and S, or a 8-, 9- or 10-membered aromatic
heterobicycle having 1 to 4 heteroatoms selected from O, N, and S.
Z:
According to one preferred embodiment Z is defined as OR0, wherein R° is
optionally substituted with R60.
In this embodiment wherein Z is OR0 the preferred meaning of
R° is H, CMalkyl, (C3.6)cycloalkyl, Ci.3alkyl-(C3-6)cycloalkyl, (C2.6)alkenyl,
(Ci.3alkyl)phenyl, (d-3)alkyl-pyridinyl, wherein said alkyl, alkyl-cycloalkyl,
cycloalkyl, alkenyl, alkyl-phenyl or alkyl-pyridinyl is optionally substituted with
1 to 3 substituents
independently selected from:
-1, 2 or 3 fluorine substituents; and
- one of each substituent selected from chlorine, bromine, iodine, CN, nitro,
d-4alkyl, CF3, COOR161, SO2R161, OR161, N(R162)2) SO2N(R162)2> NR162COR162
or CON(R162)2, wherein R161 and each R162is independently H, (d^alkyl,
(C3.7)cycloalkyl or (d-3)alkyl-(C3-7)cycloalkyl; or both R162 are covalently
bonded together and to the nitrogen to which they are attached to form a 5, 6
or 7-membered saturated heterocycle.
A most preferred meaning of Z according to this embodiment is OH.
According to another preferred embodiment Z is defined as N(RN2)RN1 wherein RN1,
including any heterocycle or heterobicycle formed by RN1 and RN2, is optionally
substituted with R60.
Preferred meanings of RN1 and RN2in this embodiment are:
RN2 is H, methyl, (C2.4)alkyl, (C3-6)cycloalkyl or (d-3)alkyl-(C3.6)cycloalkyl, all of
which being optionally substituted with Ci.3-alkyl, halogen, carboxy or
(Ci_4)alkoxycarbonyl; and/or wherein said alkyl, cycloalkyl or alkyl-cycloalkyl,
but preferably not the C-atom thereof directly bonded to the N-atom, is
optionally substituted with hydroxy, amino, -NH(d.4-alkyl), -N(d.4-alkyl)2
and/or -O-(d-4-alkyl); whereby RN2 is most preferably H; and
RN1 is methyl, (C2-6)alkyl, (d.4)alkyl-phenyl or (d.4)alkyl-Het; wherein all of the
methyl and alkyl groups are optionally substituted with d-3-alkyl, halogen,
carboxy or (C1.4)alkoxycarbonyl, CONH2, CONH(d.4-alkyl), CON(d.4-alkyl)2;
and/or wherein said alkyl, but preferably not the C-atom thereof directly
bonded to the N-atom, is optionally substituted with hydroxy, amino, -NH(d.4-
alkyl), -N(d-4-alkyl)2 and/or-O-(d-4-alkyl); and
wherein Met is a 4-, 5-, 6- or 7-membered, preferably 5- or 6-membered,
monocyclic group which contains 1 or 2 heteroatoms selected from N, 0 and
S, wherein a benzene ring may be fused to the monocyclic group; and
wherein said phenyl group, heterocycle, heterobicycle or Met is optionally
substituted by 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
-1 to 3 substituents selected from: (d.4)alkyl, hydroxy, O-(C1.4)alkyl, amino,
-COOH, -COO(d.4)alkyl, CONH2, CONH(d.4-alkyl), CON(d.4-alkyl)2,
-NH(d.4-alkyl), -N(d.4-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl,
N-thiomorpholinyl, N-piperazinyl, -(d-4)alkyl-OH, -(d.4)alkyl-O-(d.4)alkyl,
-(d.4)alkyl-COOH, -(d.4)alkyl-COO(d.4)alkyl, -(d.4)alkyl-CONH2> -(d.4)alkyl-
CONH(d.4-alkyl), -(d.4)alkyl-CON(d.4-alkyl)2, -(d.4)alkyl-amino, -(d.4)alkyl-
NH(d.4-alkyl),-(d.4)alkyl-N(d.4-alkyl)2,
wherein the alkyl-groups may be substituted with halogen; and
wherein the N-piperazinyl-group may be N-substituted with d.4-alkyl, C3.6-
cycloalkyl or d.3-alkyl-C3.6-cycloalkyl.
Most preferred meanings of RN1 and RN2in this embodiment wherein Z is defined as
N(RN2)RN1 are:
RN2 is H, methyl, ethyl, n-propyl, i-propyl, all of which being optionally substituted
with methyl, fluorine, chlorine, carboxyl or methoxycarbonyl; and/or wherein
said ethyl, n-propyl or i-propyl, but preferably not the C-atom thereof directly
bonded to the N-atom, is optionally substituted with hydroxy, amino, -
NH(CH3), -N(CH3)2 and/or -O-(CH3);
RN1 is methyl, ethyl, n-propyl, i-propyl, benzyl, phenylethyl, pyridinylmethyl or
pyridinylethyl; wherein said methyl, ethyl, n-propyl, and i-propyl, groups are
optionally substituted with fluorine, chlorine, methyl, ethyl, n-propyl, i-propyl,
carboxy, methoxycarbonyl, CONH2, CONH(CH3), CON(CH3)2; and/or
wherein said ethyl, n-propyl or i-propyl, but preferably not the C-atom thereof
directly bonded to the N-atom, is optionally substituted with hydroxy, amino,
-NH(CH3), -N(CH3)2 and/or-O-CH3; and
wherein said phenyl and pyridinyl group is optionally substituted by 1, 2 or 3
substituents independently selected from:
-1, 2 or 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
-1, 2 or 3 substituents selected from: methyl, trifluoromethyl, ethyl, n-propyl,
i-propyl, hydroxy, methoxy, ethoxy, -COOH, -COOCH3, CONH2, CONH(CH3),
CON(CH3)2, amino, -NH(CH3), -N(CH3)2, -CH2-OH, -CH2-O-CH3, -CH2-NH2,
-CH2-N(CH3)2 and -(CH2)2-OH.
In the latter embodiment RN2 is preferably H, methyl or ethyl, most preferably H, and
RN1 is preferably benzyl or phenylethyl, both of which are optionally substituted with
methyl, ethyl, n-propyl, i-propyl, fluorine, chlorine, carboxy, methoxycarbonyl,
CONH2, CONH(CH3), CON(CH3)2; and which at the phenyl group is optionally
substituted with 1, 2 or 3 substituents independently selected from:
-1, 2 or 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
-1, 2 or 3 substituents selected from: methyl, trifluoromethyl, ethyl, n-propyl, i-propyl,
hydroxy, methoxy, ethoxy, -COOH, -COOCH3, CONH2, CONH(CH3), CON(CH3)2,
amino, -NH(CH3), -N(CH3)2, -CH2-OH, -CH2-O-CH3, -CH2-NH2, -CH2-N(CH3)2 and
-(CH2)2-OH.
Therefore most preferred meanings of Z according to this embodiment are:
wherein those groups wherein the phenyl is substituted twice with OMe and/or OH
are the very most preferred ones.
According to another preferred embodiment Z is defined as NRN2-SO2-RC or
NRN2-CO-RC wherein RN2 and Rc are preferably defined as follows:
RN2 is H, (Ci-4)alkyl, (C3.6)cycloalkyl or (Ci-3)alkyl-(C3.6)cycloalkyl; in particular H;
and
is (d.6)alkyl, (C3-6)cycloalkyl, (d.^alkyHCs^cycloalkyl, (C2-6)alkenyl, phenyl,
naphthyl, Met, (C^alkyl-phenyl, (CvaJalkyl-naphthyl, (Ci.3)alkyl-Het, wherein
said alkyl, cycloalkyl, alkyl-cycloalkyl, alkenyl, phenyl, naphthyl, Het, alkylphenyl,
alkyl-naphthyl, or alkyl-Het, are all optionally substituted with 1 to 4
substituents selected from R60.
In this embodiment the preferred meaning of Rc is methyl, ethyl, n-propyl, i-propyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine,
phenyl, naphthyl, benzyl, thiophene, furan, pyrrole, imidazole, pyrazole, oxazole,
isoxazole, thiazole, pyridazine, pyrimidine, pyrazine, diazepine, azepine, quinoline,
isoquinoline, benzofuran, benzothiophene, benzothiazole, purine, pteridine,
2,1,3-benzothiadiazole LW,,/3 , and
imidazo[2,1 -B][1 ,3]thiazole
all of which are optionally substituted with 1 to 3 substituents selected from R60,
particularly OH, CN, halogen, nitro, (Ci.3)alkyl, O(d.3)alkyl, carboxyl, COO(d.3)alkyl,
amino, NH(d.3)alkyl, N((Ci.3)alkyl)2, NHCO(Ci-3)alkyl, wherein the alkyl groups may
be substituted by halogen.
According to another preferred embodiment wherein Z is OR6b or N(R5b)R6b wherein
R5b is defined as RN2 and R6b is:
wherein
R7b is defined as H, COOH, CONH2, (d.6)alkyl, (C3.6)cycloalkyl, (d.4)alkyl-
(C3.6)cycloalkyl, (C2-6)alkenyl, aryl, Met, (d.4)alkyl-aryl, (d-4)alkyl-Het; all of
which are optionally substituted with R60; and
,8b is H or (d.4)alkyl; or
R7b and R8b are covalently bonded together to form a second (C3.7)cycloalkyl or a 4,
5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from
O, N, and S; and
when Z is N(R5b)R6b, either of R7b or R8b may be covalently bonded to R5b to
form a nitrogen-containing 5-or 6-membered heterocycle, wherein said
cycloalkyl or heterocycle being optionally substituted by R150; and
W2 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
wherein the alkylene and alkenylene groups according to b), c) and d) may
be substituted with (d-a) alkyl;
Q2 is a group of the subformula 1Mb
Q2a is aryl, Hetaryl, (d.3) alkyl-aryl or (Ci.3)alkyl-Hetaryl;
Q2b is phenyl or Hetaryl;
Q2c is a bond, O-Ci-4-alkyl, S-C^-alkyl, C^-alkyl, C2-4-alkenyl or
C2.4-alkynyl, wherein said O-Ci.4-alkyl, S-Ci.4-alkyl, Ci_4-alkyl, C2.4-
alkenyl or C2.4-alkynyl are optionally substituted with R170;
wherein R170 is defined as H or as 1 , 2 or 3 substituents
independently selected from:
- 1 , 2, or 3 substituents selected from halogen;
- one or two of each substituent selected from (Ci-4) alkyl, (d.
4) alkoxy, (C3.5) cycloalkyl, orcyano; wherein (Ci.4) alkyl may
optionally be substituted with 1 to 3 halogen atoms;
and
R2q is selected from H, CM, COOR161, CON(R162)2, S02N(R162)2, -N(R162)2,
OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2,
NHSO2RC, CONHSO2RC, SO2NHCORC, tetrazole, triazole and
CONHSO2N(R162)2;
qa isOorl;
qb isOorl;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is
optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2
heteroatoms selected from 0, N, and S, or a 9- or 10-membered aromatic
heterobicycle having 1 to 4 heteroatoms selected from O, N, and S.
Most preferably the index qa is 1.
In another above described preferred case, wherein Z is OR6b or N(R5b)R6b wherein
R5b is defined as RN2 and R6b is:
the substituents have most preferably one of the following meanings:
R7band R8bare each independently defined as R°, wherein said R° is optionally
substituted with R60; or
R7b and R8b are covalently bonded together to form a (Ca^cycloalkyl or a 4, 5- or 6-
membered heterocycle having from 1 to 3 heteroatom selected from O, N,
andS;
or when Z is N(R5b)R6b, either of R7b or R8b may be covalently bonded to R5b
to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said
cycloalkyl or heterocycle being optionally substituted by R150; and
Y3 is O or S;
R9b is defined as R°, wherein said R° is optionally substituted with R60; or
R9b is covalently bonded to either of R7b or R8b to form a 5- or 6-membered
heterocycle;
Q2 is a group of the subformula 1Mb
Description (Complete)3Q2a is aryl, Hetaryl, (d.3) alkyl-aryl or (d-3)alkyl-Hetaryl;
Q2b is a phenyl or Hetaryl;
Q2c is a bond, O-d-4-alkyl, S-Ci.4-alkyl, Ci-4-alkyl, C2-4-alkenyl or C2.4-alkynyl,
wherein said O-d-4-alkyl, S-d^-alkyl, d-4-alkyl, C2.4-alkenyl or C2.4-alkynyl
are optionally substituted with R170
wherein R170 is defined as H or as 1, 2 or 3 substituents independently
selected from:
-1, 2, or 3 substituents selected from halogen;
- one or two of each substituent selected from (d-4) alkyl, (d.4)
alkoxy, (63.5) cycloalkyi, or cyano; wherein (d_4) alkyl may optionally
be substituted with 1 to 3 halogen atoms;
and
R2q is selected from H, CN, COOR161, CON(R162)2, SO2N(R162)2, -N(R162)2,
OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2,
NHS02RC, CONHSO2RC, S02NHCORC, tetrazole, triazole and
CONHSO2N(R162)2;
qa is 0 or 1 ;
qb isOoM;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is
optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2
heteroatoms selected from O, N, and S, or a 9- or 10-membered aromatic
heterobicycle having 1 to 4 heteroatoms selected from O, N, and S.
Most preferably the index qa is 1.
Hereinafter, preferred groups and substituents are described for those cases
wherein either L or Z, or both L and Z are defined as follows:
Most preferably one of W1 and W2 or both W1 and W2 represent a single bond.
Preferred meanings of one of R7a and R7bor both R7a and R7b are H, COOH, CONH2,
CF3, (d-^alkyl, (C3.7)cycloalkyl, (d.3)alkyl-(C3.7)cycloalkyl, Hetaryl or (d.3)alkyl-
Hetaryl, wherein the alkyl, cycloalkyi groups and Hetaryl groups are optionally
subsituted with R160.
Preferred meanings of one of R8a and R8bor both R8a and R8b are H and CH3.
Furthermore, it is preferred that R7a and R8a and/ or R7b and R8b are covalently
bonded together to form a second (C3.7)cycloalkyl or a 4, 5- or 6-membered
heterocycle having from 1 to 2 heteroatom selected from O, N, and S, wherein said
cycloalkyl or heterocycle being optionally substituted with R160, preferably with 1 to 3
substituents selected from hydroxy, (Ci.3)alkyl, CO(d.3)alkyl and SO2(Ci.3)alkyl.
According to the hereinbefore described embodiment R7a and R7b is each
independently preferably selected from COOH, CONH2, methyl, ethyl, n-propyl, ipropyl,
2-methylpropyl, hydroxy-methyl, 1-hydroxy-ethyl, amino-methyl, 1-aminoethyl,
2-hydroxy-ethyl, 2-methylthio-ethyl, 2-amino-ethyl, 2-(dimethylamino)-ethyl and
thiazolyl, wherein the thiazolyl group is optionally substituted with R160; or
R7b and R8b are covalently bonded together to form a cyclic group preferably
Most preferably, the groups CR7aR8a and CR7bR8b are independently selected from:
R9a and/or R9b is preferably H, (Ci-3 alkyl), (C3.6)cycloalkyl or
(Ci-3)alkyl-(C3.6)cycloalkyl, all of which optionally substituted with 1 to 3
substituents selected from halogen, hydroxy and methyl; most preferably R9a
and/or R9b is H or methyl.
Preferably Q1a and Q2a are independently selected from
wherein 1 or 2 C-atoms of each cyclic group as listed above may be substituted with
RL is H, (d.4alkyl) or (d-^alkoxy, and
RQ is H or CH3, (C2.6alkyl), -CH2-(C2-6alkenyl), -CH2-(C2.6alkynyl), (C3.6)cycloalkyl,
(d,4)alkyl-(C3.6)cycloalkyl; all of which being optionally substituted with Ci-6-
cycloalkyl or alkylcycloalkyl, but preferably not the C-atom thereof directly
bonded to the N-atom, is optionally substituted with hydroxy, Ci-e-alkoxy,
amino, -NH(d.4-alkyl) and/or -N(d^-alkyl)2;
Preferably Q1b and/or Q2b are selected from the group consisting of phenyl, furan,
thiophene, oxazole, thiazole, pyridine, pyrimidine, pyrrazole, imidazole and pyrazine.
Most preferably Q and Q are independently selected from the group consisting of
Description (Complete)3wherein all shown cyclic groups are optionally substituted with R 160.
Q1c and Q2c are preferably selected from a bond, -O-CH2-, -CH2-CH2-, -C(R170)=CHand
-CH=C(R170)-;
most preferably selected from a bond and -CH=C(R170)-,
wherein R170 is preferably selected from H, F, -CH3, -CH2CH3, -CF3 and
cyclopropyl;
most preferably selected from H, F, -CH3 and -CH2CH3.
R1q and R2q are preferably selected from H, CN, COOR161, CON(R162)2, SO2N(R162)2,
-N(R162)2, OR161,-NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2,
NHSO2RC, CONHSO2RC, SO2NHCORC, tetrazole, triazole and
CONHSO2N(R162)2;
most preferably selected from COOR161, CON(R162)2 and SO2N(R162)2;
wherein R161 and R162 are as defined, but most preferably H and/or methyl.
In the case of L comprising the group Q1 as defined hereinbefore, especially
preferred compounds obey one of the following conditions
a) Q1a is phenyl, q is 1 and Q1c is a bond;
b) Q1a is phenyl, q is 0 and Q1c is vinyl; or
c) Q1a is a 9- or 10-membered aromatic heterobicycle having 1 or 2
heteroatoms selected from O, N, and S, said heterobicycle optionally being
substituted with R160; q is 0 and Q1c is a bond, -CH2-CH2- or -CH=CH-.
Furthermore, those compounds of the above described embodiment are especially
preferred wherein the group Q1c-R1q is -CH=CH-COOH.
In the case of Z comprising the group Q2 as defined hereinbefore, especially
preferred compounds obey one of the following conditions:
a) qa is 1, Q2a is phenyl, qb is 1 and Q2c is a bond;
b) qa is 1, Q2a is phenyl, qb is 0 and Q2c is-CH=C(R170)-,
wherein R170 is selected from H, F, -CH3 or -CH2CH3; or
c) qa is 1, Q2a is a 9- or 10-membered aromatic heterobicycle having 1 or 2
heteroatoms selected from O, N, and S, said heterobicycle optionally being
substituted with R160; qb is 0 and Q2c is a bond, -CH2-CH2- or -CH=C(R170)-,
wherein R170 is selected from H, F, -CH3 or -CH2CH3.
Furthermore, those compounds of the above described embodiment are especially
preferred wherein the group Q2c-R2q is -CH=C(R170)-COOH, wherein R170 is selected
from H, F,-CH3 or-CH2CH3.
Preferably Q1 and Q2 are independently selected from:
wherein all shown cyclic groups are optionally substituted with R160; most preferably
1 or 2 substituents selected from fluorine, chlorine, bromine, OH, methoxy, ethoxy,
amino, NH(CH3), methyl, ethyl, i-propyl and n-propyl;
wherein R170 is each independently defined as hereinbefore; preferably R170 is
defined as H, F, -CH3, -CH2CH3, -CF3, or cyclopropyl; most preferably H, F, -CH3, or
-CH2CH3; and
wherein RQ is each independently defined as hereinbefore; preferably RQ is defined
as H, (Ci.6alkyl), (C3.6)cycloalkyl or (Ci-4)alkyl-(C3.6)cycloalkyl; most preferably H or
methyl.
Most preferably, Q1 and Q2 are independently selected from:
wherein all shown cyclic groups are optionally substituted with R160; most preferably
1 or 2 substituents selected from fluorine, chlorine, bromine, OH, methoxy, ethoxy,
amino, NH(CH3), methyl, ethyl, i-propyl and n-propyl;
wherein R170 is each independently defined as hereinbefore; preferably R170 is
defined as H, F, -CH3, -CH2CH3, -CF3, or cyclopropyl; most preferably H, F, -CH3, or
-CH2CH3; and
wherein RQ is each independently defined as hereinbefore; preferably RQ is defined
as H, (Ci-6alkyl), (C3.6)cycloalkyl or (CT-^alkyKCs^cycloalkyl; most preferably H or
methyl.
In case Q1a or Q2a is a phenylene or Hetaryl group, preferred substituents of this
group are selected from (Ci-3)alkyl and (d.3)alkoxy, especially from methyl, ethyl,
methoxy, ethoxy. In the case where Q1a or Q2a is phenylene, the subsituent is
preferably in meta-position to Q1b, in case q = 1, or to Q2b, in case qb = 1; or to Q1c,
in case q = 0, or to Q2c, in case qb = 0, respectively. Thus, most preferred groups Q1
and Q2 which are substituted are for example:
wherein R170 is each independently defined as hereinbefore; preferably R170 is
defined as H, F, -CH3, -CH2CH3, -CF3, or cyclopropyl; most preferably H, F, -CH3, or
Hereinafter preferred groups N(R5a)R6a and N(R5b)R6bare described for those cases
wherein either L or Z, or both L and Z are defined as follows:
6a L is N(Rsa)RM wherein Rba ii«s.:
Z is N(R5b)R6b wherein R6b is:
W
Therefore, according to this embodiment examples of very preferred groups L and Z,
in case qa is 1, are independently selected from the group consisting of:
wherein all shown cyclic groups are optionally substituted with R160; most preferably
1 or 2 substituents selected from fluorine, chlorine, bromine, OH, methoxy, ethoxy,
amino, NH(CH3), methyl, ethyl, i-propyl and n-propyl;
wherein R170 is each independently defined as hereinbefore; preferably R170 is
defined as H, F, -CH3, -CH2CH3, -CF3, or cyclopropyl; most preferably H, F, -CH3, or
-CH2CH3; and
wherein RQ is each independently defined as hereinbefore; preferably RQ is defined
as H, (Ci.6alkyl), (C3.6)cycloalkyl or (Ci.4)alkyl-(C3.6)cycloalkyl; most preferably H or
methyl.
Examples of preferred groups Z, in case qa is 0, are independently selected from the
group consisting of:
Hereinafter, preferred groups N(R5a)R6a and N(R5b)R6b are described for those
cases wherein either L or Z, or both L and Z are defined as follows:
L is N(R5a)R6a wherein R6a is:
Z is N(R5b)R6b wherein R6b is:
Therefore, according to this embodiment L and Z are more preferably independently
selected from the group consisting of:
wherein all shown cyclic groups are optionally substituted with R160; most preferably
1 or 2 substituents selected from fluorine, chlorine, bromine, OH, methoxy, ethoxy,
amino, NH(CH3), methyl, ethyl, i-propyl and n-propyl;
wherein R170 is each independently defined as hereinbefore; preferably R170 is
defined as H, F, -CH3, -CH2CH3, -CF3, or cyclopropyl; most preferably H, F, -CH3, or
-CH2CH3; and
wherein RQ is each independently defined as hereinbefore; preferably RQ is defined
as H, (Ci.6alkyl), (C3.6)cycloalkyl or (Ci.4)alkyl-(C3.6)cycloalkyl; most preferably H or
methyl.
Preferably R2 is R21, wherein R21 is a phenyl or Met selected from the group of
formulas
and wherein said R21 is optionally substituted with R150.
A very most preferred definition of R is '—o , N
N
-N or I/^N all of which may be unsubstituted or substituted as
NH2
defined.
In the case R2 as defined above is substituted, it is preferably substituted with 1, 2 or
3 substituents selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
-1 to 2 substituents selected from:
a) (d-4)alkyl or (d.4)alkoxy, both optionally substituted with OH, O(d.4)alkyl,
SO2(d.4 alkyl); 1 to 3 halogen atoms, amino, NH(CH3) or N(CH3)2);
b) NR111R112 wherein both R111 and R112are independently H, (d.4)alkyl, or R112 is
(C3.7)cycloalkyl, (d.3)alkyl(C3.7)cycloalkyl, phenyl, benzyl; or both R111 and R112
are covalently bonded together and to the nitrogen to which they are attached to
form a nitrogen-containing heterocycle, each of said alkyl, cycloalkyl,
alkylcycloalkyl, phenyl and benzyl, being optionally substituted with halogen or:
-OR2h or N(R2h)2, wherein each R2h is independently H, (d.4)alkyl, or both R2h
are covalently bonded together and to the nitrogen to which they are attached to
form a nitrogen-containing heterocycle;
c) NHCOR117 wherein R117 is (d.4)alkyl, O(d_4)alkyl or O(C3.7)cycloalkyl; and
e) CONH2, CONH(d.4alkyl), CON(d.4alkyl)2.
Most preferred substituents of R2 are selected from:
-1 to 2 substituents selected from fluorine;
- one of each substituent selected from: chlorine, bromine, NO2, cyano; and
-1 to 2 substituents selected from:
a) methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, methoxy, trifluoromethoxy,
ethoxy, n-propoxy or i-propoxy, wherein said methyl, ethyl, n-propyl, i-propyl,
ethoxy, n-propoxy and i-propoxy are optionally substituted with OH, methoxy,
amino, NH(CH3) or N(CH3)2;
b) NR111R112 wherein both R111 and R112are independently H or methyl, or R112 is
phenyl or benzyl;
c) NHCOR117 wherein R117 is methyl or methoxy; and
e) CONH2, CONH(CH3), CON(CH3)2.
R3 is preferably selected from (C3.7)cycloalkyl, (C5.7)cycloalkenyl, (C6-io)bicycloalkyl,
(C6-io)bicycloalkenyl, or HCy wherein said groups are unsubstituted or mono- or
disubstituted by halogen, hydroxy, d.4alkyl and/or O-Ci-4alkyl, wherein the alkyl
groups may be fluorinated.
Most preferably R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl,
or a group selected from: and
wherein all said cyclic groups are unsubstituted or substituted by fluorine, d-aalkyl or
CF3.
The very most preferred meaning of R3 is cyclopentyl, or cyclohexyl.
R4a. R4b. R5:
Preferably R4a, R4b, R5 each are independently H, hydroxy, halogen, cyano, nitro,
carboxyl, (d.4)alkyl, CF3, (d.4)alkoxy, -O-(C3.7)cycloalkyl, -O-(C1.3)alkyl-
(C3.7)cycloalkyl, -O-aryl, -O-(d.3)alkyl-aryl, -O-Het, -O-(d.3)alkyl-Het, NRN1RN2, or
COR°, NRN2CORC, CONRN2RN1, NRN3CONRN1RN2, in particular NHCO(d.4)alkyl or
CONHRN1, NHCONHRN1;
wherein R°, RN1, RN2, RN3 are as defined; preferably R°, RN1 are independently of
each other H, (d_4)alkyl, aryl, (d.3)alkyl-aryl, wherein aryl is preferably optionally
substituted phenyl; and preferably RN2, RN3 are H or methyl; wherein all said alkyl
groups, including alkoxy, may be mono-, di- or trisubstituted by fluorine or monosubstituted
by chlorine or bromine.
Most preferred substituents R4a, R4b, R5 each are independently H, hydroxy, halogen,
cyano, nitro, methyl, CF3, methoxy, carboxy, amino, -NMe2, -CONH2, -NHCONH2l
-CO-NHMe, -NHCONHMe, -CO-NMe2 or -NHCONMe2; in particular H, methyl or
methoxy. Preferably R4ais H or methyl. Very most preferably at least two of the
substituents selected from R4a, R4b, R5 are H.
The substituents R60 are preferably each defined as 1 to 4 substituents
independently selected from:
- 1 to 3 substituents selected from halogen;
- one of each substituent selected from: NO2, cyano, azido; and
- 1 to 3 substituents selected from:
a) (Ci_4) alkyl, (C3.7)cycloalkyl, (C2.4)alkenyl, (C2.4)alkynyl, (Ci.3)alkyl-(C3.7)cycloalkyl,
all of which optionally being substituted with R150;
b) OR0;
e) N(RN2)RN1;
f) N(RN2)CORC;
j) COOR°;
k) CON(RN2)RN1;
I) phenyl, Het, (d.3alkyl)phenyl or (d.3alkyl)Het; wherein
Met is selected from furan, tetrahydrofuran, thiophene, tetrahydrothiophene,
tetrahydropyran, pyridinyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine,
thiomorpholine, homopiperidine and homopiperazine;
wherein said RN1, Rc and/or R° are optionally substituted with R150as defined.
R150:
R150 is preferably defined as 1 to 4 substituents independently selected from:
- 1 to 3 fluorine-substituents;
- one of each substituent selected from: chlorine, bromine, iodine, NO2, cyano, azido;
and
- 1 to 3 substituents selected from:
a) (Ci-3) alkyl, CF3, (C3.6)cycloalkyl, (Ci.3) alkyl-(C3.6)cycloalkyl, all of which optionally
substituted with R160;
b) OR0;
e) N(RN2)RN1;
f) N(RN2)CORC;
j) COOR°;
k) CON(RN2)RN1;
wherein said RN1, Rc and/or R° are optionally substituted with R160 as defined.
R160:
R160 is preferably defined as 1, 2 or 3 substituents independently selected from:
- 1, 2 or 3 fluorine substituents; and
- one of each substituent selected from chlorine, bromine, iodine, CN, nitro, methyl,
trifluoromethyl, ethyl, n-propyl, i-propyl, COOH, COOCH3, OH, OCH3, OCF3, NH2,
NHCH3, N(CH3)2, SO2NH2, NHCOCH3, SO2NHCOCH3, CONH2> CONHCH3 and
CON(CH3)2.
R°. Rc:
Preferably R°, Rcare independently selected from (Ci.4)alkyl, (C3.6)cycloalkyl,
(Ci_3)alkyl-(C3-6)cycloalkyl, phenyl, benzyl, Met, (Ci.3)alkyl-Het; all of which are
optionally substituted as defined; and R° may also be H.
pN1 pN2 pN3 pN4.
RN1 is preferably selected from H, (d)alkyl, (C3.6)cycloalkyl, (d.3)alkyl-
(C3.6)cycloalkyl, phenyl, benzyl, phenylethyl, Met, (Ci.3)alkyl-Het; wherein said
alkyl, cycloalkyl, alkyl-cycloalkyl, phenyl, benzyl, phenylethyl, Het and alkyl-
Het are optionally substituted as defined; and
RN2, RN3, RN4 are independently selected from H, methyl, ethyl, n-propyl, i-propyl,
cyclopropyl, cyclopropylmethyl; all of which being optionally substituted with
methyl, fluorine, carboxy or methoxycarbonyl; and/or wherein said ethyl, npropyl
or i-propyl, but preferably not the C-atom thereof directly bonded to the
N-atom, is optionally substituted with hydroxy, methoxy, amino, -NH(CH3)
and/or -N(CH3)2; and
in the case
a) of a group N(RN2)RN1, RN2 and RN1 or
b) of a group NRN3-N(RN2)RN1, RN3 and RN1, or RN2 and RN1
may be covalently bonded together to form a 5-, 6- or 7-membered saturated
heterocycle which may have additionally one heteroatom selected from O, N, and S,
wherein said heterocycle is optionally substituted as defined.
Included within the scope of this invention are all compounds of formula I as
presented in Tables 1 to 8.
Preferred compounds according to this invention are listed in the tables. Particularly
compounds of these tables are preferred which show an IC50 value of below 200 nM,
as for example those compounds included in the claims 51, 52, 53, 54 and 55.
Polymerase activity
The ability of the compounds of formula (I) to inhibit RNA synthesis by the RNA
dependent RNA polymerase of HCV can be demonstrated by any assay capable of
measuring RNA dependent RNA polymerase activity. A suitable assay is described
in the examples.
Specificity for RNA dependent RNA polymerase activity
To demonstrate that the compounds of the invention act by specific inhibition of HCV
polymerase, the compounds may be tested for inhibitory activity in a DNA dependent
RNA polymerase assay.
When a compound of formula (I), or one of its therapeutically acceptable salts, is
employed as an antiviral agent, it is administered orally, topically or systemically to
mammals, e.g. humans, cattle, pigs, dogs, cats, rabbits or mice, in a vehicle
comprising one or more pharmaceutically acceptable carriers, the proportion of
which is determined by the solubility and chemical nature of the compound, chosen
route of administration and standard biological practice.
For oral administration, the compound or a therapeutically acceptable salt thereof
can be formulated in unit dosage forms such as capsules or tablets each containing
-99-
a predetermined amount of the active ingredient, ranging from about 25 to 500 mg,
in a pharmaceutically acceptable carrier.
For topical administration, the compound can be formulated in pharmaceutically
accepted vehicles containing 0.1 to 5 percent, preferably 0.5 to 5 percent, of the
active agent. Such formulations can be in the form of a solution, cream or lotion.
For parenteral administration, the compound of formula (I) is administered by either
intravenous, subcutaneous or intramuscular injection, in compositions with
pharmaceutically acceptable vehicles or carriers. For administration by injection, it is
preferred to use the compounds in solution in a sterile aqueous vehicle which may
also contain other solutes such as buffers or preservatives as well as sufficient
quantities of pharmaceutically acceptable salts or of glucose to make the solution
isotonic.
Suitable vehicles or carriers for the above noted formulations are described in
pharmaceutical texts, e.g. in "Remington's The Science and Practice of Pharmacy",
19th ed., Mack Publishing Company, Easton, Penn., 1995, or in "Pharmaceutical
Dosage Forms And Drugs Delivery Systems", 6th ed., H.C. Ansel et al., Eds.,
Williams & Wilkins, Baltimore, Maryland, 1995.
The dosage of the compound will vary with the form of administration and the
particular active agent chosen. Furthermore, it will vary with the particular host under
treatment. Generally, treatment is initiated with small increments until the optimum
effect under the circumstance is reached. In general, the compound of formula I is
most desirably administered at a concentration level that will generally afford
antivirally effective results without causing any harmful or deleterious side effects.
For oral administration, the compound or a therapeutically acceptable salt is
administered in the range of 10 to 200 mg per kilogram of body weight per day, with
a preferred range of 25 to 150 mg per kilogram.
For systemic administration, the compound of formula (I) is administered at a dosage
of 10 mg to 150 mg per kilogram of body weight per day, although the
aforementioned variations will occur. A dosage level that is in the range of from
about 10 mg to 100 mg per kilogram of body weight per day is most desirably
employed in order to achieve effective results.
When the compositions of this invention comprise a combination of a compound of
formula I and one or more additional therapeutic or prophylactic agent, both the
compound and the additional agent should be present at dosage levels of between
about 10 to 100%, and more preferably between about 10 and 80% of the dosage
normally administered in a monotherapy regimen.
When these compounds or their pharmaceutically acceptable salts are formulated
together with a pharmaceutically acceptable carrier, the resulting composition may
be administered in vivo\o mammals, such as man, to inhibit HCV polymerase or to
treat or prevent HCV virus infection. Such treatment may also be achieved using the
compounds of this invention in combination with agents which include, but are not
limited to: immunomodulatory agents, such as a-, P-, or y-interferons; other antiviral
agents such as ribavirin, amantadine; other inhibitors of HCV NS5B polymerase;
inhibitors of other targets in the HCV life cycle, which include but are not limited to,
helicase, NS2/3 protease, NS3 protease, or internal ribosome entry site (IRES); or
combinations thereof. The additional agents may be combined with the compounds
of this invention to create a single dosage form. Alternatively these additional agents
may be separately administered to a mammal as part of a multiple dosage form.
Methodology and Synthesis
Indole derivatives or analogs according to the present invention can be prepared
from known monocyclic aromatic compounds by adapting known literature
sequences such as those described by J.W. Ellingboe et al. (Tet. Lett. 1997, 38,
7963) and S. Cacchi et al. (Tet. Lett. 1992, 33, 3915). Scheme 1, shown below
wherein R1, R2, Sp, Y and L are as described herein, illustrate how these procedures
can be adapted to the synthesis of compounds of formula I of this invention.
In carrying out the route illustrated in Scheme 1, a suitably protected form of 3-
trifluoroacetamido-4-iodobenzoic acid l(i) is reacted with an alkyne l(ii) in the
presence of a metal catalyst (e.g. a palladium metal complex such as PdCI2(PPh3)2,
Pd2dba3, Pd(PPh3)4 and the like), a base (Et3N, DIEA and the like or an inorganic
basic salt including metal carbonates, fluorides and phosphates), and optionally in
the presence of an additional phosphine ligand (triaryl or heteroarylphosphine, dppe,
dppf, dppp and the like). Suitable solvents for this reaction include DMF, dioxane,
THF, DME, toluene, MeCN, DMA and the like at temperatures ranging from 20 °C to
170 °C, or alternatively without solvent by heating the components together.
Alternatively, the cross-coupling reaction can be carried out on a suitably protected
form of 3-amino-4-iodobenzoate and the amino group can be trifluoroacetylated in
the subsequent step as described by J.W. Ellingboe et al. (Tet. Lett. 1997, 38, 7963).
Reaction of the above diarylalkynes l(iii) with an enol triflate or equivalent under
cross-coupling conditions similar to those described above gives after hydrogenation
of the double bond, indole derivatives l(iv). Enol Inflates are known and can be
prepared from the corresponding ketones by following known literature methods (for
example, cyclohexene triflate can be prepared from cyclohexanone, triflic anhydride
and a hindered organic base such as 2,6-di-tert-butyl-4-methylpyridine). The
hydrogenation of the double bond originally present in R3 can be carried out with
hydrogen gas or a hydrogen donor (ammonium formate, formic acid and the like) in
the presence of a metal catalyst (preferably Pd) in a suitable solvent (lower alkyl
alcohols, THF etc.).
The indole derivative l(iv) is then alkylated on nitrogen with an appropriate spacer
(Sp) and further elaborated if necessary to give AAalkylated indole carboxylates
where Y, Sp and L are as defined herein.
Finally, following hydrolysis of the indole ester protecting group, the resulting
carboxyindole derivative is converted to compounds of formula 1 by coupling with the
appropriate Z group. Condensation of the 6-indolecarboxylic acid with amines or
alcohols can be accomplished using standard amide bond forming reagents such as
TBTU, HATU, BOP, BroP, EDAC, DCC, isobutyl chloroformate and the like, or by
activation of the carboxyl group by conversion to the corresponding acid chloride
prior to condensation with an amine. Any remaining protecting group is removed
following this step to give compounds of formula 1.1.
Alternatively, compounds of formula 1.1 can be prepared by elaboration from a preexisting
indole core by following adaptations of literature procedures as described,
for example, by P. Gharagozloo et al. (Tetrahedron 1996, 52, 10185) or K. Freter (J.
Org. Chem. 1975, 40, 2525). Such a methodology is illustrated in Scheme 2:
(Figure Removed) In carrying out the route illustrated in Scheme 2, commercially available 6-
indolecarboxylic acid 2(i), which can also be prepared according to the method of S.
Kamiya et al. (Chem. Pharm. Bull. 1995, 43,1692) is used as the starting material.
The indole 2(i) is reacted with a ketone 2(ii) under basic or acidic aldol-type
conditions. Suitable conditions to affect this condensation include strong bases such
as alkali metal hydroxides, alkoxides and hydrides in solvents such as lower alkyl
alcohols (MeOH, EtOH, terfBuOH etc.), THF, dioxane, DMF, DMSO, DMA and the
like at reaction temperature ranging from -20 °C to 120 °C. Alternatively, the
condensation can be carried out under acid conditions using organic or mineral
acids or both. Appropriate conditions include mixtures of AcOH and aqueous
phosphoric acid at temperatures ranging from 15°C to 120 °C.
The carboxylic acid group is then protected in the form of an ester (usually lower
alkyl) using known methods. Halogenation (usually bromination, but also iodination)
of the 2-position of the indole 2(iii) gives 2(iv). Suitable halogenating agents
include, for example, elemental bromine, A/-bromosuccinimide, pyridine tribromide,
dibromohydantoin and the corresponding iodo derivatives. Suitable solvents for this
reaction are inert to reactive halogenating agents and include for example
hydrocarbons, chlorinated hydrocarbons (DCM, CCI4, CHCI3), ethers (THF, DME,
dioxane), acetic acid, ethyl acetate, IPA, and mixtures of these solvents. Reaction
temperature ranges from -40 °C to 100 °C. A method of choice to carry out the
bromination of indoles as shown in Scheme 2 was described by L. Chu (Tet. Lett.
1997,35,3871).
The 2-bromoindole derivatives 2(iv) can be converted to fully substituted key
intermediates l(v) by different sequences: (1) Trans-metallation of the 2-
bromoindole to tin, boron, zinc species and the like, followed by cross-coupling
reaction with aryl or heteroaryl halides under transition metal catalysis as described
in scheme 1 gives indole derivative 2(vii) which can then be elaborated on nitrogen
as described in scheme 1 to give key intermediate 1(v). In this approach, the indoleic
NH is optionally protected with known protecting groups such as BOC, MOM, SEM,
SO2Ph and the like. The protecting group is removed at a later stage of the
sequence, prior to linker attachment. The conversion of 2-bromoindole derivatives
2(iv) to the corresponding organotin species 2(vi) is carried out via initial lowtemperature
(usually-78 ° to -30 °C) halogen-metal exchange using an alkyllithium
reagent (e.g. nBuLi or fert-BuLi) or using lithium metal. The transient 2-lithioindole
species is then trapped with a trialkyltin halide (e.g. nBu3SnCI or Me3SnCI) or a
borate ester (e.g. trimethyl or triisopropyl borates). Alternatively, the lithioindole
intermediate can be trapped with zinc chloride to form the corresponding
organozincate which can also undergo transition metal-catalyzed cross-coupling with
aromatic and heteroaromatic halides or triflates as described, for example, by M.
Rowley (J. Med. Chem. 2001, 44, 1603). Alternatively, species such as 2(vi) where
the indoleic NH is masked with a protecting group, can be generated directly from
2(iii) by ester formation followed by indole NH protection and abstraction of the 2-H
proton with strong base (e.g. alkyllithiums, alkalimetal amides) followed by transmetallation.
Alternatively, 2-bromoindole 2(iv) can be cross-coupled directly to aryl
and heteroaryl stannanes or boronic acid derivatives to give 2(vii) directly. Boron or
tin organometallic species are from commercial sources or can be prepared by
standard literature procedures. (2) In a second approach, 2-bromoindole 2(iv) is first
elaborated on nitrogen to give 2(v) which is then cross-coupled to R2 to give the
same intermediate 1(v) as described above.
Cross-coupling with organoboron reagents can be carried out by any variations of
the Suzuki cross-coupling reaction reported in the literature. This usually involves
the use of a transition metal catalyst (usually Pd°), triaryl or triheteroarylphosphine
ligands, an additive such as an inorganic chloride (e.g. LiCI), and a base (usually an
aqueous inorganic base such as sodium or potassium carbonate or phosphate).
The reaction is usually carried out in an alcoholic solvent (EtOH), DME, toluene, THF
and the like at temperatures ranging from 25 °C to 140 °C.
Cross-coupling with tin reagents can be carried out by any variations of the Stille
cross-coupling reaction reported in the literature. This usually involves the use of a
transition metal catalyst (usually Pd°), triaryl or triheteroaryl phosphine ligands, and
an additive such as an inorganic chloride (e.g. LiCI) or iodide (e.g. Cul). Suitable
solvents for this reaction include toluene, DMF, THF, DME and the like at
temperatures ranging from 25 °C to 140 °C. Intermediate l(v) is then converted to
compounds of formula 1.1 as described for Scheme 1.
Reaction conditions to alkylate the nitrogen of an indole derivative are well known to
those skilled in the art and include the use of strong bases such as alkali metal
hydrides, hydroxides, carbonates, amides, alkoxides and alkylmetals, in the
appropriate solvent (such as THF, dioxane, DME, DMF, MeCN, DMSO, alcohols and
the like) at temperatures ranging from -78 °C to 140 °C. An electrophilic form of Sp
is used for the alkylation of the indole anion. Such electrophilic species include
iodides, bromides, chlorides and sulfonate esters (mesylate, tosylate, brosylate or
triflate).
EXAMPLES
The present invention is illustrated in further detail by the following non-limiting
examples. All reactions were performed in a nitrogen or argon atmosphere.
Temperatures are given in degrees Celsius. Flash chromatography was performed
on silica gel. Solution percentages or ratios express a volume to volume
relationship, unless stated otherwise. Mass spectral analyses were recorded using
electrospray mass spectrometry. Hereinbefore and hereinafter the following
abbreviations or symbols are used:
AcOH: acetic acid
BOC or Boc: te/t-butyloxycarbonyl
BOP: benzotriazole-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
BroP: Bromo tris(dimethylamino)phosphonium hexafluorophosphate
Bu: butyl
Cbz: carbobenzyloxy carbonyl;
DBA: dibenzylideneacetone;
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC: 1,3-Dicyclohexyl carbodiimide
DCM: dichloromethane
DEPC: diethyl pyrocarbonate;
DIEA: diisopropylethylamine;
DMAP: 4-(dimethylamino)pyridine;
DME: dimethoxyethane;
DMF: AV-dimethylformamide;
DMSO: dimethylsulfoxide;
dppe: 1,2-bis(diphenylphosphino)ethane
dppf: 1,1 '-bis(diphenylphosphino)ferrocene
dppp: 1,2-bis(diphenylphosphino)propane
DTT: dithiothreitol
EDAC: see EDC
EDC: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
EDTA: ethylenediaminetetraacetate
ES": electro spray (negative ionization)
ES+: electro spray (positive ionization)
Et: ethyl;
Et2O: diethyl ether;
EtOAc: ethyl acetate;
EtOH: ethanol
Fmoc: 9-Fluorenylmethyloxycarbonyl
HATU: 0-(7-azabenzotriazol-1 -yO-N.NX.N'-tetramethyluronium
hexafluorophosphate
HBTU: O-Benzotriazol-1 -yl-/V,A/,/V',A/'-tetramethyluronium hexafluorophosphate
HOAT: 1 -hydroxy-7-azabenzotriazole
HOBt: 1-Hydroxybenzotriazole
HPLC: high performance liquid chromatography;
I PA: isopropyl acetate
'Pr: isopropyl
'PrOH: isopropanol
Me: methyl;
MeCN: acetonitrile;
MeOH: Methanol;
MOM: methoxymethyl;
MS (ES): electrospray mass spectrometry;
NMP: N-methylpyrrolidone
PFU: plaque forming units;
Ph: phenyl;
RNAsin: A ribonuclease inhibitor marketed by Promega Corporation
RT: room temperature (approximatly 25°C)
SEM: trimethylsilylethoxymethyl;
TBE: tris-borate-EDTA;
TBME: tert-butylmethyl ether
TBTU: 2-( 7H-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;
tBu: tert.-butyl;
TFA: trifluoroacetic acid;
TFAA: trifluoroacetic anhydride;
THF: tetrahydrofuran;
TLC: thin layer chromatography
Tris: 2-amino-2-hydroxymethyl-1,3-propanediol
UMP: uridine 5'-monophosphate
UTP: uridine 5'-triphosphate
Examples 1 -33 illustrate methods of synthesis of representative compounds of this
invention.
EXAMPLE 1
3-Cyclohexyl-2-phenylindole-6-carboxylicacid:
(Figure Removed)Methyl 3-amino-4-iodobenzoate:
3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH (150mL) and
SOCI2 (4.8 ml_, 65.8 mmol, 1.3 equivalent) was added. The mixture was refluxed for
3 h and then volatiles were removed under reduced pressure. The residue was coevaporated
3 x with MeOH and dried in vacuo (15.23 g).
Methyl 3-trifluoroacetamido-4-iodobenzoate:
The aniline derivative from above (14.53 g, 52 mmol) was dissolved in DCM (200
ml) and TFAA (15 ml_, 104 mmol) was added. The dark purple solution was
refluxed overnight. Volatiles were removed under reduced pressure and the residue
was passed through a short pad of silica gel using DCM as eluent. The desired
product was obtained as a pink solid (13.81 g): MS (ES") m/z 371.9 (M-H).
4-Phenylethynyl-3-(2,2,2-trifluoro-ethanoylamino)-benzoic acid methyl ester:
The iodide from above (0.742 g, 2 mmol), phenylacetylene (0.37 ml, 3.9 mmol, 1.7
equivalent) and Et3N (6 ml) were charged in a dry flask under argon. PdCI2(PPh3)2
(0.241 g, 0.3 mmol) was added and the mixture was stirred at room temperature until
judged complete by HPLC analysis (~5 h). The reaction mixture was concentrated to
1/2 volume under reduced pressure and diluted with water (80 mL). The mixture was
extracted with EtOAc (3 x 100 mL) and the organic extract washed with 5% HCI (100
mL), after (100 mL) and brine (40 mL). After drying over MgSO4) the residue was
purified by flash chromatography using 20% EtOAc - hexane as eluent to give the
desired cross-coupled alkyne as a tan solid (0.442 g): MS (ES+) m/z348.0 (MH+).
Methyl 3-(cyclohexenyl)-2-phenylindole 6-carboxylate:
A flame-dried flask was charged with finely powdered anhydrous K2CO3 (0.153 g, 1.1
mmol) and the alkyne derivative from above (0.390 g, 1.1 mmol). Dry DMF (4 mL)
was added and the suspension degassed with a stream of argon. The enol triflate
derived from cyclohexanone, prepared following the procedure described by A.G.
Martinez, M. Hanack et al. (J. Heterocyclic Chem. 1988, 25, 1237) or equivalent
methods described in the literature (0.802 g, 3.3 mmol, 3 equivalents) was added
followed by Pd(PPh3)4 (0.086 g, 0.07 mmol) and the mixture was stirred for 8 h at
room temperature. DMF was removed under vacuum and the residue purified by
flash chromatography using DCM as eluent (0.260 g): MS (ES+) m/z332.2 (MH+).
Methyl 3-cyclohexyl-2~phenylindole-6-carboxylate:
The material from above was hydrogenated (1 atm H2 gas) over 20% Pd(OH)2 in the
usual manner, using MeOH as solvent. The desired cyclohexane indole was
isolated after filtration of the catalyst: MS (ES+) m/z 334.1 (MH+).
3-Cyclohexyl-2-phenylindole-6-carboxylicacid:
The methyl ester from above (0.154 g, 0.15 mmol) was refluxed overnight in a
mixture of MeOH (10 mL) and 2N NaOH (6 mL) until complete hydrolysis had
occurred as shown by HPLC analysis. After cooling to room temperature, 2N HCI (5
mL) was added followed by AcOH to pH 7. MeOH was removed under reduced
pressure, water (50 mL) was added and the product extracted with EtOAc. The
extract was washed with water and brine, and dried (MgSO4). Removal of volatiles
under reduced pressure gave the title indole carboxylic acid of example 1 as a lightorange
solid (0.149 g): MS (ES~) m/z319 (M-H).
Following the same procedure but using 2-ethynylpyridine instead of
phenylacetylene, 3-cyclohexane-2-(2-pyridyl)indole-6-carboxylic acid was obtained.
EXAMPLE 2
Methyl 2-bromo-3-cyclohexyl-6-indole carboxylate:
3-Cyclohexenyl-6-indole carboxylic acid:
A 12 L round-bottomed flask was equipped with a reflux condenser and a
mechanical stirrer, and the system was purged with nitrogen gas. 6-indole carboxylic
acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by
MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579
ml, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37
mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then
refluxed for 48 h. After cooling to room temperature, water (4 L) was added and
methanol removed under reduced pressure. The residual aqueous phase was
acidified to pH 1 with concentrated HCI (-1.2 L). The resulting yellowish precipitate
was collected by filtration, washed with water and dried under vacuum at 50 °C. The
desired cyclohexene derivative was obtained as a beige solid (451 .Og, 100% yield).
3-Cyclohexyl-6-indole carboxylic acid:
The unsaturated derivative from above was hydrogenated for 20 h under 55 psi
hydrogen gas pressure over 20% Pd(OH)2/C (10.25 g) using 1:1 THF - MeOH (2.5
L) as solvent. After filtration of the catalyst, volatiles were removed under reduced
pressure and the residue was triturated with hexane. The beige solid was collected
by filtration, washed with hexane and dried under vacuum (356.4 g, 78% yield).
Methyl 3-cyclohexyl-6-indole carboxylate (thionyl chloride procedure):
A 5 L three-necked flask was equipped with a reflux condenser and a mechanical
stirrer, and the system was purged with nitrogen gas. The indole carboxylic acid
from above (300.00 g, 1.233 mole) was charged into the flask and suspended in
MeOH (2 L). Thionyl chloride ( 5 ml, 0.0685 mole, 0.05 equivalent) was added
dropwise and the mixture was refluxed for 48 h. Volatiles were removed under
reduced pressure and the residue was triturated with hexane to give a beige solid
that was washed with hexane and dried under vacuum (279.6 g, 88% yield).
Methyl 3-cyclohexyl-6-indole carboxylate (carbonate / iodomethane
procedure):
A 2 L flask equipped with a dropping funnel and mechanical stirrer was charged with
crude 3-cyclohexyl-6-indole carboxylic acid (99.4 g, 0.409 mole) and anhydrous DMF
(665 ml) was added followed by anhydrous potassium carbonate (78.13 g, 0.565
mole), lodomethane (63.72 g, 0.449 mole) was added dropwise over 35 min with
stirring to the slurry which was then stirred overnight at room temperature until
complete disappearance of starting material (TLC). The resulting suspension was
then poured into water (1350 ml) and acidified to pH 4 with 4N HCI (200 ml). The
product was extracted into ether (3 x 1700 ml_), washed with water and brine and
dried (Na2SO4). Volatiles were removed under reduced pressure and the residue
was triturated with hexane (700 ml). The beige solid was filtered and dried under
vacuum (94.3 g, 90 % yield).
Methyl 2-bromo~3-cyclohexyl-6-indole carboxylate:
Adapting the procedure of L. Chu (Jet. Lett. 1997, 38, 3871) methyl 3-cyclohexyl-6-
indole carboxylate (4.65 g, 18.07 mmol) was dissolved in a mixture of THF (80 ml)
and CHCI3 (80 ml). The solution was cooled in an ice bath and pyridinium bromide
perbromide (pyridine tribromide, 7.22 g, 22.6 mmol, 1.25 equivalent) was added.
After stirring for 1.5 h at 0 °C, the reaction was judged complete by TLC. It was
diluted with CHCI3 (200 ml), washed with 1M NaHSO3 (2 x 50 ml_), saturated
aqueous NaHCO3 (2 x 50 ml_) and brine (50 ml_). After drying over Na2SO4, the
solvent was removed under reduced pressure and the residue crystallized from
TBME - hexane. The desired 2-bromoindole derivative was collected by filtration,
washed with hexane and dried (3.45 g). Evaporation of mother liquors gave a red
solid that was purified by flash chromatography using 15% EtOAc in hexane yielding
an additional 3.62 g of pure material. Total yield was 5.17 g (85% yield).
EXAMPLE 3
Methyl 2-bromo-3-cyclopentyl-6-indole carboxylate:
3-Cyclopentenyl-6-indole carboxylic acid:
A 3 L three-necked flask equipped with a mechanical stirrer was charged with indole
6-carboxylic acid (220 g, 1.365 mole) and KOH pellets (764.45 g, 13.65 mole, 10
equivalents). Water (660 ml) and MeOH (660 ml) were added and the mixture
heated to 75 °C. Cyclopentanone (603.7 ml_, 6.825 mole, 5 equivalents) was added
dropwise over 18 h using a pump. The reaction mixture was heated for an additional
3 h (after which the reaction was judged complete by HPLC) and cooled to 0 °C for 1
h. The precipitated potassium salt is collected by filtration, and washed with TBME
(2 X 500 ml_) to remove cyclopentanone self-condensation products. The brown
solid was re-dissolved in water (2.5 L) and the solution washed with TBME (2 X 1 L).
Following acidification to pH 3 with cone. HCI (425 ml_), the beige precipitate was
collected by filtration, washed with water ( 2 X 1 L) and dried under vacuum at 70 °C.
The crude product weighed 275.9 g (88.9 % mass recovery) and had an
homogeneity of 85% (HPLC).
3-Cyclopentyl-6-indole carboxylic acid:
The crude product from above (159.56 g, 0.70 mole) was dissolved in MeOH (750
ml_) and 20% Pd(OH)2 on charcoal (8.00 g) was added. The mixture was
hydrogenated in a Parr apparatus under 50 psi hydrogen gas for 18 h. After
completion, the catalyst was removed by filtration through celite and the solvent
removed under reduced pressure. The resulting brown solid was dried at 70 °C
under vacuum for 12 h. The crude product (153.2 g) was obtained as a brown solid
and was 77% homogeneous by HPLC.
Methyl 3-cyclopentyl-6-indole carboxylate:
The indole carboxylic acid from above was converted to the corresponding methyl
ester using the carbonate / iodomethane procedure described in example 2.
Methyl 2-bromo-3-cyclopentyl-6-indole carboxylate:
The indole carboxylate from above was brominated using pyridinium bromide
perbromide following the procedure described in example 2.
EXAMPLE 4
General procedure for the Suzuki cross-coupling of aryl and heteroarylboronic
acids with 2-bromoindole derivatives:
Cross-coupling of aromatic/heteroaromatic boronic acid or ester derivatives with 2-
bromoindoles such as the ones described in examples 2 and 3 can be performed
using any variations of the standard metal-catalyzed Suzuki cross-coupling reaction
as described in the literature and well known to those skilled in the art. The following
example serves to illustrate such a process and is non-limiting.
3-Cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylic acid methyl ester:
COOMe
The 2-bromoindole of example 2 (8.92 g, 26.5 mmol), 3-furanboronic acid (B.P.
Roques et al. J. Heterocycl. Chem. 1975, 12, 195; 4.45 g, 39.79 mmol, 1.5
equivalent) and LiCI (2.25 g, 53 mmol, 2 equivalents) were dissolved in a mixture of
EtOH (100 ml) and toluene (100 ml). A 1M aqueous Na2CO3 solution (66 ml, 66
mmol) was added and the mixture was degassed with argon for 45 min. Pd(PPh3)4
(3.06 g, 2.65 mmol, 0.1 equivalent) was added and the mixture stirred overnight at
75-85 °C under argon. Volatiles were removed under reduced pressure and the
residue re-dissolved in EtOAc (500 ml). The solution was washed with water,
saturated NaHC03 (100 ml) and brine (100 ml). After drying over a mixture of
MgSO4 and decolorizing charcoal, the mixture was filtered and concentrated under
reduced pressure. The residual oil was triturated with a mixture of TBME (20 ml_)
and hexane (40 ml_), cooled in ice and the precipitated solid collected by filtration,
washed with cold 25% TBME in hexane, and dried (3.09 g). The filtrate and
washings from the above trituration were combined, concentrated and purified by
flash chromatography using 10-25% EtOAc in hexane to give an additional 4.36 g of
product. The total yield of the 2-(3-furyl)indole of example 4 was 8.25 g.
Example 5
General procedure for the Stille cross-coupling ofaryl and
heteroarylstannanes with 2-bromoindole derivatives:
Cross-coupling of aromatic/heteroaromatic stannane derivatives with 2-bromoindoles
such as the ones described in examples 2 and 3 can be performed using any
variations of the standard metal-catalyzed Stille cross-coupling reaction as described
in the literature and well known to those skilled in the art. The following example
serves to illustrate such a process and is non-limiting.
3-Cyclohexyl-2-thiophen-2-yl-1H-indole-6-carboxylic acid methyl ester:
PdCI2(PPh3)2
THF/80°C
A 1L flask equipped with a reflux condenser was charged with 2-
trimethylstannylthiophene (11.16 g, 45 mmol), the 2-bromoindole of example 2 (7.00
g, 21 mmol) and anhydrous THF (300 ml). The solution was degassed by bubbling
argon through the solution for 1 h. The catalyst, dichlorobis(
triphenylphosphine)palladium (1.76 g, 2.5 mmol) was added and the mixture was
stirred at 80 °C under an argon atmosphere for 24 h. The reaction mixture was
cooled to room temperature, filtered to remove solids and concentrated under
reduced pressure. The residue was purified by flash chromatography using 9 : 1
hexane - EtOAc as eluent, to give the desired 2-(2-thiophene)indole product of
example 5 (7.10 g, 99% yield).
EXAMPLE 6
General procedure for N-alkylation ofindole derivatives to give N-
(methylcarboxy)indoles:
The following example serves to illustrate such a process and is non-limiting.
Methyl1-carboxymethyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate:
Methyl 1-tert-butoxycarbonylmethyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-
carboxylate:
The indole derivative from example 4 (18.50 g, 57.4 mmol) was dissolved in
anhydrous DMF (120 ml_) and the solution was cooled in an ice bath under an argon
atmosphere. NaH (60 % oil dispersion, 2.88 g, 72 mmol) was added in 3 portions
and the mixture stirred 1 h at 0 °C. fert-Butylbromoacetate (13.88 g, 71 mmol, 1.24
equiv.) was added dropwise over 10 min and then the ice bath was removed. The
reaction mixture was stirred overnight at room temperature. It was then diluted with
TBME (1500 ml) and washed with 10 % HCI (2 x 250 ml), water (3 x 500 ml) and
brine (1 x 400 ml). After drying (Na2SO4), the solvent was removed under reduced
pressure to give a white solid. The solid was triturated with hexane (300 ml_), filtered
and triturated a second time with hexane (500 ml). Filtration followed by drying
under vacuum gave the desired fert-butyl ester as a white solid (21.6 g, 86 % yield).
Methyl 1-carboxymethyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate:
The tert-butyl ester from above (21.5 g, 49 mmol) was dissolved in dichloromethane
(90 ml) and TFA (65.6 mL) was added dropwise to the solution which was stirred for
5 h at room temperature. Volatiles were removed under reduced pressure, the
residue was co-evaporated 3 x with DCM and then dried under vacuum. The crude
product was triturated with a mixture of hexane (200 mL) and DCM (20 mL), filtered
and dried under vacuum to give the title compound of example 6 as a white solid
(18.62 g, 99% yield).
EXAMPLE 7
Methyl 1-carboxymethyl-3-cyclopentyl-2-furan-3-yl-1H-indole-6-carboxylate:
The procedures for examples 4 and 6 were followed, using the 2-bromoindole of
example 3 as starting material.
EXAMPLE 8
Methyl 2-bromo-1-carboxymethyl-3-cyclohexyl-1 H-indole-6-carboxylate:
The 2-bromoindole from example 2 was A/-alkylated with fert-butylbromoacetate
using NaH in DMF and the tert-butyl ester cleaved with TFA as described in example
6 to give the title compound of example 8 as a white solid.
EXAMPLE 9
General procedure for amidation of N-(methylcarboxy)indoles with amines and
saponification to give inhibitors of general formula 1.1:
The following example serves to illustrate such a process and is non-limiting.
3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-6-
carboxylic acid:
Methyl 3-cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-6-
carboxylate:
The A/-(methylcarboxy)indole derivative of example 6 (0.500 g, 1.31 mmol, 1 equiv.),
morpholine (141 fjL, 1.6 mmol, 1.22 equiv.) and triethylamine (432/ul_, 3.1 mmol,
2.36 equiv.) were dissolved in a mixture of THF (13 rnLO and DMF (3 m). TBTU
(0.514 g, 1.6 mmol, 1.22 equiv.) was added and the mixture stirred at room
temperature for 3 h (complete by TLC). The reaction mixture was diluted with EtOAc
and washed successively with 10% aqueous HCI, water and brine. The extract was
dried (MgSO4), concentrated and the residue purified by flash chromatography on
silica gel using 70 % EtOAc in hexane as eluent. The methyl ester of example 9 was
obtained as a yellow solid (0.498 g, 84 % yield).
3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-6-
carboxylic acid:
The methyl ester from above (0.480 g, 0.995 mmol) was dissolved in a mixture of
THF (8 ml_) and MeOH (4 mL) and the solution heated to 50 °C. 4N NaOH (2.5 ml_)
was added dropwise to the mixture that was then stirred for an additional 3.5 h at 50
°C, at which it was judged complete by TLC. The reaction mixture was evaporated
to dryness under reduced pressure and the residue partitioned between 10%
aqueous HCI and DCM. The organic phase was separated, dried (MgSO4) and
concentrated to give a residue that was purified by flash chromatography with 60%
EtOAc in hexane + 3 % AcOH. The title compound of example 9 was obtained as a
yellow solid (0.320 g, 74 % yield).
EX AM RLE 10
Methyl 2-(2-bromo-ethanoyl)-3-cyclohexyl-1-dimethylcarbamoylmethyl-1Hindole-
6-carboxylate:
(Figure Removed)Methyl 2-bromo-3-cyclohexyl-1-dimethylcarbamoylmethyl-1H-indole-6-
carboxylate:
The 2-bromoindole derivative of example 8 (7.00 g, 17.75 mmol) was dissolved in
THF (150 ml) and triethylamine (8.7 mt_, 62.14 mmol, 3 equiv.) was added followed
by TBTU (7.13 g, 22.44 mmol, 1.25 equiv.). The white suspension was stirred for 20
min and dimethylamine hydrochloride (1.81 g, 22.2 mmol, 1.25 equiv.) was added
followed by DMF (75 ml). After stirring overnight at room temperature, the reaction
was judged complete by TLC (additional TBTU, Et3N and dimethylamine
hydrochloride can be added if required to complete the reaction). The reaction
mixture was diluted with EtOAc (200 ml_), washed with 10 % HCI (100 ml), water (12
x 320 ml) and brine. After drying over Na2SO4, the solvent was removed under
reduced pressure and the residue purified by flash chromatography to give the
desired dimethyl amide as a white solid (6.10 g, 81 % yield).
Methyl 3-cyclohexyl-1-dimethylcarbamoylmethyl-2-(1-ethoxy-vinyl)-1H-indole-
6-carboxylate:
The 2-bromoindole derivative from above (6.10 g, 13.54 mmol) was charged in a 100
mL flask equipped with a stirrer and reflux condenser. Anhydrous dioxane (50 mL)
was added and tributyl(1-ethoxyvinyl)tin (6.27 g, 17.37 mmol, 1.2 equiv.) was added.
The reaction mixture was degassed by bubbling argon through the suspension for
40 min. Dichlorobis(triphenylphosphine)palladium (0.51 g, 0.72 mmol) was added
and the reaction mixture was stirred overnight at 100 °C under an argon
atmosphere. The reaction mixture was then cooled to room temperature and
volatiles removed under reduced pressure. EtOAc (120 ml_) was added and
insoluble solids removed by filtration through celite. Removal of solvent under
reduced pressure and trituration of the residue with THF gave the desired product as
a beige solid. Purification of the mother liquors by flash chromatography gave
additional material. The total yield was 5.36 g (89 %).
Methyl 2-(2-bromo-ethanoyl)-3-cyclohexyl-1-dimethylcarbamoylmethyl-1Hindole-
6-carboxylate:
The vinyl ether from above (5.30 g, 12.85 mmol) was dissolved in THF (300 ml) and
the solution cooled in an ice-water bath. Water (30 ml_) was added followed by Nbromosuccinimide
(2.29 g, 12.85 mmol, 1 equiv.) in five equal portions over 10 min.
After stirring for 1 h, addition /V-bromosuccinimide (0.5 g) was added and after
stirring for an additional 30 min at 0 °C, a final portion (0.5 g) was added to complete
the reaction. The reaction mixture was diluted with ether (200 ml) and water (100
mL) was added. The organic phase was separated and the aqueous phase
extracted with ether (2 x 100 mL). The extract was washed with water (3 x 100 mL)
and brine and then dried over Na2SO4. Removal of volatiles under reduced pressure
gave a yellow oil that was purified by flash chromatography on silica gel using 20 -
50% EtOAc in hexane as eluent to give the desired bromoketone of example 10 as a
yellow solid (3.74 g, 62% yield).
EXAMPLE 11
Methyl 2-(2-bromo-ethanoyl)-3-cyclohexyl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1Hindole-
6-carboxylate:
The same procedures described in example 10 were used but dimethylamine
hydrochloride was replaced with morpholine in step 1.
EXAMPLE12
General procedure for the conversion of bromomethylketones (such as those
of examples 10 and 11) to thiazolyl-substituted indoles and hydrolysis to give
inhibitors of general formula 1.1 where A?2 is a (2-substituted 5-thiazolyl)
heterocycle:
Bromomethylketones such as those described in examples 10 and 11 were reacted
with thioamides and thioureas and then saponified to give the carboxylic acids of
example 12. The following example serves to illustrate such a process and is nonlimiting.
2-(2-tert-Butylamino-thiazol-4-yl)-3-cyclohexyl-1-(2-morpholin-4-yl-2-oxo-ethyl)-
1H-indole-6-carboxylic acid:
The bromomethylketone of example 11 (39.6 mg, 0.078 mmol, 1 equiv.) was
dissolved in DMSO (1 mL) and A/-fertbutylthiourea (12.4 mg, 0.094 mmol, 1.2 equiv.)
was added. The mixture was stirred for 2 h at room temperature. 10 N NaOH (24
was added and after stirring for 4 h at room temperature, another portion of 10 N
NaOH (24 //L) was added and the mixture stirred 24 h at room temperature to
complete the hydrolysis. The reaction mixture was then neutralized by addition of
TFA and the title product of example 12 isolated directly from the reaction mixture by
preparative HPLC as a white amorphous TFA salt (21 mg).
EXAMPLE 13
3-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-furan-3-yl-1H-indole-6-carboxylic
acid:
The indole ester of example 4 (0.080 g, 0.247 mmol, 1 equiv.) was dissolved in DMF
(2 ml) and NaH (60 % oil dispersion; 0.016 mg, 0.3 mmol, 1.6 equiv.) was added.
After stirring for 30 min, 1 -bromopinacolone (45 yuL, 0.3 mmol, 22 equiv.) was added
and the mixture stirred for 2.5 h at room temperature. The reaction was quenched
by addition of 10 % aqueous HCI and extracted with TBME. The extract was
washed with water, dried (MgSO4) and concentrated to give a residue that was
purified by flash chromatography on silica gel using 15-20 % EtOAc in hexane as
eluent. The methyl ester of example 13 was obtained as a light-yellow solid.
The methyl ester from above (0.040 g, 0.095 mmol) was dissolved in a mixture of
THF (3 ml) and MeOH (2 ml) and 2.5 N NaOH (400 fjL) was added. The mixture
was stirred at 50 °C for 5 h after which the reaction was judged complete by TLC.
Volatiles were removed under reduced pressure and the residue was partitioned
between 10 % aqueous HCI and DCM. The organic phase was washed with water,
dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to
give the title compound of example 13 as a white amorphous solid (22 mg).
EXAMPLE14
3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-thioxo-ethyl)-1H-indole-6-
carboxylic acid:
The amide of example 9 (0.060 g, 0.137 mmol, 1 equiv.) was dissolved in THF (2
ml) and P2S5 (0.031 g, 0.07 mmol, 0.51 equiv.) was added. The mixture was stirred
at 50 °C for 15 h after which another portion of P2S5 (0.020 g) was added. After
stirring for an additional 2 h at 50 °C, the reaction mixture was concentrated under
reduced pressure and the residue passed through a plug of silica gel using 60 %
EtOAc in hexane + 3 % AcOH as eluent. The fractions containing the product were
combined and after removal of solvents under reduced pressure, the residue was
purified by preparative HPLC to give the title compound of example 14 as a white
amorphous solid (11 mg).
EXAMPLE 15
Procedures for the preparation of benzimidazole-derivatives (group Q1 or Q2)
Example 15a: (E)-3-[2-(1-Amino-cyclobutyl)-1-methyl-1H-benzoimidazol-5-yl]-
acrylic acid methyl ester
(Figure Removed)A mixture of 4-chloro-3-nitrocinnamic acid (500 mg, 2.2 mmol) and methylamine (8
ml of 2M in THF, 16 mmol) were heated in a sealed tube at 80 °C for 20 hours. The
mixture was then cooled to room temperature and concentrated to an orange solid
that was used in the following step without further purification.
The crude 4-methylamino-3-nitrocinnamic acid intermediate (488 mg, 2.2 mmol) was
dissolved in methanol (20 ml_) and an ether solution of diazomethane was added
until HPLC analysis indicated complete conversion of the acid to the methyl ester.
The solution was concentrated to dryness to obtain 540 mg of the methyl ester as an
orange solid which was used further without purification.
The crude methyl ester (540 mg, -2.2 mmol) and SnCI2 dihydrate (2.25 g, 10 mmol)
were dissolved in ethanol (20 ml_) and the mixture was stirred at 80 °C for 4 hours.
After that period, the mixture was cooled to room temperature and was slowly added
to aqueous solution of saturated NaHCO3. The reaction mixture was extracted with
ethyl acetate (100 ml_), the organic layer was dried over anhydrous MgSO4 and the
solvent was removed under reduced pressure. The residue was purified by flash
column chromatography, using a gradient of hexane in ethyl acetate (from 50 % to
30 %) to give the pure diamino cinnamate ester intermediate as a yellow solid (245
mg). ES+ MS m/z 207.1 (M+H)+, ES" MS m/z 205.0 (M-H)'
A sample of the above diamino intermediate (40 mg, 0.194 mmol) was suspended in
CH2CI2 (3 ml) and the aminocyclobutyl acid chloride prepared from 1-
aminocyclobutanecarboxylic acid, following a similar procedure to that described in
example 20, (31 mg, 0.18 mmol) was added. The reaction mixture was stirred at
room temperature for 2 hours and then concentrated to obtain a white solid. The
solid was then dissolved in acetic acid (5 ml_) and heated to 60 °C for 20 hours. The
reaction crude was diluted with aqueous saturated NaHCO3, extracted with CH2CI2
(2x50 ml) and brine, the organic layer was dried over anhydrous MgSO4 and the
solvent was removed under reduced pressure to give the title compound of example
15a as a light brown foam (53 mg): ES+ MS m/z. 286.0 (M+H)+
Example 15b: (E)-3-[2-(1 -Amino-cyclobutyl)-3-methyl-3H-benzoimidazol-5-yl]-
acrylic acid methyl ester
A mixture of 3-hydroxy-4-nitrobenzaldehyde (1.24 g, 7.4 mmol) and (carbethoxymethylene)
triphenylphophorane (2.6 g, 7.4 mmol) were dissolved in THF (60 ml)
and stirred at 60 °C for 2 hours. The mixture was then concentrated and purified by
flash column chromatography, using hexane in ethyl acetate (70 %) as the eluent, to
obtain a the frans-cinnamate ester derivative as a pure yellow solid (1.73 g).
The above cinnamate ester was dissolved in DMF (15 ml_), methyl iodide (1.35 ml_,
21.7 mmol) and K2C03 (3.0 g, 21.7 mmol) and the mixture was stirred at room
temperature for 20 hours. After that period, water was added and the precipitate
formed was filtered and washed with water (2x). The solid was dissolved in ethyl
acetate, dried over anhydrous MgSO4, filtered and concentrated to dryness to give
the crude methoxy analogue as a white solid (~1.7 g).
The crude 3-methoxy-4-nitrocinnamate ester (570 mg, 2.27 mmol) and methylamine
(30 mL of 2M in THF, 60 mmol) were heated in sealed tube at 85 °C for 40 hours.
After that period the mixture was cooled to room temperature, concentrated and
purified by flash column chromatography, using ethyl acetate in hexane (10 %) as
the eluent, to obtain the desired 3-methylamino-4-nitrocinnamate ester (-160 mg).
ES+ MS m/z. 251.0 (M+H)+
Intermediate 3-methylamino-4-nitrocinnamate ester (-150 mg) and SnCI2 dihydrate
(950 mg, 4.2 mmol) were dissolved in ethanol (10 mL) and the mixture was stirred at
80° C for 20 hours. The mixture was cooled to room temperature and concentrated
to dryness. The residue was dissolved in ethyl acetate (100 ml_) and was slowly
added to an aqueous solution of saturated NaHCO3 and stirred for 30 min. The
organic layer was then extracted with ice cold brine, dried over anhydrous MgSO4
and the solvent was removed under reduced pressure. The residue was purified by
flash column chromatography (using a gradient from 70 % to 60 % of hexane in ethyl
acetate) to give the pure diamino cinnamate ester as a yellow solid (100 mg). ES+
MSm/z221.0(M+H)+
The above diamino intermediate (100 mg, 0.45 mmol) was suspended in CH2CI2 (5
ml_) and the aminocyclobutyl acid chloride prepared from
1-aminocyclobutanecarboxylic acid, following a similar procedure to that described in
example 20 (77 mg, 0.45 mmol) was added. The reaction mixture was stirred at
room temperature for 2 hours and then concentrated to obtain a white solid. The
solid was then dissolved in acetic acid (5 ml) and heated to 60 °C for 16 hours. The
reaction mixture was cooled and the precipitate formed was filtered and washed with
cold acetic acid, and then dissolved in ethyl acetate (100 mL) and washed with
aqueous saturated NaHCO3 (2x) and ice cold brine. The organic layer was dried
over anhydrous MgSO4 and the solvent was removed under reduced pressure to
give the title compound of example 15b (E)-3-[2-(1-amino-cyclobutyl)-3-methyl-3/-/-
benzoimidazol-5-yl]-acrylic acid methyl ester as a white solid (58 mg).
Note: it will be apparent to the person skilled in the art that the
(carbethoxymethylene)triphenylphosphorane used in this procedure can be replaced
by appropriately substituted derivatives to prepare analogues bearing various
substituents on the cinnamate double bond. In addition, cinnamate methyl esters
can also be prepared in an analogous fashion using the appropriate reagent.
Example 15c: 2-(1-Amino-cyclobutyl)-1H-benzoimidazole-5-carboxylic acid
methyl ester
(Figure Removed)Methyl 3,4-diaminobenzoate (320 mg, 1.9 mmol), the SEM-protected
cyclobutylamino acid (500 mg, 1.9 mmol) of example 21 and TBTU (836 mg, 2.2
mmol) were dissolved in CH2CI2 (10 mL) and DIPEA (1.1 mL, 6 mmol) was added.
The reaction mixture was stirred at room temperature for 20 hours, then diluted with
ethyl acetate (100 mL) and extracted with aqueous saturated NaHCO3 (2x) and
brine. The organic layer was dried over anhydrous MgSO4 and filtered, and the
solvent was evaporated under vacuum to isolate the crude amide intermediate as a
yellow oil (407 mg). The amide was dissolved in acetic acid (10 mL) and stirred at
70 °C for 3 hours to induce dehydration and cyclization to the benzymidazole. The
reaction mixture was concentrated to dryness, diluted with ethyl acetate (100 mL)
and washed with 10% aqueous citric acid (2x), aqueous saturated NaHCO3 and
brine. The organic layer was dried over MgSO4, filtered and concentrated to
dryness. The residue was purified by flash column chromatography, using a solvent
gradient of hexane in ethyl acetate (from 80 % to 50 %), to give the SEM-protected
benzymidazole intermediate as a pink solid (574 mg). ES+ MS m/z: 390.2 (M+H)+
The protecting group was then removed by dissolving this solid in TFA/CH2CI2 (2 mL,
1:1 ratio) and stirring the solution at room temperature for 2 hours. The solution was
evaporated to dryness under vacuum to give the products, 2-(1-amino-cyclobutyl)-
1 H-benzoimidazole-5-carboxylic acid methyl ester, which was used for the synthesis
of inhibitors without further purification.
EXAMPLE16
General procedure for N-allylation of indole derivative of example 6:
wherein R, FT, R" are H or alkyl. The following example serves to illustrate such as
process and is non-limiting:
1-Allyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylic acid:
The indole derivative of example 4 (0.050 g, 0.156 mmol, 1 equiv.) was dissolved in
DMF (1 ml) and the solution was cooled in ice-water. NaH (60 % oil dispersion, 7
mg, 0.175 mmol, 1.13 equiv.) was added and the ice-bath removed. Allyl bromide
(15/vL, 0.17 mmol, 1.11 equiv.) was added and the reaction stirred overnight at room
temperature (complete by TLC). The reaction mixture was diluted with DMSO (1 mL)
and 5N NaOH (200 jjl) was added. The mixture was stirred at 60 °C for 3 h
(complete by HPLC), neutralized by addition of TFA and the product isolated directly
from the reaction mixture by preparative HPLC. The title product of example 16 was
isolated as a white amorphous solid (33 mg).
EXAMPLE 17
3-Cyclohexyl-2-furan-3~yl~ 1 -(3-morpholin-4-yl-3-oxo-propyl)-1 H-indole-6-
carboxylic acid:
Methyl 1 -(2-tert-butoxycarbonyl-ethyl)-3-cyclohexyl-2-f uran-3-yl-1 H-indole-6-
carboxylate:
The indole ester of example 4 (0.100 g, 0.31 mmol, 1 equiv.) was dissolved in DMF
(2 ml_) and NaH (60 % oil dispersion, 0.020 g, 0.50 mmol, 1.6 equiv.) was added.
After stirring for 1 h at room temperature, tert-butyl 3-bromopropionate (0.102 g, 0.49
mmol, 1.6 equiv.) was added and the mixture stirred overnight at room temperature.
The solvent was the removed under vacuum and the residue purified by flash
chromatography on silica gel to give the N-alkylated indole (41 mg).
Methyl 1-(2-carboxy-ethyl)-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate:
The tert-butyl ester from above (40 mg) was dissolved in DCM (1 ml_) and TFA (2
ml_) was added. The mixture was stirred for 1 h at room temperature after which
volatiles were removed under reduced pressure. The residue was co-evaporated
twice with DCM and used as such in the next step.
3-Cyclohexyl-2-furan-3-yl-1-(3-morpholin-4-yl-3-oxo-propyl)-1H-indole-6-
carboxylic acid:
The acid from above (18 mg, 0.046 mmol, 1 equiv.) was dissolved in DMSO (0.5 ml_)
and HATU (26 mg, 0.069 mmol, 1.5 equiv.), DIEA (16 //!_, 0.092 mmol, 2 equiv.) and
morpholine (8 //L, 0.092 mmol, 2 equiv.) were added. The mixture was stirred for 3.5
h at room temperature (complete by HPLC). 5N NaOH (184//L) was added and the
mixture stirred overnight at room temperature. The reaction was then quenched by
addition of AcOH (100//L) and the product isolated directly by preparative HPLC.
The title compound of example 17 was isolated as a brownish amorphous solid (1.2
mg).
EXAMPLE 18
1-(2-Benzenesulfonylamino-2-oxo-ethyl)-3-cyclohexyl-2-furan-3-yl-1H-indole-6-
carboxylic acid:
The acid derivative of example 6 (0.050 g, 0.13 mmol, 1 equiv.) was dissolved in
DCM (5 mL) and EDCI (25 mg, 0.13 mmol, 1 equiv.), DMAP (16 mg, 0.13 mmol, 1
equiv.) and benzene sulfonamide (23.6 mg, 0.15 mmol, 1.14 equiv.) were added.
The greenish reaction mixture was stirred for 24 h at room temperature (> 80 %
conversion by HPLC). The reaction mixture was diluted with DCM, washed with 10
% aqueous HCI and dried (Na2SO4). Evaporation of the solvent gave a residue that
was dissolved in DMSO (2 mL) and 2.5N NaOH (0.5 mL) was added. The mixture
was stirred for 2.5 h at room temperature (complete by HPLC), neutralized with
AcOH and the product isolated directly by preparative HPLC. The title compound of
example 18 was obtained as a beige amorphous solid (15 mg).
EXAMPLE 19
(E)-3-(4-{[1-(5-Amino-1,3-dioxinan-5-yl)-methanoyl]-amino}-phenyl)-acrylicacid
ethyl ester (building block for group L and/or Z according to formula I)
(Figure Removed)1,3-Dioxinane-5,5-dicarboxylic acid diethyl ester:
A 500 mL round-bottomed flask equipped with a reflux condenser was charged with
diethyl bis(hydroxymethyl)malonate (5.00 g, 22.7 mmol, 1.00 equiv.), 1,3,5-trioxane
(4.09 g, 45.41 mmol, 2.00 equiv.), (1R)-(-)-10-camphorsulfonic acid (CSA) (10.55 g,
45.41 mmol, 2.00 equiv.), and 4A molecular sieves (2.00 g). Chloroform (200 ml)
was then added and the mixture was refluxed for 72 h (complete by TLC). The
reaction mixture was filtered on celite and the filtrate was washed with aqueous 0.5
N sodium hydroxide (100 ml_). The layers were separated and the aqueous phase
was back-extracted with chloroform (50 ml). Organic layers were then combined,
dried (MgSO4), filtered and concentrated in vacuo. The resulting crude mixture was
finally purified by flash chromatography (eluting hexane/EtOAc 4:1) to give the
desired dioxane malonate as a colorless oil (3.41 g, 65 %).
1,3-Dioxinane-5,5-dicarboxylic acid ethyl ester:
A 50 mL round-bottomed flask was charged with the intermediate from above (1.00
g, 4.31 mmol, 1.00 equiv.). EtOH and aqueous 1.0 N sodium hydroxide (4.50 mL,
4.50 mmol, 1.05 equiv.) was added and the resulting mixture was stirred at RT for 16
hrs (TLC monitoring). Then the pH of the reaction mixture was brought to 12 using
aqueous 1.0 N sodium hydroxide and EtOH was removed in vacuo. The resulting
aqueous solution was diluted with water (50 mL) and extracted with EtOAc (2 X 50
mL). Then the pH of the aqueous solution was brought to 2 using aqueous cone.
HCI. The aqueous solution was extracted with EtOAc (2 X 50 mL). Organic phases
were combined, dried (MgS04), filtered and concentrated in vacuo. To give the
desired monoester contaminated with -10 mole % of the corresponding diacid as a
colorless oil (0.91 g). The material was used in the next step without further
purification.
5-(2-Trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxinane-5-carboxylicacid
ethyl ester:
In a 100 mL round-bottomed flask equipped with a reflux condenser was mixed the
above monoester (0.91 g, 4.31 mmol of monoacid, 1.00 equiv.) contaminated with
approximately 10 % of diacid, anhydrous toluene (20 mL) and triethylamine (TEA)
(750 uL, 5.39 mmol, 1.25 equiv.) under nitrogen. The resulting mixture was heated to
80 °C and then diphenylphosphoryl azide (1.07 mL, 4.96 mmol, 1.15 equiv.) was
slowly added in one minute. The mixture was then stirred at 80 °C for 1 h. 2-
(Trimethylsilyl)ethanol (680 uL, 4.74 mmol, 1.10 equiv.) was added drop wise and
the reaction mixture was stirred at 110 °C. After 24 h, the reaction was judged to be
complete. The reaction mixture was then diluted with EtOAc (50 mL) and washed
successively with water (25 mL), aqueous 1.0 N HCI and sat. aqueous sodium
carbonate. The organic layer was then dried (MgSO4), filtered and concentrated in
vacua. The crude material was finally purified by flash chromatography (eluting
Hexane/EtOAc 9:1) to give the desired SEM-carbamate-protected amino ester as a
colorless oil (0.61 g, 45 %).
5-(2-Trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxinane-5-carboxylic acid:
The ester from above (612 mg, 1.91 mmol, 1.00 equiv.) was dissolved in 15 ml of a
4:1 THF / MeOH mixture in a 50 ml round-bottomed flask. Aqueous. 10 N Sodium
hydroxide (0.96 ml_, 9.56 mmol, 5.00 equiv.) was then added, and the mixture was
stirred at RT for 4h (TLC monitoring). The solvent was removed in vacua and the
residue was dissolved in dichloromethane (20 ml_). The organic phase was washed
with 20 mL of 1.0 N aqueous HCI, layers were separated and the organic phase was
back-extracted with dichloromethane (2 X 20 mL). Organic layers were combined,
dried (MgSO4), filtered and concentrated in vacuoto give the desired acid as a white
foam (466 mg, 84 %).
(E)-3-[4-({1-[5-(2-Trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxinan-5-yl]-
methanoyl}-amino)-phenyl]-acrylic acid ethyl ester:
5-(2-trimethylsilanylethoxycarbonylamino)-1,3-dioxane-5-carboxylic acid from above
(0.050 g, 0.17 mmol), ethyl-4-aminocinnamate (0.036 g, 0.19 mmol), HATU (0.098 g,
0.26 mmol), HOAt (0.035 g, 0.26 mmol) and 2,4,6-collidine (0.062 ml, 0.51 mmol)
were combined in anhydrous DMSO (1 mL). The solution was warmed to 60 °C and
stirred for 6 h before another 1.5 equivalents of HATU was added and stirring was
continued for another 2 hours to ensure complete consumption of the acid. The
reaction mixture was diluted with dichloromethane and washed with 1N HCI (x 2).
The organic phase was dried with MgSO4, filtered and concentrated. The residue
was subjected to flash chromatography to afford 0.043 g (54 %) of the protected
amide derivative as a yellow oil.
(E)-3-(4-{[1 -(5-Amino-1,3-dioxinan-5-yl)-methanoyl]-amino}-phenyl)-acrylic acid
ethyl ester:
Deprotection of the SEM carbamate from above was carried out with TFA-DCM in
the usual manner.
EXAMPLE 20
General procedure for coupling o,o-disubstituted amino acids to aromatic
amines:
Ethyl (E)-3-[4-(2-amino-2-methyl-propanoylamino)-phenyl]-acrylate:
Adapting the procedure described by E. S. Uffelman et al. (Org. Lett. 1999, 1,1157),
2-aminoisobutyric acid was converted to the corresponding amino acid chloride
hydrochloride: 2-oxazolidinone (12.30 g, 0.141 mole) was dissolved in MeCN (150
mL) and phosphorous pentachloride (49.02 g, 0.235 mole, 1.7 equivalent) was
added in one portion. The homogeneous mixture was stirred for 24 h at room
temperature. 2-Aminoisobutyric acid (14.55 g, 0.141 mole) was added and the
suspension was stirred for 48 h at room temperature. The desired acid chloride
hydrochloride was collected by filtration, washed with MeCN and dried under
vacuum. Other a,a-disubstituted amino acid chloride hydrochlorides can be prepared
in an analogous fashion starting from the corresponding amino acid (e.g. 1-
aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-
aminocyclohexanecarboxylic acid and the like).
The acid chloride (12.778 g, 80 mmol, 1.4 equivalent) was suspended in DCM (200
ml) and ethyl 4-aminocinnamate (11.045 g, 57.7 mmol, 1 equivalent) was added.
Pyridine (7.01 mL, 86.6 mmol, 1.5 equivalent) was added drop wise and the mixture
was stirred for 3.5 h at room temperature. The reaction was then poured into a
mixture of 1N NaOH (25 mL) and saturated aqueous NaHCO3 (100 mL) and
extracted with EtOAc. The organic phase was washed with aqueous NaHCO3, water
and brine, and dried over MgS04. Removal of solvent under reduced pressure gave
the title compound as a white solid (15.96 g, 101% yield).
EXAMPLE 21
Ethyl(E)-3-(4-{[1-(1-amino-cyclobutyl)~methanoyl]-amino}-phenyl)-acrylate:
Diethyl 1,1-cyclobutanedicarboxylate (20.00 g, 100 mmol) and KOH (6.60 g, 100
mmol) were refluxed in EtOH (100 ml_) for 2 h. After cooling to room temperature,
volatiles were removed under reduced pressure and the residue partitioned between
Et2O and 4N HCI. The organic extract was washed with water and brine, and dried
over MgSO4. Removal of the solvent under reduced pressure gave the monoester
as a clear oil (14.45 g, 84% yield).
The monoester from above (14.45 g, 84 mmol), Et3N (14.1 ml_, 100 mmol) and
diphenylphosphoryl azide (DPPA) (24.05 g, 87.4 mmol) were dissolved in dry toluene
(114 ml) and the mixture heated at 80 °C for 1 h and 110 °C for an additional hour.
Trimethylsilylethanol (9.94 g, 100 mmol) was added in one portion and the mixture
refluxed for 48 h. Toluene was then removed under reduced pressure and the
residue dissolved in DCM. The solution was washed with water and brine and dried
over MgSO4. Concentration under reduced pressure gave a dark oil which was
purified by passage through a pad of silica gel using 30% EtOAc in hexane as
eluent. The desired carbamate was obtained as a clear yellow liquid (21.0 g).
The carbamate from above (1.50 g, 5.22 mmol) was dissolved in THF (5 ml_) and 2N
NaOH (5 ml_) was added. The mixture was stirred at 70 °C for 1 h. Following
dilution with water, the aqueous phase was washed with Et2O to remove unreacted
starting material. The aqueous phase was then acidified with KHSO4 and the
product extracted with EtOAc. The desired free carboxylic acid was obtained as an
o\\(1.25g).
The acid from above (0.519 g, 2.0 mmol) was dissolved in DCM (10 ml). DIEA
(1.39 ml_, 8.0 mmol, 4 equivalents) was added, followed by ethyl 4-aminocinnamate
(0.573 g, 3.0 mmol, 1.5 equivalent) and HATU (1.143 g, 3.0 mmol, 1.5 equivalents).
The mixture was stirred at room temperature for 3 days. The reaction was poured
into TBME (100 ml_) and the solution washed successively with 10% aqueous citric
acid (2 x 25 ml) and saturated aqueous NaHCO3 (25 ml_), and dried over MgSO4.
The solvent was removed under reduced pressure and the residue stirred with TFA
(10 ml_) for 30 min. Volatiles were then removed under reduced pressure and the
residue was co-evaporated twice with hexane. The crude product was dissolved in
TBME (60 ml) and the solution washed with 1N NaOH (2 x 25 ml). After drying
(Na2SO4), volatiles were removed in vacuum to give the title compound as a beige
solid (0.500 g).
EXAMPLE 22
Methyl (Z)-3-[2-(1-amino-cyclopentyl)-1H-benzoimidazol-5-yl]-acrylate:
(Figure Removed)Diazomethane was slowly added to a solution of 4-chloro-3-nitrocinnamic acid in
CH3OH/CH2CI2 until the yellow color persisted, indicating the presence of excess
diazomethane. The solution was evaporated to dryness under reduced pressure
and the residue was dissolved in DMSO. The solution was heated to 140 °C and
ammonia gas was bubbled through for a period of 4 hours. The mixture was cooled
to room temperature and degassed with N2, and poured onto ice. The precipitate
formed was filtered, washed with cold water and dried under vacuum for 16 hours to
give the crude 4-amino-3-nitrocinnamic ester as a yellow solid (2.05 g). The solid
was dissolved in ethanol (40 ml_), SnCI2.dihydrate (9.91 g, 43.9 mmol) was added
and the reaction mixture was heated to reflux for 4 hours. The solution was
concentrated to remove most of the ethanol, diluted with EtOAc and saturated
aqueous NaHCO3 was added slowly. The mixture was stirred for 20 min, the organic
layer was extracted with brine, dried over anhydrous Na2SO4 and evaporated to
dryness under reduced pressure. The residue was purified by flash column
chromatography (using 50% to 70% EtOAc in hexane) to give the diamino
intermediate as a yellow solid (1.03 g).
A portion of the 3,4-diaminocinnamate ester (186 mg, 0.970 mmol) and N-Boc-1-
aminocyclopentane-1-carboxylic acid (222 mg, 0.970 mmol) were coupled in the
presence of HATU / DIEA (in the usual way) and the amide product formed was
dehydrated by heating at 65 °C in a solution of acetic acid (4 ml). The reaction
residue was purified by reversed HPLC to give the N-Boc protected (Z)-3-[2-(1-
amino-cyclopentyl)-1H-benzoimidazol-5-yl]-acrylic acid ethyl ester.
The Boc protecting group was removed with 4N HCI in dioxane in the usual way to
give (Z)-3-[2-(1-amino-cyclopentyl)-1H-benzoimidazol-5-yl]-acrylic acid ethyl ester as
yellow foam (200 mg).
EXAMPLE 23
tert-Butyl (S)-3-amino-3-[4-((E)-2-ethoxycarbonyl-vinyl)-phenylcarbamoyl]-
pyrrolidine- 1-carboxylate:
N-Fmoc-(3-N-Boc)-(S)-cucurbitine (0.495 g, 1.09 mmol), ethyl 4-aminocinnamate
(0.300 g, 1.57 mmol), HOAt (0.224, 1.65 mmol) and HATU (0.626 g, 1.65 mmol)
were dissolved in DMF (7 ml). To this mixture, 2,4,6-collidine (0.435 ml, 3.30
mmol) was added and the solution was stirred at room temperature for 2 days. The
reaction mixture was poured into EtOAc (100 ml) and the solution washed
successively with 10% aqueous citric acid (2 x 25 ml), saturated aqueous NaHCO3
(25 ml) and brine (25 ml_), and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure and the residue was dissolved in CH2CI2, DBU
(0.658 ml, 4.4 mmol) was added and the reaction mixture was stirred at room
temperature for 15 hours.
The reaction mixture was poured into EtOAc (100 ml) and the solution washed
successively with saturated aqueous NaHCO3 (2 x 25 ml_) and brine (25 ml_), and
dried over anhydrous MgS04. The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography (40% to 70% EtOAc in
hexane) to give the product shown above as a white solid (0.234 mg).
EXAMPLE 24
Ethyl (E)-3-(4-{[1-(3-amino-piperidin-3-yl)-methanoyl]-amino}-phenyl)-acrylate:
Commercially available N-Fmoc-amino-(3-N-Boc-piperidinyl)carboxylic acid was
coupled to the ethyl ester of 4-aminocinnamic acid using HATU / HOAT / collidine in
DMF and the Fmoc protecting group was removed with piperidine to give the title
compound of example 24 in racemic form.
Racemic N-Fmoc-amino-(3-N-Boc-piperidinyl)carboxylic acid, could also be resolved
into its two enantiomers by preparative HPLC on a chiral support (Chiralcel OD, 10
micron, 2.00 cm I.D. x 25 cm), using 35% H2O in MeCN as the eluent. Enantiomeric
amines could then be coupled to indole carboxylic acids to prepare enantiomerically
pure inhibitors.
EXAMPLE 25
4'-Nitro-2-bromoacetophenone (6.100 g, 25 mmol) and ethyl thioxamate (3.460 g, 26
mmol) were dissolved in MeOH (20 ml_) and the solution was refluxed for 1 h. After
cooling to room temperature, the precipitated solid was collected by filtration,
washed with cold MeOH and dried under vacuum (5.15 g, 75% yield).
A suspension of the nitroester from above (2.50 g, 8.98 mmol) and 20% Pd(OH)2 on
carbon (200 mg) in 2:1 EtOH - THF (60 ml) was stirred for 3 h under 1 atm of
hydrogen gas. The suspension was filtered to remove the catalyst and volatiles
removed under reduced pressure to give the title compound of example 25 as a
reddish foam (2.05 g, 92% yield).
EXAMPLE 26
4-(4-Ethoxycarbonyl-thiazol-2-yl)-phenyl-ammonium chloride:
para-Bromoaniline (13.0 g, 76 mmol) and Boc2O (19.8 g, 91 mmol) were dissolved in
toluene (380 ml) and stirred at 70 °C for 15 h. The reaction mixture was cooled to
RT, evaporated to dryness, re-dissolved in EtOAc and washed with 0.1M HCI and
brine. The organic solution was dried over anhydrous MgSO4, evaporated to
dryness and purified by flash column chromatography, using 5% to 10% EtOAc in
hexane as the eluent, to obtain the Boc-protected aniline (23 g). The Boc-protected
bromoaniline (10.7 g, 39.2 mmol) was dissolved in anhydrous THF (75 ml) in a flask
equipped with an overhead stirrer. The solution was cooled to 0 °C and MeLi (1.2 M
in Et2O, 33 ml_, 39.2 mmol) was added drop wise while maintaining the internal
temperature below 7 °C. The reaction mixture was stirred at 0 °C for 15 min and
then cooled to -78 °C before n-BuLi (2.4 M in hexane, 17 ml_, 39.2 mmol) was
added drop wise, maintaining the internal temperature below -70 °C). The reaction
mixture was stirred at -78 °C for 1 h, B(OEt)3 (17 ml, 98 mmol) was added drop wise
(internal temperature at 0 °C for 1 h. The reaction mixture was then treated with 5% aqueous HCI (-100
ml, to pH ~1) for 15 min and NaCI(s) was added to saturate the aqueous layer. The
aqueous layer was extracted with 0.5 M NaOH (4 x 100 ml_) and the combined
aqueous layers were acidified with 5% HCI (150 ml, to pH ~1) and extracted with
Et2O (3 x 200 ml_). The combined organic layers were dried over anhydrous MgSO4,
filtered and concentrated to give the N-Boc carbamate of 4-aminophenylboronic acid
as a solid (7.5 g).
Thiourea (7.60 g, 100 mmol) and ethyl bromopyruvate (12.6 ml, 100 mmol) were
mixed and heated to 100 °C for 45 min. After cooling of the reaction mixture, the
solid obtained was triturated with acetone, filtered and recrystallized from EtOH to
obtain the desired aminothiazole product (10.6 g, 40 mmol). The aminothiazole was
then added slowly (over a period of 20 min) to a solution of t-butylnitrite (6.2 g, 60
mmol) and CuBr2 (10.7 g, 48 mmol) in MeCN (160 mL) at 0 °C. The reaction mixture
was allowed to warm-up to RT and to stirred for 2.5 h. The mixture was then added
to an aqueous HCI solution (20%) and extracted with Et2O (2 x 400 ml). The
organic layer was washed with aqueous HCI (10%), dried over anhydrous MgS04
and evaporated to dryness. The desired bromothiazole product was isolated in
-85% yield (4.3 g) after flash column chromatography using 15% EtOAc in hexane
as the eluent.
To a de-gassed solution of the bromothiazole product (230 mg, 0.97 mmol), the
boronic acid derivative from above (230 mg, 0.97 mmol) and aqueous Na2CO3 (2M,
3 mL) in DME (3mL), a catalytic amount of Pd(PPh3)4 (56 mg, 0.049 mmol) was
added and the reaction mixture was stirred at 80 °C under argon for 20 h. The
reaction mixture was then cooled to RT, diluted with EtOAc and extracted with brine,
aqueous NaHCO3 (2 x) and brine. The organic layer was dried over anhydrous
MgS04 and concentrated to dryness. The carbamate-ester product was isolated
after flash column chromatography using 20% to 30% EtOAc in hexane: 180 mg.
The aniline hydrochloride of example 26 was isolated after removal of the Boc
protecting group with 4N HCI in dioxane for 30 min.
EXAMPLE 27
Ethyl 5-amino-1-methyl-1 H-indole-2-carboxylate:
1) NaH, Mel
2) SnCI2 2H2O
COOEt
The ethyl ester of 5-nitroindole-2-carboxylic acid (0.300 g, 1.28 mmol) was dissolved
in anhydrous DMF (6 ml) and NaH (0.078 g, 60%, 1.92 mmol) was added. The
reaction was stirred at RT for 20 min, then Mel (160//L, 2.56 mmol) was added and
stirring was continued for 3 h. The reaction was quenched with the addition of
aqueous NaHCO3 (-1%) while stirring vigorously. The brown solid formed (0.096 g)
was filtered and dried in air overnight.
The N-methyl nitro derivative (196 mg, 0.79 mmol) was then dissolved in DMF (4
ml_), H2O (400 /jl) and SnCI22H2O (888 mg, 3.95 mmol) were added, and the
mixture was stirred at 60 °C for 3 h. The mixture was then partitioned between 10%
aqueous NaHCO3 and EtOAc and stirred vigorously. The aqueous layer was reextracted
with EtOAc and the combined EtOAc layers were washed with brine, dried
over anhydrous MgSO4 and concentrated to dryness. The residue was purified by
flash column chromatography, using 1:1 ration EtOAc/hexane as the eluent, to
obtain the pure 5-aminoindole derivative (118 mg) of example 27.
EXAMPLE 28
Ethyl 5-{[1-(4-amino-1-ethyl-piperidin-4-yl)-methanoyl]-amino}-1-methyl-1Hindole-
(Figure Removed)The 5-aminoindole derivative of example 27 was coupled to N-Fmoc-amino-(4-NBoc-
piperidinyl)carboxylic acid. The Boc protecting group was removed with 25%
TFA in CH2CI2 in the usual way, and the product was then dissolved in EtOH (6 ml_).
AcOH (133 mg), acetaldehyde (33 mg, 0.74 mmol) and NaCNBH3 (23mg, 0.37
mmol) were added and the reaction mixture was stirred at room temperature for 2 h.
The reaction mixture was concentrated to remove most of the solvent, the residue
was re-dissolved in EtOAc and washed with saturated NaHCO3 and brine. The
organic layer was dried over anhydrous MgSO4 and concentrated to give the N-ethyl
derivative as an orange solid.
This solid was dissolved in THF (2.5 ml), DBU (113 mg, 0.74 mmol) was added and
the mixture was stirred at room temperature for 30 min. The solvent was
evaporated, the remaining residue was dissolved in EtOAc and the organic layer was
washed with saturated NaHCO3 and brine. The organic layer was further extracted
with 1N HCI and H2O (2 x), and the pH of the combined aqueous layers was
adjusted to pH -10 with 1N NaOH. The aqueous layer was then extracted with
EtOAc (3 x), the combined organic layers were washed with brine, dried over
anhydrous MgSO4 and concentrated to dryness to give the title amine derivative of
example 28 (44 mg): MS (ES+) m/z 373.1 (MH+).
A similar reductive amination procedure was used to prepare other N-alkylated
pyrrolidine (e.g. cucurbitine) and piperidine derivatives. Alternatively, the reductive
amination can be performed as the last step on a fully assembled inhibitor.
EXAMPLE 29
General procedure for coupling amines to 6-indole carboxylic acids to give
amide derivatives of general formulae I:
Indole carboxylic acids were coupled to various amines (for example according to
the examples 15a, 15b, 15c, 19, 20, 21, 22, 23, 24, 25, 28, 34, 35, 36, 42, 43, or 45)
using standard amide bond forming procedures familiar to those skilled in the art.
Amide bond forming reagents include but are not limited to carbodiimides (DCC,
EDC), TBTU, HBTU, HATU and BOP-CI in the presence or absence of additives
such as HOBt or HOAT. Indole carboxylic acids can also be activated for coupling
by conversion to the corresponding acid chloride, symmetrical anhydride or
unsymmetrical anhydrides using standard protocols familiar to those skilled in the art
of organic chemistry. The coupling of indole carboxylic acids with amines is
generally carried out in solvents such as THF, DCM, DMF, DMSO or MeCN, in the
presence of a tertiary organic base including, but not limited to triethylamine, Nmethylmorpholine,
collidine and diisopropylethylamine. Following coupling of the
indole carboxylic acid with the amine, any remaining protecting group that remains in
the molecule can then be removed using the appropriate procedure. The following
example serves to illustrate such a process and is non-limiting.
(E)-3-[4-({1-[1-({1-[3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-
1H-indole-6-yl]-methanoyl}-amino)-cyclobutyl]-methanoyl}-amino)-phenyl]-
acrylic acid:
The indole carboxylic acid of example 9 (0.030 g, 0.069 mmol, 1 equiv.), the amine
of example 21 (0.044 g, 0.153 mmol, 2.2 equiv.) and TBTU (0.076 g, 0.24 mmol, 3.4
equiv.) were dissolved in DMSO (2 ml) and triethylamine (84 //L, 0.6 mmol, 8.7
equiv.) was added. The mixture was stirred overnight at room temperature
(complete by HPLC). 3N NaOH (0.7 ml_) was added and the mixture stirred at 50 °C
for 40 min (complete hydrolysis by HPLC). Acetic acid was added to neutralize the
reaction mixture and the product was isolated directly by preparative HPLC as a
beige amorphous solid (19 mg).
EXAMPLE 30
General procedure for the preparation of indole 6-acylsulfonamide derivatives:
Indole carboxylic acids were converted to the corresponding acid chloride and
coupled to various sulfonamides in the presence of DMAP and an organic base such
as triethylamine, DIEA, /V-methylmorpholine and the like. Alternatively, the
carboxylic acid was activated using amide bond forming agents such as
carbodiimides (DCC, EDC), TBTU, HATU and the like and treated with sulfonamides
in the presence of DMAP. Sulfonamides were either from commercial sources or
prepared from the corresponding sulfonyl chlorides and a solution of ammonia in
dioxane.
.0-
The following example serves to illustrate such as process and is non-limiting.
4-Bromo-N-{1-[3-cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1Hindole-
6-yl]-methanoyl}-benzenesulfonamide:
o-
3-Cyclohexyl-2-f u ran-3-yl-1 -(2-morpholin-4-yl-2-oxo-ethyl)-1 H-indole-6-carbonyl
chloride:
The carboxylic acid of example 9 (0.800 g, 1.833 mmol, 1 equiv.) was suspended in
DCM (15 mL) and DMF (20 //L) was added followed by oxalyl chloride (323 /ul, 3.7
mmol, 2 equiv.). After stirring for 2 h at room temperature, volatiles were removed
under reduced pressure and the residue co-evaporated twice with DCM. After drying
under vacuum for 1.5 h, the acid chloride was obtained as a brown solid that was
used directly in the next step.
4-Bromo-N-{1-[3-cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1Hindole-
6-yl]-methanoyl}-benzenesulfonamide:
The acid chloride from above (0.032 g, 0.07 mmol, 1 equiv.) was dissolved in DCM
(2 ml) and 4-bromobenzenesulfonylamide (0.0205 g, 0.085 mmol, 1.2 equiv.) was
added. Triethylamine (21 /jl, 0.15 mmol, 2.16 equiv.) and DMAP (0.018 g, 0.147
mmol, 2.1 equiv.) were added and the mixture was stirred overnight at room
temperature (complete by HPLC). DCM was then evaporated in air and the residue
re-dissolved in DMSO (2 ml_). The title compound of example 30 was isolated
directly by preparative HPLC as a light yellow powder (27 mg).
EXAMPLE 31
N-{1 -[3-Cyclohexyl-2-f uran-3-yl-1 -(2-morpholin-4-yl-2-oxo-ethyl)-1 H-indole-6-yl]-
methanoyl}-N-methyl-benzenesulfonamide:
The A/-methylacylsulfonamide of example 31 was prepared from the acid chloride
described in example 30 and A/-methylbenzenesulfonamide using the procedure of
example 30.
EXAMPLE 32
3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-6-
carboxylic acid acetyl-amide:
Acetamide (9 mg, 0.152 mmol, 1.38 equiv.) was dissolved in THF (2 ml) and NaH
(60 % oil dispersion, 8 mg, 0.2 mmol, 1.81 equiv.) was added. The mixture was
stirred for 30 min and the acid chloride of example 30 (0.050 g, 0.11 mmol, 1 equiv.)
in THF (1 mL) was added. The reaction mixture was then stirred for 2 h at room
temperature (complete by TLC). The reaction was diluted with EtOAc and the
solution washed with 10 % aqueous HCI and dried (Na2SO4). After evaporation of
the solvent under reduced pressure, the residue was purified by flash
chromatography on silica gel using EtOAc as eluent. The title compound of example
32 was obtained as a white solid (24 mg).
EXAMPLE 33
Methyl 2-bromo-3-cyclohexyl-1H-indole-5-carboxylate:
COOMe
Using the same series of reactions described in example 2 but starting from indole 5-
carboxylic acid, the title compound of example 33 was obtained. This compound is a
starting material for the synthesis of compounds according to the general formula I.4,
whereby the methods as described hereinbefore, e.g. 4 to 8 and/or in combination
with 9 to 32, can be employed in an analogous manner.
EXAMPLE 34
2-(1-Amino-cyclobutyl)-3-methyl-benzofuran-5-carboxylic acid methyl
Methyl 4-hydroxybenzoate (20.00 g, 131 mmol) was dissolved in DMF (350 mL) and
K2CO3 (24.19 g, 175 mmol) was added. The mixture was stirred for 30 min and
crotyl bromide (85%, 16.47 mL, 160 mmol) was added dropwise over 4 min. The
resulting amber suspension was stirred for 4 h at room temperature. It was then
poured into DCM and the solution washed with water and brine. The extract was
dried (MgSO4) and evaporated to a pale yellow oil consisting of a mixture of two
isomeric allyl ether (4:1 ratio). Upon standing at room temperature, the oil partially
crystallized. The supernatant was decanted and the crystals washed with hexane to
provide 12.5 g of the desired ether as white crystals.
The above material (10.30 g, SOmmol) was added to a flask heated to 230 °C in a
sand bath and the melted oil was stirred for 25 min at that temperature. The material
was then brought back to room temperature and the resulting waxy solid used
without purification in the next step.
The rearranged phenol from above (10.00 g, 48.5 mmol) was dissolved in MeOH
and the solution cooled to -78 °C in a dry ice - acetone bath. Ozone was bubbled
through the solution until complete disappearance of starting material (TLC).
Dimethyl sulfide (7 ml_) was then added dropwise at -78 °C and the mixture stirred
for 10 min at -78 °C and at room temperature for 30 min. Volatiles were removed
under reduced pressure, the residue was dissolved in ether and the solution washed
with water (2 X) and brine. After drying (MgSO4) and removal of volatiles, the crude
product which consists of a mixture of aldehyde and lactol was obtained as a milky
oil (9.9 g).
The crude product from above (9.9 g, 48 mmol) was suspended in 85% phosphoric
acid (40 ml_) and heated to 50 °C for 50 min after which a white solid precipitated.
Water (50 ml) was added and the solid collected by filtration. The material was then
dissolved in EtOAc and washed with saturated aqueous NaHCO3 and water. The
solution was dried (MgSO4) and concentrated to yield a residue that was purified by
flash chromatography on silica gel using 10% EtOAc - hexanes as eluent. The
desired benzofuran derivative was obtained (2.39 g).
The benzofuran derivative from above (2.20 g, 11.6 mmol) was dissolved in THF (65
ml_) and the solution cooled to -78 °C. A solution of lithium diisopropylamide (IDA,
2M in heptahe/THF/ethylbenzene, 6.9 mL) was added dropwise over 10 min. After
stirring for 35 min, cyclobutanone (1.793 mL, 24 mmol) was added dropwise and
stirring continued at -78 °C for 15 min. The reaction mixture was then warmed to
room temperature and quenched with 1N HCI. The product was extracted with
EtOAc, washed with water and brine and dried (Na2SO4). Purification by flash
chromatography on silica gel using 25% EtOAc in hexanes gave the desired
cyclobutyl carbinol (1.39 g) as a clear gum.
The alcohol from above (1.38 g, 5.3 mmol) and sodium azide (1.105 g, 17 mmol)
were suspended in CHCI3 (30 ml) and the mixture cooled in ice. TFA (1.695 ml, 22
mmol) was added dropwise over 10 min, the cooling bath was removed and the
mixture stirred at room temperature for 20 min. The reaction mixture was diluted
with CHCI3, washed with saturated aqueous NaHCO3 and dried (MgSO4). Removal
of solvents under reduced pressure gave a amber oil that was purified by flash
chromatography on silica gel using 5% EtOAc in hexane as eluent. The desired
azide was obtained as a clear oil (882 mg).
The azide from above (880 mg) was hydrogenated (1 atm H2) in MeOH over 5%
Lindlar catalyst (374 mg). After 15 min, the reduction was judged complete by TLC.
Removal of the catalyst by filtration and solvent under reduced pressure gave the
desired amine derivative of example 34 (785 mg) as a colorless oil: ES-MS: m/z
243 (M-NH2).
EXAMPLE 35
3-[2-(1-Amino-cyclobutyl)-1-(toluene-4-sulfonyl)-1H-indol-6-yl]-acrylicacid
ethylester
Indole 6-carboxylic acid (10.00 g, 62 mmol) was esterified by refluxing overnight in a
mixture of MeOH (200 ml) and cone. H2SO4 (1 ml). After cooling, the reaction
mixture was poured into sat. aqueous NaHC03 and extracted with EtOAc. The
extract was washed with aqueous NaHCO3 twice and water. Drying (MgSO4) and
removal of volatiles gave the desired methyl ester as a brown oil (10.4 g).
The ester from above (10.40 g, 62 mmol) was dissolved in DMF (80 mL) and the
solution cooled in ice. Sodium Hydride (60% oil dispersion, 2.852 g, 71.3 mmol) was
added in small portions and the mixture was stirred at room temperature for 40 min.
The reaction mixture was brought back to 0 °C and para-toluenesulfonyl chloride
(14.49 g, 76 mmol) was added. The mixture was stirred for 2 h at room temperature.
The reaction mixture was then diluted with EtOAc, washed consecutively with 10%
citric acid (2 X), NaHCO3 (2 X) and brine. After drying (MgSO-O, removal of solvent
gave a beige residue that was triturated twice with ether - hexanes (7.7 g).
Concentration of mother liquors and trituration of the residue with MeOH gave an
additional 5.8 g of the desired tosylated indole.
The material from above (1.750 g, 5.31 mmol) was dissolved in DCM (40 mL) and
the solution cooled to -78 °C. Diisobutylaluminum hydride (1M in DCM, 12.72 mL,
12.72 mmol) was added dropwise and the mixture stirred for 30 min at -78 °C. The
reaction mixture was then warmed to room temperature, quenched with aqueous
potassium sodium tartrate and stirred overnight at room temperature. The organic
phase was decanted, washed with brine and dried (MgSO4). Removal of volatiles
and purification by flash chromatography on silica gel gave the desired alcohol as a
colorless oil (1.35 g).
The alcohol from above (1.250 g, 4.15 mmol) was dissolved in THF (150 ml) and
the solution was cooled to -78 °C. Lithium diisopropylamide (2M in
THF/heptane/ethyl benzene, 10.37 mL) was added dropwise over 5 min. After
stirring for an additional 30 min at -78 °C, cyclobutanone (1.55 mL, 20.7 mmol) was
added and the reaction mixture allowed to warm up to 0 °C. The reaction was
quenched with 10% citric acid and THF removed under reduced pressure. Water
was added and the product was extracted with EtOAc, washed with aqueous
NaHCO3 and brine, and dried (MgSO4). The material was purified by flash
chromatography on silica gel using 30-50% EtOAc in hexanes as eluent. The
desired cyclobutyl carbinol was obtained as an oil (0.94 g).
The alcohol from above (0.870 g, 2.34 mmol) was dissolved in DCM (20 mL) and
1,1,1 -tris(acetyloxy-1,1 -dihydro-1,2-benzodioxol-3-(1 H)-one (Dess-Martin
periodinane) (1.060 g, 2.50mmol) was added. The mixture was stirred at room
temperature for 3 h, quenched with aqueous NaHC03 an d extracted with EtOAc.
The extract was washed with brine, dried (MgSO4) and concentrated to give the
desired aldehyde as an oil that was used directly in the next step.
The crude aldehyde (assume 2.34 mmol) from above was dissolved in DCM (20 mL)
and (carbethoxymethylene)triphenylphosphorane (0.871 g, 2.5 mmol) was added.
The mixture was refluxed for 4 h, concentrated and the product isolated by flash
chromatography on silica gel using 20-30% EtOAc in hexanes as eluent. The
desired cinnamate was obtained as a foam (0.400 g).
The cinnamate derivative from above (0.400 g, 0.9 mmol) was dissolved in CHCI3
(15 mL) and sodium azide (138 mg, 2.1 mmol) was added. TFA (0.39 mL, 5.1 mmol)
was added dropwise over 5 min and the mixture was then stirred at 60 °C for 4 h.
The reaction mixture was diluted with CHCI3, washed with aqueous NaHCO3 and
dried (MgSO4). The product was purified by flash chromatography on silica gel using
20% EtOAc in hexane as eluent, to give the desired azide as a yellow foam (0.207
The azide from above (0.183 g) was dissolved in THF (5 mL) containing 1% water
and triphenylphosphine (180 mg) was added. The mixture was stirred at 60 °C for
20 h and the final product of example 35 isolated by preparative reversed-phase
HPLC (42 mg).
This amine was coupled in the usual manner to indole carboxylic acid derivative to
give final inhibitors after cleavage of the N-tosyl and ester protecting groups with
NaOH.
Final products obtained as above were also methylated on the indole nitrogen by
treating the fully deprotected molecules with NaH and iodomethane, followed by
saponification of the methyl ester which was formed concomitantly.
EXAMPLE 36
2-Ethoxy-4-nitrobenzoic acid (1.56 g; 7.38 mmol) was dissolved in methanol (15 mL)
and the resulting solution stirred at 0°C. A solution of diazomethane in ethyl ether
was slowly added until the yellow color persisted and was stirred for a further 20 min.
The solvents were evaporated to afford the methyl ester as a pale yellow solid (1.66
g, quant.) which was used without further purification.
The ester from above (1.60 g; 7.10 mmol) was dissolved in dry toluene and the
solution cooled to -78 °C under a nitrogen atmosphere. A solution of
diisobutylaluminum hydride in tetrahydrofuran (1M; 8 mL; 8 mmol) was added and
the reaction allowed to warm to ambient temperature. Two additional portions of
DIBAL-H were added in this way (7 and 10 mL) after 1 h and a further 1.5 h. 0.5 h
after the last addition, the reaction was cooled to 0°C and 1N HCI (25 mL) was slowly
added and the mixture stirred vigorously for 0.5 h. The organic solvents were then
evaporated and the aqueous residue was extracted with ethyl acetate (2 x 50 mL)
and washed with water (50 mL) and brine (50 mL). The combined extracts were
then dried over MgSO4 and evaporated to afford the alcohol as a pale yellow, fibrous
solid (1.40 g; quant.) which was used as such.
A turbid solution of 1,1,1 -tris(acetyloxy-1,1 -dihydro-1,2-benzodioxol-3-(1 H)-one
(Dess-Martin periodinane) (2.32 g; 5.47 mmol) in dichloromethane (40 mL + 5 ml
rinse) was added to a stirred solution of the above alcohol (0.98 g; 4.97 mmol) in
DCM (40 mL) and the reaction stirred at ambient temperature under a nitrogen
atmosphere. After 4 h, saturated NaHC03 710% Na2S2O3 (1:1, 160 mL) was added
and the mixture stirred vigorously until the phases were clear (ca. 0.5 h). The
organic phase was separated and the aqueous phase was extracted with
dichloromethane (50 mL) and washed with saturated NaHCO3 (2 x 150 mL). The
combined organic phases were then dried over MgSO4 and evaporated to yield the
aldehyde as a pale yellow solid (960 mg; 99 %) which was used as such.
Sodium hydride (95% dry powder; 158 mg; 6.25 mmol) was suspended in anhydrous
THF (10 mL) and trimethyl phosphonoacetate (0.945 mL; 5.84 mmol) added
dropwise at 0°C under a nitrogen atmosphere resulting in a solid white mass which
could not be stirred. A solution of the aldehyde from above (950 mg; 4.87 mmol) in
THF (7 mL + 3 mL rinse) was then added dropwise resulting in a yellow colour and
slow dissolution of the white solid mass. After the addition, the reaction was allowed
to warm to ambient temperature. After 15 h, the cloudy reaction mixture was
evaporated to a pale yellow solid which was extracted with ethyl acetate (2 x 50 mL)
and washed with saturated NaHCO3 (3 x 75 mL). The combined extracts were dried
over MgSO4 and evaporated to afford the cinnamate ester as pale yellow solid
(1.212 g; 99 %) which was used without further purification.
The nitro cinnamate from above (0,300 g, 1.2 mmol) was suspended in EtOH (12
mL) and water (7.5 mL) and K2CO3 (0.990 g, 7.16 mmol) and 85% sodium
hydrosulfite (1.247 g. 7.16 mmol) were added successively. The mixture was stirred
vigorously at room temperature for 1.5 h. It was then diluted with water (10 mL) and
the ethanol removed under reduced pressure. The reaction mixture was extracted
with EtOAc (2 x), washed with water and brine and dried (MgSO4). Removal of the
solvent under reduced pressure gave the desired aniline as a yellow solid.
Note: the analogous methoxy derivative was prepared in the same manner using
commercially available 2-methoxy-4-nitrobenzoic acid as starting material.
EXAMPLE 37
3-(4,5-Diamino-2-alkoxy-phenyl)-acrylic acid methyl esters
-149-
The procedures will be illustrated for R = Et but similar protocols can be used to
prepare derivatives with other alkoxy substituents.
The ortho-ethoxy-para-nitro cinnamate derivative prepared as described in example
36 (600 mg; 2.39 mmol) was dissolved in concentrated sulphuric acid (5.5 ml) at
0°C and potassium nitrate (253 mg; 2.50 mmol) added in portions over 3 min. After
5 min, the resulting yellow-brown solution was allowed to warm to ambient
temperature and was stirred under a nitrogen atmosphere. After 3 h, the reaction
was added to ice (75 g) resulting in a pale yellow precipitate. Once the ice had
melted, the suspension was sonicated, filtered and washed several times with
distilled water. Air drying overnight afforded the dinitrocinnamate as a pale yellow,
chalky solid (661 mg; 93 %) which was used without further purification.
The dinitrocinnamate (657 mg; 2.22 mmol) was dissolved/suspended in ethanol /
water (1:1; 40 mL) resulting in a yellow suspension which was stirred vigorously at
ambient temperature. Potassium carbonate (3.06 g; 22.2 mmol) and sodium
hydrosulfite (3.86 g; 22.2 mmol) were successively added resulting immediately in a
dark violet/green colour which quickly began to lighten to a pale orange. After 3 h,
the reaction was diluted with water (20 mL) and the ethanol evaporated. The
aqueous residue was extracted with ethyl acetate (2 x 50 mL) and washed with
saturated NaHCO3 (2 x 60 mL) and brine (30 mL). The combined extracts were
dried over Na2SO4 and evaporated to afford the dianiline as a dark orange syrup
which solidified under high vacuum (377 mg; 72 %).
Such dianiline derivatives as described in this example could be converted to
benzimidazole derivatives by coupling to amino acid derivatives as described in
example 22 to prepare inhibitors.
EXAMPLE 38
3-(4-Amino-2-alkyl-phenyl)-acrylic acid methyl esters and 3-(4,5-diamino-2-
alkyl-phenyl)-acrylic acid methyl esters
As one skilled in the art would recognize, analogs of derivatives presented in
examples 36 and 37 where the alkoxy group has been replaced by an alkyl, alkenyl
or alkynyl substitutent (e.g. R = Me, Et, Pr, vinyl, allyl) can be prepared by converting
such an alkoxy derivative (e.g. methoxy) to the corresponding phenol by cleaving the
ether linkage with reagents such as BBr3 and then converting the phenol substituent
to the corresponding triflate. Such Inflates can then be used as substrates in a
variety of transition metal catalyzed cross-coupling reactions with organometallic
reagents that would allow replacement of the triflate functionality by an alkyl
substituent. Such reagents might include tetraalkyltin, tetraalkenyltin, alkylboronic
acid and alkenylboronic acid derivatives that would undergo cross-coupling under
Pd° catalysis. In some cases (e.g. allyl or vinyl), the substituent can be further
elaborated (e.g. the double bond can be converted to a cyclopropane ring using a
cyclopropanating reagent known to people skilled in the art)
Once the alkyl group has been introduced, the intermediates can then be elaborated
to inhibitors following synthetic sequences described in previous examples.
EXAMPLE 39
1-Carboxymethyl-3-cyclohexyl-2-furan-3-yl-7-methyl-1H-indole-6-carboxylic
acid methyl ester
Step 1: 3-amino-4-methylbenzoic acid (15.00 g, 0.099 mol) was suspended in
MeOH (150 mL) and thionyl chloride (25.33 ml_, 0.347 mol, 3.5 equiv.) was added
dropwise. The mixture was heated overnight at 70 °C. After cooling to RT, volatiles
were removed under reduced pressure and the residue triturated with ether (150
ml). The solid was filtered off and dried (18.36 g). The solid was suspended in
DCM (600 mL) and saturated aqueous NaHCO3 (250 mL) was added. After stirring
for 15 minutes, the organic layer was separated and washed successively with
NaHCO3 solution (2 x 250 mL), water (250 mL) and brine (250 mL). The solution
was dried (Na2SO4), filtered and evaporated to dryness to give the desired aniline
(14.8 g, 90% yield).
Steps 2 and 3: the ester from above (12.50 g, 75.6 mmol) was dissolved in DCM
(190 mL) and methylthioaldehyde dimethyl acetal (10.1 mL, 75.6 mmol) was added.
The solution was cooled to -30 °C. N-chlorosuccinimide (10.10 g, 75.6 mmol) was
added in 6 portions over 30 minutes. Triethylamine (10.6 mL, 75.6 mmol) was then
added dropwise over 10 min and after stirring for an additional 15 min, the cooling
bath was removed and the temperature brought to reflux. After 5 h, the reaction
mixture was cooled to RT and evaporated to dryness. The residue was dissolved in
ether (750 mL) and 2M HCI (303 mL) was added. After stirring at RT for 1.5 h, the
ether layer was separated and washed with NaHCO3 solution (2 x 150 mL) and brine
(250 mL). The original acidic aqueous phase was extracted with DCM (2 x 100 mL)
and the extracts washed as above and then combined with the first ether phase.
The combined organic phases were dried (Na2SO4) and evaporated to dryness and
the material purified by flash chromatography on silica gel using 30-0% hexane in
DCM as eluent to give the desired 3-thiomethylindole derivative (9.37 g).
Step 4: the thiomethyl indole from above (8.37 g, 35.4 mmol) was dissolved in
absolute EtOH (220 mL) and Raney-nickel (Ra-Ni) (25 g) was added. After stirring
at RT for 3 h, another portion of Ra-Ni (15 g) was added and stirring resumed for an
additional 45 min. The mixture was filtered and the filtrate evaporated to dryness to
give the desired indole (6.26 g, 93%).
Steps 5: the indole ester from above (4.00 g, 21 mmol) was dissolved in a mixture of
MeOH (18 mL) and water (18 mL). KOH (11.86 g, 210 mmol) was added and the
mixture stirred at 75 °C for 2 h. Cyclohexanone (7.26 g, 74 mmol, 3 equiv.) was
added dropwise over 15 min and stirring at 75 °C was continued overnight. MeOH
was removed under reduced pressure and water (500 mL) was added to the residue.
Insoluble material was removed by filtration and the aqueous phase was then
washed with TBME (200 mL). The aqueous phase was acidified to pH 4 with formic
acid to produce a white precipitate that was collected by filtration, washed with water
and dried. The desired cyclohexenylindole was obtained (4.77 g, 89%).
Steps 6-8: as described in example 2.
Steps 9-11: as described in examples 4 and 6.
EXAMPLE 40
1-Carboxymethyl-3-cyclohexyl-2-furan-3-yl-5-methoxy-1H-indole-6-carboxylic
acid methyl ester
Step 1: 4-methylsalicylic acid (100 g, 0.66 mol) was dissolved in acetone (1 L) and
K2CO3 (227 g, 1.64 mol, 2.5 equiv.) was added in portions. The mixture was heated
to reflux and dimethylsulfate (155 mL, 1.64 mol, 2.5 equiv.) was added dropwise
over 1 h. The mixture was refluxed overnight. Additional K2CO3 (90 g) and
dimethylsulfate (60 mL) were added and the mixture refluxed for an additional 20 h.
K2CO3 (20 g) and dimethylsulfate (15 mL) were again added and after refluxing for 7
h, the reaction was judged complete by TLC. Solids were removed by filtration using
acetone for washings and the filtrate concentrated to a volume of 200 mL. The
solution was diluted with MeOH (1 L) and stirred with ammonium hydroxide (300 mL)
for 30 min. MeOH was removed under reduced pressure and the residue extracted
with EtOAc (2 x 400 mL). The extract was washed with brine (500 mL) and dried
(Na2SO4). Removal of volatiles gave the desired product as a yellow oil (119 g).
Step 2: the ester from above (117 g, 0.649 mol) was charged in a flask cooled in
ice. The ester was dissolved in cone. H2SO4 (600 mL) and the solution cooled to -3
°C. Cone. HNO3 (51 mL) was added dropwise over 1.5 h keeping the internal
temperature around 0 °C. The ice bath was removed and the mixture stirred at RT
for 3.5 h. The reaction mixture was poured over ice and allowed to stand overnight.
The precipitated solid was collected by filtration, washed with water and dried. The
material was purified by trituration from hot methanol and flash chromatography on
silica gel to separate the desired product from a dinitro side product.
Step 3: The nitro ester from above (75.7 g, 0.336 mol) was dissolved in DMF (322
mL) and DMF dimethylacetal (120.1 g, 1.01 mol) was added dropwise over 10 min.
The mixture was heated to 115 °C for 3h (complete by TLC). The reaction mixture
was cooled to RT and volatiles removed under vacuum. The residue was coevaporated
twice with DCM and triturated with ether to give a total of 90.02 g (95%
yield) of the desired enamine derivative.
Step 4: The enamine from step 3 (90.02 g, 0.321 mol) was dissolved in 1:1 THFMeOH
(1.48 L) and the mixture heated to 35 °C in a water bath. Raney nickel
(washed with THF, 6.3 g) was added followed by dropwise addition of hydrazine
(18.5 g, 0.369 mol) over 15 min. After stirring for 1h (internal temperature: 49 °C), a
second portion of hydrazine (18.5 g) was added dropwise and the mixture stirred
overnight at 49 °C. Evaporated solvent was replenished and Raney-nickel (6.3 g)
and hydrazine (18.5 g) were again added followed by another portion of hydrazine
(18.5 g) after stirring for an additional 3 h. After stirring at 54 °C overnight, the
reaction was completed by addition of a last portion of Raney-nickel (6.3 g) and
hydrazine (36 mL) and stirring 20 h. The reaction mixture was then brought back to
RT and filtered using DCM for washings. The filtrate was evaporated to dryness
under reduced pressure and the residue purified by flash chromatography on silica
gel using 2-30% EtOAc in DCM as eluent. The desired indole was obtained (41.1 g).
The indole from step 4 was elaborated to the title compound of example 40 using
procedures similar to those described in the previous example.
EXAMPLE 41
3-Cyclohexyl-2-furan-3-yl-5-hydroxy-1-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-
yl)-ethyl]-1 H-indole-6-carboxylic acid
(Figure Removed)This is a representative procedure that can be applied to analogs with other amide
substituents: the methoxyindole (30 mg) was dissolved in DCM (1 ml_) and the
solution was cooled in ice under a nitrogen atmosphere. Boron tribromide (1M in
DCM, 0.3 ml) was added dropwise and the mixture was stirred for 40 min at 0 °C
and then 30 min at RT. The reaction was then quenched by addition of ice, diluted
with DCM and neutralized by addition of solid NaHCO3. The organic phase was
separated and dried (MgSO4). Evaporation of the solvent under reduced pressure
gave the desired phenol derivative as a yellow solid (21 mg) that was saponified to
give the title compound of example 41 under standard conditions. Alternatively, the
intermediate phenolic ester can be alkylated under standard conditions (e.g. NaH in
DMF) to produce various ether derivatives (e.g. with tert-butyl bromoacetate)
EXAMPLE 42
1-(2-Methyl-thiazol-4-yl)-cyclobutylaminehydrochloride
Step 1: The starting protected amino acid was obtained using a similar procedure to
that described in example 21 but using benzyl alcohol instead of trimethylsilyl ethanol
in the curtius rearrangement. The acid (7.48 g, 30mmol) was dissolved in THF (50
ml_) and the solution cooled to -8 °C under a nitrogen atmosphere. NMethylmorpholine
(3.63 ml_, 33 mmol) was added dropwise followed by
isobutylchloroformate (3.89 ml, 30 mmol). The suspension was stirred for 10 min
and filtered under nitrogen, keeping the filtrate at -8 °C. The solution was then
added to an excess ethereal diazomethane solution and the mixture stirred for 30
min (TLC shows complete conversion to the diazomethylketone). 48% HBr in water
(3.50 mL, 31 mmol) was then added dropwise over 5 min to the cold solution. A
second portion of HBr (3.5 mL) was added after 5 min, the cooling bath was
removed and the mixture stirred at RT overnight. Ether (250 mL) was added and the
solution washed with water (2 x 50 mL), saturated NaHCO3 (50 mL) and brine (50
mL). After drying (MgS04), volatiles were removed under reduced pressure and the
residue triturated with 1:4 ether/ hexanes. The white solid was filtered, washed with
hexane and dried in vacuum. The desired bromomethylketone (7.35 g, 75% yield)
was obtained as a white solid.
Step 2: The bromomethylketone from above (228 mg, 0.7 mmol) and thioacetamide
(56.3 mg, 0.75 mmol) were heated to reflux in isopropanol (5 mL). After 1 h, the
reaction mixture was evaporated to dryness and the oily residue triturated with water
to give a white precipitate that was collected, washed with water and dried in vacuum
(185 mg, 87% yield).
Step 3: 10% Pd on charcoal (70 mg) was suspended in EtOH (5 mL) and the
protected thiazole derivative from above (180 mg) was added. Hydrochloric acid
was added to acidify the reaction mixture which was then stirred under 1 atm of H2
gas for 20 h. The catalyst was removed by filtration and the filtrate evaporated to
dryness under reduced pressure to give the desired amine hydrochloride as a white
solid (104 mg) after trituration with ether.
The amine hydrochloride was coupled to indole derivatives under standard
conditions.
Note: Analogous thiazole derivatives can be prepared in a similar way by using
differently substituted thioamide, thiourea or acylthiourea derivatives. In addition,
other protected amino acids can be used as starting materials in this sequence and
converted to their respective bromo or chloromethylketones to be used in turn to
prepare various substituted thiazole derivatives.
EXAMPLE 43
(Z)-3-[2-(1-Amino-cyclobutyl)-6-ethoxy-1-methyl-1H-benzimidazol-5-yl]-acrylic
acid methyl ester
The 4-nitro-2-ethoxycinnamate (303 mg, 1.206 mmol), prepared as described in
example 36 was dissolved in concentrated sulfuric acid ( 3 ml_) and the solution
cooled to 0 °C. Potassium nitrate (128 mg, 1.27 mmol) was added and the mixture
stirred for 3.5 h at room temperature. After completion, the reaction mixture was
poured over ice and the precipitated solid was collected by filtration. The crude
product was washed with water, dried under vacuum and used without purification in
the next step (390 mg).
The dinitro derivative from above (390 mg) was dissolved in THF (3 ml_) and
methylamine in THF (3.02 ml_ of a 2M solution in THF) was added. After stirring for
30 min, volatiles were removed under reduced pressure and the orange solid used
as such in the next step.
The nitro arene from above was suspended in a mixture of EtOH (12 ml) and water
(12 ml_) and K2CO3 (1.00 g, 6 equivalents ) was added followed by sodium
hydrosulfite (1.26 g, 6 equivalents). The mixture was stirred for 4 h at room
temperature and EtOH was removed under reduced pressure. The residue was
extracted with EtOAc and the organic phase washed with brine and dried (MgSO4).
Removal of the solvent and purification of the residue by flash chromatography (50
to 75% EtOAc in hexane) gave the desired diamine (162 mg).
The dianiline from above (162 mg) was dissolved in acetonitrile (6 mL) and
aminocyclobutanecarboxyl chloride hydrochloride prepared as in example 20 (116
mg) was added. The mixture was stirred overnight at room temperature, diluted with
EtOAc and the solution washed with aqueous NaHCO3 and brine. After drying
(MgSO4), volatiles were removed under reduced pressure. The residue was
dissolved in AcOH (3 ml) and the solution heated to 80 °C for 1 h. After cooling to
room temperature, the reaction mixture was poured into water and basified to pH 9
by addition of solid K2CO3. The organic phase was then extracted with EtOAc,
washed with brine and dried (MgSO4). Removal of the solvent gave a residue that
was purified by flash chromatography on silica gel using 0 to 5% MeOH in EtOAc to
give the title compound of example 43 (68 mg).
EXAMPLE 44
7-Methoxy-1H-indole-6-carboxylic acid methyl ester:
Step 1: 4-methylsalicylic acid (32.1 g, 0.21 mol) and potassium carbonate (61.2 g,
0.44 mol) were suspended in acetone (300 mL) and the mixture brought to reflux
temperature. Dimethyl sulfate (66.5 g, 0.53 mol) was added dropwise within 1 h and
stirring continued overnight at reflux. Additional dimethylsulfate (30 mL) and
potassium carbonate (2 X 15 g) were added and refluxing for an additional 24 h was
required to complete the reaction. The reaction mixture was then cooled to room
temperature and inorganic salts removed by filtration using acetone for washings.
The filtrate was evaporated under reduced pressure and the oily residue was
dissolved in MeOH (300 mL). Concentrated ammonium hydroxide (90 mL) was
added and the mixture was stirred for 30 minutes at room temperature. Methanol
was removed in vacuo and the residue portioned between ether (300 mL) and water
(200 mL). The organic phase was separated and washed with brine and dried
(Na2SO4). Evaporation of the ether gave the desired di-methylated product as a
yellow oil (38.1 g) that was used directly in the next step.
Step 2: The ester from above (38.0 g, 0.21 mol) was dissolved in AcOH (250 ml_)
and bromine (37.2 g, 0.23 mol, 1.1 equiv.) was added dropwise over 30 min with
stirring at room temperature. After completion, the reaction mixture was stirred for
an additional hour, at which point TLC analysis indicated complete conversion. The
reaction mixture was poured into water (1 L) and solid Na2CO3 was added cautiously
with stirring until the mixture was neutral. The off-white precipitate that formed was
collected by filtration, washed with water and dried to give the desired bromo
derivative (47.2 g).
Step 3: The bromo derivative from above (44.5 g, 0.17 mol) was added in small
portions to cone. H2SO4 (170 ml) and the mixture was stirred in an ice-salt bath until
all solids dissolved. Cone. HN03 (17 ml_) was then added dropwise over 20 min and
stirring continued for an additional hour in the ice bath. The reaction mixture was
then slowly added to ice-water (2 L) and the precipitated yellow solid was collected
by filtration. The solid was washed with water, NaHCO3 solution and water again.
After drying, the desired nitro derivative was obtained as an orange solid (36.8 g).
Step 4: The product from above (129.0 g, 0.42 mol) was dissolved in DMF (400 ml)
and DMF-dimethyl acetal (151.6 g, 1.27 mol, 3 equiv.) was added in one portion.
The mixture was heated at 110-120 °C under an argon atmosphere until conversion
was judged complete by TLC (24 h). The reaction mixture was cooled to room
temperature and volatiles removed under vacuum to give a dark colored residue
(-180 g). Trituration from ether-THF gave the desired enamine as red crystals (72
Step 5: The enamine from above (72.0 g, 0.20 mol) was dissolved in a mixture of
THF (600 ml) and MeOH (600 ml_). The dark red solution was heated to 30 °C and
Raney-Nickel (18 g) was added to the solution. Hydrazine hydrate (11.6 g, 0.23 mol,
1.15 equiv.) was then added dropwise over 30 min. The reaction temperature was
increased to 50 °C and a second portion of hydrazine hydrate (11.6 g, 0.23 mol, 1.15
equiv.) was added over 30 min. After stirring overnight at 50 °C, additional Raneynickel
(20 g) and hydrazine hydrate (11.6 g, 0.23 mol, 1.15 equiv.) were added and
after stirring for another 7 h at 50 °C, the reaction was judged complete by TLC.
After cooling, the catalyst was removed by filtration through a pad of celite and the
filtrate was evaporated under reduced pressure. The dark brown residue was
dissolved in EtOAc (3 L) and the solution washed with water (1.5 L), 10% HCI (1 L)
and brine (700 mL). After drying (Na2SO4), removal of solvents gave the desired
bromoindole derivative as a brown solid (35 g).
Step 6: The bromoindole derivative from above (35 g) was dissolved in MeOH (1 L)
and triethylamine (16.3 g, 1.2 equiv.) was added followed by 10% Pd/C (1.06 g).
The mixture was stirred under hydrogen (35 psi) until completion of the reaction (7
h). The catalyst was then removed by filtration and volatiles removed under reduced
pressure. The residue was dissolved in EtOAc (700 mL) and the solution washed
with 10% HCI (SOOmL), water (350 mL), NaHCO3 (350 mL) and brine. The solution
was dried (Na2SO4) and concentrated under reduced pressure to give the desired
indole as a light brown solid (25 g).
This indole derivatives was saponified under standard conditions and elaborated to
final inhibitors as previously described for analogous derivatives.
EXAMPLE 45
2-(1~AminO"Cyclobutyl)-6~methoxy-3-methyl-3H-benzimidazole-5-carboxylic
acid methyl ester
Methyl 2-methoxy-5-nitrobenzoate (6.21 g, 29.4 mmol) was suspended in MeOH
(100 mL) and 20% Pd(OH)2/C (500 mg) was added. The mixture was stirred under a
hydrogen atmosphere (1 atm) for 18 h. The catalyst was removed by filtration and
the solvent evaporated under reduced pressure (5.256 g).
The aniline from above (5.23 g) was dissolved in THF (50 mL) and acetic anhydride (
2.984 g) was added. The mixture was stirred overnight at room temperature. The
white suspension was concentrated under reduced pressure to a white paste, tertbutylmethyl
ether (TBME, 20 mL) was added and while stirring, hexane (100 mL)
was added slowly. The suspension was then stirred for an additional 2h and the
solid collected by filtration. The product was washed with hexane and dried in air
(6.372 g).
90% Nitric acid (9 ml) was diluted with water (9 ml_) and cooled to 0 °C. The anilide
from above (5.905 g) was added in one portion and the mixture stirred for 30 min in
the ice-water bath. The reaction mixture was then added dropwise to ice-water (700
ml) and the precipitated yellow solid was collected by filtration, washed with water
and dried in air. The orange solid (5.907 g) was shown by 1H NMR to consist of a
2:1 mixture of compounds. Extraction of the aqueous filtrate from above with EtOAc
gave an additional 1 g of material that was combined with the first crop and purified
by flash chromatography on silica gel using 015% EtOAc in CHCI3 as eluent. An
orange solid (4.11 g) was obtained (one isomer).
The nitroanilide from above (3.580 g) was dissolved in THF (50 ml) and the solution
cooled in ice. lodomethane (4.155 mL, 66.7 mmol, 5 equivalents) and sodium tertbutoxide
(6.414 g, 66.7 mmol, 5 equivalents) were added in two portions at a 3.5 h
interval. Stirring at room temperature was continued for an additional 20 h after the
second addition. THF was evaporated under reduced pressure and water (100 mL)
was added. The deep red solution was washed with TBME (100 mL). The aqueous
phase was acidified with cone. HCI and extracted with EtOAc (2 x 100 mL). The
combined organic extracts were dried and concentrated to a dark red powder (3.78
g) that was used directly in the next step.
The free carboxylic acid (3.75 g) was suspended in 8M HCI (100 mL) and the
mixture stirred at 100 °C for 8 h. After cooling to room temperature, volatiles were
evaporated under vacuum and the residue was co-evaporated 3 times with MeOH.
The residue was suspended again in MeoH (100 mL) and cooled in ice-water.
Thionyl chloride (5.10 mL, 5 equivalents) was added dropwise and the suspension
stirred at 65 °C for 4 h. Volatiles were removed under reduced pressure and the
residue co-evaporated twice with MeOH (100 mL) and then toluene (2 x 100 mL).
The residue was then dissolved in MeOH (200 mL), 20% Pd(OH)2 / C (500 mg) was
added and the mixture stirred overnight under 1 atm of hydrogen gas. The catalyst
was then removed by filtration and the solution evaporated to dryness. The residue
was dissolved in EtOAc and the solution washed with aqueous NaHCO3 and dried
(MgSO4). Removal of solvents gave a solid that was suspended in TBME (50 mL)
and heated to 60 °C for 30 min. An equal volume of hexane was then slowly added
to the hot solution and the precipitated material was collected by filtration, washed
with TBME-hexane and dried (2.00 g).
The diamine from above (1.950 g) was dissolved in DCM (50 mL) and the solution
cooled in ice. 1-Aminocyclobutyryl chloride hydrochloride prepared using a similar
procedure as in example 20 (1.50 g) was added in 3 portions over a 1.5 h period.
The mixture was then warmed to room temperature and stirred overnight. Additional
acid chloride (0.50 g) was added and stirring continued for another 2 h. DCM was
evaporated under reduced pressure and AcOH (30 ml) was added and the mixture
heated to 80 °C for 3 h. The reaction mixture was cooled to room temperature and
volatiles evaporated under reduced pressure. The residue was dissolved in water
(100 ml) and solid NaHCO3 was added in portions until a pH of 8 was reached. The
product was then extracted with EtOAc (3 x 100 ml), dried (Na2SO4) and
concentrated to dryness. The residue was purified by flash chromatography on silica
gel using 0 to 15% EtOH in EtOAc as eluent. The title compound of example 45 was
obtained as a grey powder (1.05 g).
EXAMPLE 46
Inhibition of NS5B RNA dependent RNA polymerase activity
The compounds of the invention were tested for inhibitory activity against the
hepatitis C virus RNA dependant polymerase (NS5B), according to protocol
described in WO 03/010141
EXAMPLE 47
Specificity of NS5B RNA dependent RNA polymerase inhibition
The compounds of the invention were tested for inhibitory activity against polio virus
RNA dependent RNA polymerase and calf thymus DNA dependent RNA polymerase
II in the format that is described for the HCV polymerase with the exception that
another polymerase was used in place of the HCV NS5B polymerase as is described
in WO 03/010141
In Tables 1 to 8 below, the following ranges apply:
IC50: A = 10 uM-1 uM; B = 1 jiM-200 nM; and C 200 nM.
(Table Removed)






WE CLAIM:
1. Indole compounds of formula (I)
(Formula Removed)

or an isomer, enantiomer, diastereoisomer or tautomer thereof, wherein:
either A or B is N and the other B or A is C, wherein — between two C-atoms represents a double bond and — between a C-atom and a N-atom represents a single bond,
the group -C(=Y1)-Z is covalently linked to either M2 or M3,
M1 is CR43,
M2 or M3, when not linked to -C(=Y1)-Z, is CR5,
M4 is CR4b,
and in addition one or two of the groups selected from M1, M2, M3 and M4 may also be N, with the proviso that the group M2 or M3 to which -C(=Y1)-Z is linked is an C-atom,
Sp is a spacer group selected from -(CR51R52)k1-, wherein k1 is 1, 2 or 3;
R51, R52are independently H, (C1.6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl, or
R51 and R52 are covalently bonded together and to the carbon-atom to which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered

saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms selected from N, O or S;
said alkyl, cycloalkyl, alkyl-cycloalkyl or cyclic system being optionally substituted by halogen, hydroxy, (C1-6)alkoxy, cyano, amino, -NH(C1-4-alkyl) and/or -N(C1-4aIkyl)2;
Y° is O, S, NR11 or CR12R13, wherein
R11, R12, R13are each independently defined as R°;
R13 may also be COOR0 or S02Rc;
wherein Rc and each R° is optionally substituted with R150;
or both R12 and R13 are covalentiy bonded together and to the carbon-atom to which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms selected from N, O or S; said cyclic systems being optionally substituted with R150;
L is C1-6alkyl, (C3-6)cycloalkyl, C1-6alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl,
(C1-6alkyl)aryl, Het, (C1-6alkyl-Het, all of which being optionally substituted with R60;
or if Y° is CR12R13, then L may also be H;
or if Y° is O, then L may also be ORc,
wherein Rc is optionally substituted with R60;
or if Y° is O, S or NR11, then L may also be N(RN2)RN1, NRN3-N(RN2)RN1

NRN3-NRN2-CO-Rc, NRN4-NRN3-CO-N(RN2)RN1, NRN2-S02-Rc, NRN2-CO-Rc, NRN3-CO-N(RN2)RN1 or N(RN1)OR°; said RN1, including any heterocycle or heterobicycle formed by RN1, RN2 and/or RN3, and Rc and R° being optionally substituted with R60;
or if Y° is O or S, then L may also be OR6a or N(R5a)R6a, wherein R5a is defined as RN2,
and wherein R6a is:
(Formula Removed)

wherein R7a and R8a are each independently defined as R°, COOR0 or CON(RN2)RN1, wherein said R° is optionally substituted with R60; or R7a and R8a are covalently bonded together to form a (C3-7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; and when L is N(R5a)R6a, either of R7a or R8a may be covalently bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyi or heterocycle being optionally substituted by R150; and
W1 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
wherein the alkylene and alkenylene groups as claimed in b), c) and d) may be substituted with (C1-3) alkyl;


Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or R9a is covaiently bonded to either of R7a or R8a to form a 5- or 6-membered heterocycle;
Q1 is aryl, Het, (C1-6) alkyl-aryl, (C1-6) alkyl-Het, (C1-6) alkyl-CONH-aryl or(C1-6 alkyl-CONH-Het, all of which being optionally substituted with R60;
Y1 is O, S or NR14, wherein R14 is H or (C1-6) alkyl;
Z is defined as
a) OR0;
b) SO2Rc;
c) N(RN2)RN1;
d) NRN3-N(RN2)RN1;
e) NRN3-NRN2-CO-Rc;
f) NRN4-NRN3-CO-N(RN2)RN1;
g) NRN2-SO2-Rc or
h) NRN3-SO2-N(RN2)RN1;
i) NRN2-CO-Rc;
j) COOR0;
k) N(RN1)OR°;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2,
and/or RN3, being optionally substituted with R60;
or Z is OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
(Formula Removed)
wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1
respectively; and
Q2 is aryl, Het, (C1-6) alkyl-aryl, (C1-6) alkyl-Het, (C1-6) alkyl-CONH-aryl or (C1-
6)alkyl-CONH-Het, all of which being optionally substituted with R60
orQ2isR160
or Q2 is selected from the group consisting of 0-C1.4-alkyl, S-d-4-alkyl, C^-
alkyl, C2-4-alkenyl and C2-4-alkynyl, all of which being optionally substituted
with R160; and
R2 is selected from: halogen or R21, wherein R21 is aryl or Het, said R21 is optionally substituted with R150;
R3 is selected from (C3-7)cycloalkyl, (C1-3)alkyl-(C3-7)cycloalkyl, (C5-7)cycloalkenyl,
(C1-3)alkyl-(C5-7)cycloalkenyl, (C6-10)bicycloalkyl, (C1-3)alkyl-(C6-10)bicycloalkyl,
(C6-10)bicycloalkenyl, (C1-3)alkyl-(C6-10)bicycloalkenyl or HCy
wherein HCy is a saturated or unsaturated 4 to 7-membered heterocyclic
group with 1 to 3 heteroatoms selected from O, S and N;
said cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and HCy
being optionally substituted with from 1 to 4 substituents selected from: a)
halogen;
b) (C1-6)alkyl optionally substituted with:
-1 to 3 substituents selected from halogen;
- OR31 or SR31 wherein R31 is H, (C1-6alkyl), (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl; or
- N(R32)2 wherein each R32 is independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl; or both R32 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
c) OR33 or SR33 wherein R33 is H, (C1-6)alkyl, (C3-7)cycloalkyl or

(C1-3)alkyl-(C3-7)cycloalkyl;
d) N(R35)2 wherein each R35 is independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl; or both R35 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
R4b, R5 each are independently H or defined as R150;
is each defined as 1 to 4 substituents independently selected from: -1 to 3 substituents selected from halogen; - one of each substituent selected from: OPO3H, N02, cyano, azido, C(=NH)NH2, C(=NH)NH(C1-6)alkyl or C(=NH)NHCO(C1-6)alkyl, SO3H; and -1 to 3 substituents selected from:
a) (C1-6) alkyl, (C3-)cycloalkyl, C3-7 spirocycloalkyi optionally containing 1 or 2 heteroatoms selected from N, O and S; (C2.6)alkenyl, (C2-8)alkynyl, (C1-6)alkyl-(C3-7)cycloalkyl, all of which optionally being substituted with R150;
b) OR0;
c) OC(0)R°;
d) SR°, S02Rc, S02N(RN2)RN1, S02N(RN2)C(0)Rc, C0NRN3S02N(RN2)RN1, or CONRN2S02Rc;
e) N(RN2)RN1, N(RN2)COORc, N(RN2)S02Rc or N(RN1)R°;
f) N(RN2)CORc;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORc, N(RN3)COCOOR°orN(RN3)COCON(RN2)RN1;
i) COR0;
j) COOR0;
k) CON(RN2)RN1;
I) aryl, Het, (C1-4alkyQaryl or (C1-4alkyl)Het, all of which optionally being
substituted with R150; wherein said RN1, Rc and R° are each independently optionally substituted with R150 as defined,
is each defined as 1 to 4 substituents independently selected from:

-1 to 3 substituents selected from halogen;
- one of each substituent selected from: OP03H, N02, cyano, azido,
C(=NH)NH2, C(=NH)NH(C1-6)alkyI or C(=NH)NHCO(C1.6)alkyl; and
-1 to 3 substituents selected from:
a) (C1-6) alkyl, (C3-7)cycloalkyl, C3-7 spirocycloalkyi optionally containing 1 or 2 heteroatoms selected from N, O and S; (C2-6)alkenyl, (C2-8)alkynyl, (C1-3)alkyl-(C3-7)cycloalkyl, all of which optionally substituted with R160;
b) OR0;
c) OC(0)R°;
d) SR°, S02Rc, S02N(RN2)RN1, S02N(RN2)C(0)Rc or CON(RN2)S02Rc;
e) N(RN2)RN1, N(RN2)COORc, N(RN2)S02Rc, or N(RN1)R°;
f) N(RN2)CORc;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORc, N(RN3)COCOOR°, N(RN3)COCON(RN2)OH,
N(RN3)COCON(RN2)OC1-4alkyl or N(RN3)COCON(RN2)RN1; i) COR0; j) COOR0;
k) tetrazole, triazole, CONRN3-S02N(RN2)RN1; or CON(RN2)RN1; wherein said RN1, Rc and/or R° are optionally substituted with R160 as defined;
R160 is each defined as 1, 2 or 3 substituents independently selected from: -1, 2 or 3 fluorine substituents; and
- one of each substituent selected from tetrazole, triazole, chlorine, bromine,
iodine, CN, nitro, C1-4alkyl, CF3, COOR161, S03H, SR161, SCF3, S02R163,
OR161, OCF3, N(R162)2, S02N(R162)2, NR162S02Rc, NR162COR162,
CON(R162)2, -NR161-CO-COOR161, -NR161-CO-CO(NR162)2, -CONR161S02Rc,
CONR161-S02N(R162)2 or-S02-NR161-CORc, wherein R161, R163and each R162
is independently (C1-4alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl; and
R161 and each R162 may each independently also be H; or both R162 are
covalently bonded together and to the nitrogen to which they are attached to
form a 5, 6 or 7-membered saturated heterocycle;
R°, Rcare independently defined as (C1-6)alkyl, (C3-6)cycloalkyl, (C1-4)alkyl-

(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl and (C1-4)alkyl-Het; and R° may also be H;
RN1 is independently selected from H, (C1-6)alkyl, (C3-7)cycloalkyl, (C1-4)alkyl-
(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl, (C1-4)alkyl-Het; or
RN2 ,RN3 ,R N4 areindependently H, CH3, (C2-6)alkyl, (C3-6)cycloalkyl, (C1-4)alkyl-
(C3-6)cycloalkyl; wherein said alkyl, cycloalkyl or alkylcycloalkyl is optionally substituted with hydroxy, halogen, carboxy, C1-6-alkoxycarbonyl, C1-6-alkyl, C1-6-alkoxy, amino, -NH(C1-4-alkyl) and/or -N(C1-4-alkyl)2; and wherein said CH3 is optionally substituted with halogen, carboxy or C1-6-alkoxycarbonyl; and
in the case
a) of a group N(RN2)RN1 the substituents RN2 and RN1; or
b) of a group NRN3-N(RN2)RN1 the substituents RN3 and RN1, or RN2 and RN1; may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11-membered N-containing heterobicycle each may have additionally from 1 to 3 heteroatoms selected from O, N, and S;
wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, or a 8-, 9-, 10- or 11-membered heterobicycle having 1 to 5 heteroatoms selected from O, N and S;
or a salt thereof.
2. A compound as claimed in claim 1 wherein:
either A or B is N and the other B or A is C, wherein — between two C-atoms represents a double bond and — between a C-atom and a N-atom represents a single bond,
the group -C(=Y1)-Z is covalently linked to either M2 or M3,

M1 is CR43, M2orM3isCR5, M4 is CR4b,
and in addition one or two of the groups selected from M1, M2, M3 and M4 may also be N, with the proviso that the group M2 or M3 to which -C(=Y1)-Z is linked is an C-atom,
Sp is a spacer group selected from -(CR51R52)ki-, wherein k1 is 1,2 or 3;
R51, R52are independently H, (C1_6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl, or
R51 and R52 are covalently bonded together and to the carbon-atom to which they are attached to form a (C3-6)cycloalkyl group, said alkyl, cycloalkyls or alkyl-cycloalkyl being optionally substituted by halogen, hydroxy, (C1-6alkoxy, cyano, amino, -NH(C1-4-alkyl) and/or -N(C1-4-alkyl)2;
Y° is O, S, NR11 or CR12R13, wherein
R11, R12, R13are each independently defined as R°;
R13 may also be COOR0 or S02Rc;
wherein Rc and each R° is optionally substituted with R150;
or both R12 and R13 are covalently bonded together and to the carbon-atom to which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms selected from N, O or S; said cyclic systems being optionally substituted with R150;
L is C1-6alky!, (C3-6)cycloalkyl, C1-6alkyl-(C3.6)cycloalkyl, (C2-6)alkenyl, aryl,
(C1-6alkyl)aryl, Het, (C1-6)alkyl-Het, all of which being optionally substituted with R60;

or if Y° is CR12R13, then L may also be H;
or if Y° is O, then L may also be ORc,
wherein Rc is optionally substituted with R60;
or if Y° is O, S or NR11, then L may also be N(RN2)RN1, NRN3-N(RN2)RN1,
NRN3-NRN2-CO-Rc, NRN4-NRN3 -CO-N(RN2) NRN2-SO2Rc,
NRN2-CO-Rc, NRN3-CO-N(RN2)RN1 or N(RN1)OR°;
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2
and/or RN3, and Rc and R° being optionally substituted with R60;
or if Y° is O or S, then L may also be OR6a or N(R5a)R6a, wherein R5a is defined as RN2,
and wherein R6a is:
(Formula Removed)
wherein R7a and R8a are each independently defined as R°, wherein said R° is optionally substituted with R60; or
R7a and R8a are covalently bonded together to form a (C3-7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; and when L is N(R5a)R6a, either of R7a or R8a may be covalently bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R150; and
Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered heterocycle;


Q1 is aryl, Het, (C1-6) alkyl-aryl, (C1-6) alkyl-Het, (C1-6) alkyl-CONH-aryl or (C1-6) alkyl-CONH-Het, all of which being optionally substituted with R60;
Y1 is O, S or NR14, wherein R14 is H or (d-e) alkyl;
Z is defined as
a) OR0;
b) S02Rc;
c) N(RN2)RN1;
d) NRN3-N(RN2)RN1;
e) NRN3-NRN2-CO-Rc;
f) NRN4-NRN3-CO-N(RN2)RN1;
g) NRN2-S02-Rc or h) NRN2-CO-Rc;
i) COOR0;
j) N(RN1)OR°;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1, RN2,
and/or RN3, being optionally substituted with R60;
or Z is OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
(Formula Removed)
wherein R7b, R8b, Y3, R9b, Q2, are defined as R7a, R8a, Y2, R9a, Q1,
respectively;
R2 is selected from: halogen or R21, wherein R21 is aryl or Het, said R21 is optionally substituted with R150;
R3 is selected from, (C-7)cycloalkyl, (C1-3)alkyl-(C3-7)cycloalkyl, (C5-7)cycloalkenyl, (C1-3)alkyl-(C5-7)cycloalkenyl, (C6-10)bicycloalkyl, (C1-3)alkyl-(C6-10)bicycloalkylJ (C6-10)bicycloalkenyl, (C1-3)alkyl-(C6-10)bicycloalkenyl or HCy,

wherein HCy is a saturated or unsaturated 4 to 7-membered heterocyclic group with 1 to 3 heteroatoms selected from O, S and N; said cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and HCy being optionally substituted with from 1 to 4 substituents selected from: a) halogen;
b) (C1-6)alkyl optionally substituted with:
- OR31 or SR31 wherein R31 is H, (C1-6alkyl), (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7) cycloalkyl; or
- N(R32)2 wherein each R32 is independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl; or both R32 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;

c) OR33 or SR33 wherein R33 is H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl;
d) N(R35)2 wherein each R3S is independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl; or both R35 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
4b, R5 each are independently H or defined as R150;
each defined as 1 to 4 substituents independently selected from: -1 to 3 substituents selected from halogen; - one of each substituent selected from: OP03H, N02, cyano, azido, C(=NH)NH2, C(=NH)NH(C1-6)alkyl or C(=NH)NHCO(C1-6)alkyl, S03H; and -1 to 3 substituents selected from:
a) (C1-6) alkyl, (C3-7)cycloalkyl, C3.7 spirocycloalkyi optionally containing 1 or
2 heteroatoms selected from N, O and S; (C2-6)alkenyl, (C2-8)alkynyl,
(C1-6)alkyl-(C3-7)cycloalkyl, all of which optionally being substituted with
R150.
b) OR0;
c) OC(O)R°;

d) SR°, S02Rc, S02N(RN2)RN\ S02N(RN2)C(0)Rc or C0NRN2S02Rc;
e) N(RN2)RN1, N(RN2)COORc, or N(RN2)S02Rc;
f) N(RN2)CORc;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORc, N(RN3)COCOOR°orN(RN3)COCON(RN2)RN1;
i) COR0;
j) COOR0;
k) CON(RN2)RN1;
I) aryl, Het, (C1-4alkyl)aryl or (C1-4alkyl)Het, all of which optionally being
substituted with R150; wherein said RN1, Rc and R° are each independently optionally substituted with R150 as defined,
is each defined as 1 to 4 substituents independently selected from: -1 to 3 substituents selected from halogen; - one of each substituent selected from: OP03H, N02, cyano, azido, C(=NH)NH2, C(=NH)NH(CC1-6)alkyl or C(=NH)NHCO(C1-6)alkyl; and -1 to 3 substituents selected from:
a) (C1-6) alkyl, (C3.7)cycloalkyl, C3-7 spirocycloalkyi optionally containing 1 or 2 heteroatoms selected from N, O and S; (C2-6)alkenyl, (C2-8)alkynyl, (C1-3)alkyl-(C3-7)cycloalkyl, all of which optionally substituted with R160;
b) OR0;
c) OC(0)R°;
d) SR°, S02Rc, S02N(RN2)RN1, S02N(RN2)C(0)RC or CON(RN2)S02Rc;
e) N(RN2)RN1, N(RN2)COORc, or N(RN2)S02Rc;
f) N(RN2)CORc;
g) N(RN3)CON(RN2)RN1;
h) N(RN3)COCORc, N(RN3)COCOOR°orN(RN3)COCON(RN2)RN1;
wherein RNi is as defined or OH, 0-d.4-alkyl; i) COR0; j) COOR0;
k) tetrazole or CON(RN2)RN1;
wherein said RN1 Rc and/or R° are optionally substituted with R160 as defined;

R160 is each defined as 1, 2 or 3 substituents independently selected from: -1, 2 or 3 fluorine substituents; and
- one of each substituent selected from tetrazole, chlorine, bromine, iodine, CN, nitro, CMalkyl, CF3, COOR161, S03H, SR161, S02R163, OR161, N(R162)2, S02N(R162)2, S02NR162COR162, NR162S02R163, NR162COR162, or CON(R162)2, wherein R161, R163and each R162is independently (C1-4)alkyl, (C3-7)cycloalkyl or (C1-3)alky-(C3-7)cycloalkyl; and R161 and each R162 may each independently also be H; or both R162 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
R°, Rcare independently defined as (C1-6)alkyl, (C3-6)cycloalkyl, (C1-4)alkyl-
(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl and (C1-4)alkyl-Het; and R° may also be H;
RN1 is independently selected from H, (C1-6)alkyl, (C3-7)cycloalkyl, (C1-4)alkyl-
(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl, (C1-4)alkyl-Het; or
RN2 ,RN3 ,RN4 are independently H, CH3, (C2-6alkyl), (C3-6)cycloalkyl, (C1-4)alkyl-
(C3-6)cycloalkyl; wherein said alkyl, cycloalkyl or alkylcycloalkyl is optionally substituted with hydroxy, halogen, carboxy, C1-6-alkoxycarbonyl, C1-6-alkyl, C1-6-alkoxy, amino, -NhK(C1-4-alkyl) and/or -N(C1_4-alkyl)2; and wherein said CH3 is optionally substituted with halogen, carboxy or C1-6-alkoxycarbonyl; and
in the case
a) of a group N(RN2)RN1 the substituents RN2 and RN1; or
b) of a group NRN3-N(RN2)RN1 the substituents RN3 and RN1, or RN2 and RN1; may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11-membered N-containing heterobicycle each may have additionally from 1 to 3 heteroatoms selected from O, N, and S;
wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4

heteroatoms selected from O, N and S, or a 8-, 9-, 10- or 11-membered heterobicycle having 1 to 5 heteroatoms selected from O, N and S;
or a salt thereof.
3. A compound as claimed in claim 1 of formula (la)


(Formula Removed)
wherein R2, R3, L, M1, M2, M3, M4, Y1, Y°, Z and Sp are as defined in claim 1.
4. A compound as claimed in claim 1 of formula (Ic):
(Formula Removed)
wherein A, B, R2, R3, L, M1, M3, M4, Y1, Y°, Z and Sp are as defined in claim 1.

5. A compound as claimed in claim 1 selected from the group of formulas 1.1 to I.4
(Formula Removed)

Y wherein R2, R3, R4a, R4b, R5, L, Y°, Y1, Z and Sp are defined as in claim

6. The compound as claimed in one or more of the preceding claims, wherein
Sp is a spacer group selected from -(CR51R52)k1-, wherein
k1 is 1,2 or 3; and
R51, R52are independently H or (C1-3)alkyl; and/or
R51, R52 are covalently bonded together and to the carbon-atom to which they
are attached to form a cyclopropyl, cyclobutyl or cyclopentyl group.
7. The compound as claimed in claim 6, wherein Sp is a spacer group selected
from -CH2-, -CH(CH3)-, -C(CH3)2l -CH2-CH2- and(Formula Removed)

8. The compound as claimed in claim 7, wherein Sp is -CH2-.
9. The compound as claimed in one or more of the preceding claims, wherein Y°
is O or S.
10. The compound as claimed in one or more of the preceding claims, wherein
L is C1-6alkyl, (C3-6)cycloalkyl, C1-6alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, all of which being optionally substituted with R60;
or if Y° is CR12R13, then L may also be H;
or if Y° is O, then L may also be ORc, wherein Rc is optionally substituted with R60;
wherein R12, R13, R60 and Rc are defined as in claim 1.
11. The compound as claimed in one or more of the preceding claims, wherein
Y° is O, S or NR11 and

L is N(RN2)RN1, NRN3-N(RN2)RN1, NRN3-NRN2-CO-Rc, NRN4-NRN3-CO-
N(RN2)RN1, NRN2-S02-Rc, orN(RN1)OR°,
said RN1, including any heterocycle or heterobicycle formed by RN1RN2
and/or RN3, and Rc being optionally substituted with R60; or
L is N(R5a)R6a wherein R5a is defined as RN2 and R6a is:
(Formula Removed)

or R6a is:
(Formula Removed)


wherein R7a and R8a are each independently defined as R°, wherein said R° is optionally substituted with R60; or
R7a and R8a are covalently bonded together to form a second (C3-7)cycloalkyI or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; and either of R7a or R8a may be covalently bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R150; and
W1 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered heterocycle;


Q1 is aryl, Het, (C1-6) alkyl-aryl, (C1-6) alkyl-Het, (C1-6) alkyl-CONH-aryl or (C1-6) alkyl-CONH-Het, all of which being optionally substituted with R60;
wherein R11, R60, R°, Rc, RN1, RN2, RN3, RN4, and Het are defined as in claim 1.
12. The compound as claimed in one or more of the preceding claims, wherein Y1 is O.
13. The compound as claimed in one or more of the preceding claims, wherein
Z is defined as
a) OR0;
c) N(RN2)RN1;
g) NRN2-S02-Rc;
h) NRN3-S02-N(RN2)RN1; or
i) NRN2-CO-Rc;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2,
being optionally substituted with R60;
or Z is ORbD or N(RSD)RbD wherein R6D is defined as RN2 and R6D is:
(Formula Removed)
wherein R7b, R8b, Y3, R9b, W2, Q2, R60, R°, Rc, RN1, RN2 and RN3 are defined as in claim 1.

The compound as claimed in one or more of the preceding claims, wherein Sp is a spacer group selected from -CH2-, -CH(CH3)-, -C(CH3)2-,

-CH2-CH2- and (Formula Removed)
and
Y° isOorS;
L is N(RN2)RN1, NRN3-N(RN2)RN1, NRN3-NRN2-CO-Rc,
NRN4-NRN3-CO-N(RN2)RN1, NRN2-S02-Rc or N(RN1)OR°;
said RN1, including any heterocycle or heterobicycle formed by RN1,
RN2 and/or RN3, and Rc being optionally substituted with R60; or
L is N(R5a)R6a wherein R5a is defined as RN2 and R6a is:

(Formula Removed)




or RM is
Y1 is O or S;
Z is defined as
a) OR0; c) N(RN2)RN1;or g) NRN2-S02-Rc;
wherein R° and Rc are optionally substituted with R60; and said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2, being optionally substituted with R60; or

Z

is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
(Formula Removed)
wherein R7a, R8a, R7b, R8b, R9a, R9b, R60, R°, Rc, RN1, RN2, RN3, RN4, Q1, Q2, W1, W2, Y2 and Y3 are defined as in claim 1.
15. The compound as claimed in claim 1 of the formula 1.1a
(Formula Removed)
wherein RN1, including any heterocycle formed by RN1 and RN2, is optionally substituted with R60;
Z is defined as
a) OR0; c) N(RN2)RN1;or g) NRN2-S02-Rc;
wherein R° and Rc are optionally substituted with R60; and said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2, being optionally substituted with R60; or
Z is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
(Formula Removed)


wherein R7b, R8b, R9b, R60, R°, Rc, RN1, RN2, RN3, RN4, Q2, W2 and Y3 are defined as in claim 1.
16. The compound as claimed in claim 1 of the formula 1.1b
(Formula Removed)

wherein
R5a is defined as RN2; and
R6a is defined as:

(Formula Removed)

or R6a is:


Z is defined as

a) OR0;
c) N(RN2)RN1;or
g) NRN2-S02-Rc;
wherein R° and Rc is optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1
and RN2, being optionally substituted with R60; or
is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:

(Formula Removed)


or R6b is:
wherein R7a, R8a, R7b, R8b, R9a, R9b, R60, R°, Rc, RN1, RN2, RN3, RN4, Q1, Q2, W1, W2, Y2 and Y3 are defined as in claim 1.
17. The compound as claimed in claim 1 of the formula 1.1c
(Formula Removed)

wherein

R is optionally substituted with R'
Z is defined as
a) OR0;

c) N(RN2)Rm;or
g) NRN2-S02-Rc;
wherein R° and Rc are optionally substituted with R60; and
said RN1, including any heterocycle or heterobicycle formed by RN1
and RN2, being optionally substituted with R60; or
is N(R5b)R6b wherein Rsb is defined as RN2 and R6b is:

(Formula Removed)


or RbD is

Y3
wherein R7b, R8b, R9b, R60, R°, Rc, RN1, RN2, RN3, RN4, Q2; W2 and Y3 are defined as in claim 1.
The compound as claimed in claim 1 of the formula l.1d
(Formula Removed)

wherein
is selected from ORc, NRN3-N(RN2)RN1, NRN3-NRN2-CO-Rc, NRN4-NRN3-CO-N(RN2)RN1, NRN2-CO-Rc, NRN3-CO-N(RN2)RN1 or N(RN1)OR°; said RN1, including any heterocycle or heterobicycle formed by RN1, RN2 and/or RN3, and Rc being optionally substituted with R60;

Z is defined as
a) OR0; c) N(RN2)RN1;or g) NRN2-S02-Rc;
wherein R° and Rc are optionally substituted with R60; and said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2, being optionally substituted with R60; or
Z is N(R5b)R6b wherein R5b is defined as RN2 and R6b is:
(Formula Removed)
wherein R7b, R8b, R9b, R60, R°, Rc, RN1, RN2, RN3, RN4, Q2, W2 and Y3 are defined as in claim 1.
19. The compound as claimed in one or more of the preceding claims, wherein
Y° is O, S or NR11, and
L is N(RN2)RN1, NRN3-N(RN2)RN1 NRN3-NRN2-CO-Rc,
NRN4-NRN3-CO-N(RN2)RN1, NRN2-S02-Rc or N(RN1)OR°, wherein
RN2, RN3, RN4 are each independently H, methyl, (C2-4)alkyl, (C3-6)cycloalkyl or (C1-3)alkyl-(C3-6)cycloalkyl, all of which being optionally substituted with halogen, carboxy or (C1-4)alkoxcarbonyl; and/or wherein said alkyl, cycloalkyl or alkyl-cycloalkyl is optionally substituted with hydroxy, C1-3-alkyl, amino, -NH(C1-4-alkyl), -N(C1-4alkyl)2and/or -0-(C1-4-alkyl);
RN1 is H, methyl, (C2-6)alkyl, (C3-6)cycloalkyl, (C1-3)alkyl-(C3-6)cycloalkyl, (C1-4)alkyl-phenyl, phenyl, Het or (C1-4)alkyl-Het;

wherein all of said methyl, alkyl, and cycloalkyi groups are optionally substituted with C1-3-alkyl, halogen, carboxy or (C1-4)alkoxcarbonyl, CONH2, CONH(C1-4-alkyl), CON(C1-4-alkyl)2; and/or
wherein all of said alkyl, and cycloalkyi, is optionally substituted with hydroxy, amino, -NH(C1-4-alkyl), -N(C1-4-alkyl)2 and/or -0-(C1-4-alkyl); and
in the case
a) of a group N(RN2)RN1 the substituents RN1 and RN2 or
b) of a group NRN3-N(RN2)RN1 the substituents RN1 and RN3 or RN1 and RN2 may be covalently bonded together to form a 5-, 6- or 7-membered saturated or unsaturated heterocycle which may have additionally 1 or 2 heteroatoms or a 8-, 9-, 10- or 11-membered saturated or unsaturated heterobicycle which may have additionally from 1, 2 or 3 heteroatoms, whereby the heteroatoms are selected from O, N, and S; and
wherein Het is a 4-, 5-, 6- or 7-membered monocyclic group which contains 1 or 2 heteroatoms selected from N, O and S, wherein a benzene ring may be fused to the monocyclic group; and
wherein said phenyl group, heterocycle, heterobicycle or Het is optionally
substituted by 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: N02, cyano, azido; and
-1 to 3 substituents selected from: (C1-4)alkyl, hydroxy, 0-(C1-4)alkyl,
amino, -COOH, -COO(C1-4)alkyl, CONH2, CONH(C1-4-alkyl), CON(C1-4-
alkyl)2, -NH(C1-4-alkyl), -N(C1-4-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-
morpholinyl, N-thiomorpholinyl, N-piperazinyl, -(C1-4)alkyl-OH, -(C1-4)alkyl-0-
(C1-4)alkyl, -(C1-4)alkyl-COOH, -(C1-4)alkyl-COO(C1-4)alkyl, -(C1-4)alkyl-CONH2,
-(C1-4)alkyl-CONH(C1-4-alkyl), -(C1-4)alkyl-CON(C1-4-alkyl)2, -(C1-4)alkyl-amino,
-(C1-4)alkyl-NH(C1-4-alkyl), -(C1-4)alkyl-N(C1-4-alkyl)2,
wherein the alkyl-groups may be substituted with halogen; and
wherein the N-piperazinyl-group may be N-substituted with C1-4-alkyl; and
wherein Rc, R°, and R11are defined as in claim 1.
The compound as claimed in one or more of the preceding claims, wherein

Y° is O, S or NR11 and
L is N(RN2)RN1 wherein
RN2 is H, methyl, (C2-4)alkyl, (C3-6)cycloalkyl or (C1-3)alkyl-(C3-6)cycloalkyl, all of which being optionally substituted with halogen, carboxy or (C1-4)alkoxcarbonyl; and/or wherein said alkyl, cycloalkyl or alkyl-cycloalkyl is optionally substituted with hydroxy, C1-3-alkyl, amino, -NH(C1-4-alkyl), -N(C1-4-alkyl)2 and/or-O-(C1-4-alkyl);
RN1 is methyl, (C2-6)alkyl, (C3-7)cycloalkyl, (C1-3)alkyl-(C3-7)cycloalkyl, (C1-4)alkyl-phenyl, Het and (C1-4)alkyl-Het; wherein the methyl, and alkyl groups are optionally substituted with C1-3-alkyl,halogen, carboxy or (C1-4)alkoxcarbonyl, CONH2, CONH(C1-4-alkyl), CON(C1-4-alkyl)2; and/or wherein said alkyl is optionally substituted with hydroxy, amino, -NH(C1-4(-alkyl), -N(Ci^-alkyl)2 and/or -O-(C1-4-alkyl); and
wherein Het is a saturated or unsaturated 4-, 5-, 6- or 7-membered monocyclic group which contains 1 or 2 heteroatoms selected from N, O and S, wherein a benzene ring may be fused to the monocyclic group; and
wherein said phenyl group, heterocycle, heterobicycle or Het is optionally
substituted by 1 to 4 substituents independently selected from: -1 to 3 substituents selected from halogen; - one of each substituent selected from: N02, cyano, azido; and -1 to 3 substituents selected from: (C1-4alkyl, hydroxy, 0-(C1-4)alkyl, amino, -COOH, -COO(C1-4)alkyl, CONH2, CONH(C1-4-alkyl), CON(C1-4-alkyl)2, -NH(C1-4-alkyl), -N(C1-4-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl, -(C1-4)alkyl-OH, -(C1-4)alkyl-O-(C1-4)alkyl, -(C1-4)alkyl-COOH, -(C1-4)alkyl-COC(C1-4)alkyl, -(C1-4)alkyl-CONH2, -(C1-4)alkyl-CONH(C1-4-alkyl)1-(C1-4)alkyl-CON(C1-4-alkyl)2,-(C1-4)alkyl-aminof -(C1-4)alkyl-NH(C1-4-alkyl), -(C1-4)alkyl-N(C1-4-alkyl)2, wherein the alkyl-groups may be substituted with halogen; and wherein the N-piperazinyl-group may be N-substituted with C1-4-alkyl; and wherein R11 is defined as in claim 1.
21. The compound as claimed in one or more of the preceding claims, wherein
Y° is O, S or NR11, and

L is N(RN2)Rm wherein
RN2 and RN1 are covalently bonded together to form a heterocycle selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine and homopiperazine;
wherein said piperazine and homopiperazine may be N-substituted with C1-4alkyl, (C3-6)cycloalkyl or C1-4alkyl-(C3-6)cycloalkyl; and
wherein said heterocycles are optionally monosubstituted by (C3-6)cycloalkyl, (C1-3)alkyl-(C3-6)cycloalkyl, HCy or C1-3alkyl-HCy , wherein HCy is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine and homopiperazine; and
wherein said heterocycles, including an optional alkyl-, cycloalkyl- or
alkylcycloalkyl-group and/or HCy or C1-3alkyl-HCy group, are optionally
substituted by 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen and C1-4)alkyl;
- one of each substituent selected from: N02, cyano, azido; and
-1 or 2 substituents selected from:
hydroxy, 0-(C1-4)alkyl, amino, -COOH, -COO(C^)alkyl, CONH2, CONH(C1-4-
alkyl), CON(C1-4-alkyl)2, -NH(C1-6-alkyl), -N(C1-6-alkyl)2, -(C1-4)alkyl-
OH, -(C1-4alkyl-O-(C1-4alkyl, -(C1-4)alkyl-COOH, -(C1-4)alkyl-
COO(C1-4)alkyl, -(C1-4)alkyl-CONH2, -(C1-4)alkyl-CONH(d-4-alkyl), -(C1-4)alkyl-
CON(C1-4-alkyl)2, -(C1-4)alkyl-amino, -(C1-4)alkyl-NH(C1-4-
alkyl), -(d-4)alkyl-N(d-4-alkyl)2;
wherein said alkyl-groups may be substituted with halogen.
22. The compound as claimed in one or more of the preceding claims, wherein Y° is O and L is OR6a, or wherein Y° is O or S and L is N(RN2)R6a, and
R are defined as:

wherein
R7a is defined as H, COOH, CONH2, (C1-6)alkyl, (C3-6)cycloalkyl, (C1-4)alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl, (C1-4)alkyl-Het; all of which are optionally substituted with R60; and
R8a is H or (C1-4)alkyl; or
R7a and R8a are covalently bonded together to form a second (C3-7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; and
when L is N(R5a)R6a, either of R7a or R8a may be covalently bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R150; and
W1 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
wherein the alkylene and alkenylene groups as claimed in b), c) and d) may be substituted with (C1-3) alkyl;
Q1 is a group of the subformula Illa

(Formula Removed)




wherein
Q1a is aryl, Hetaryl, (C1-3) alkyl-aryl or (C1-3)alkyl-Hetaryl;
Q1b is phenyl or Hetaryl;
Q1c is a bond, 0-C1-4-alkyl, S-C1-4-alkyl, C1-4-alkyl, C2-4-alkenyl or C2-4-alkynyl; and
R1q is selected from is selected from H, CN, COOR161, CON(R162)2, S02N(R162)2, -N(R162)2, OR161,
SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2, NHS02Rc, CONHS02Rc, S02NHCORc, tetrazole, triazole and CONHS02N(R162)2;;
q is 0 or 1;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from O, N, and S, or a 9- or 10-membered aromatic heterobicycle having 1 to 4 heteroatoms selected from O, N, and S; and
wherein R°, Rc, RN2, R150, R160, R161 and R162 are defined as in claim 1.
23. The compound as claimed in one or more of the preceding claims, wherein
Y° is O and L is OR6a, or wherein Y° is O or S and L is N(R5a)R6a, wherein R5a is
defined as RN2; and
R is defined as:

(Formula Removed)
wherein R7a and R8a are each independently defined as R°, wherein said R° is optionally substituted with R60; or
R7a and R8a are covalently bonded together to form a second (C3.7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; and when L is N(R5a)R6a, either of R7a or R8a may be covalently bonded to R5a to form a nitrogen-containing 5-or 6-membered

heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R150; and
Y2 is O or S;
R9a is defined as R°, wherein said R° is optionally substituted with R60; or R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered heterocycle;
Q1 is a group of the subformula Ilia

(Formula Removed)
wherein
Q1a is aryl, Hetaryl, (C1-3) alkyl-aryl or (C1-3)alkyl-Hetaryl; Q1b is phenyl or Hetaryl;
Q1c is a bond, O-C1-4-alkyl, S-C1-4-alkyl, C1-4-alkyl, C2-4-alkenyl or C2_4-alkynyl; and
R1q is selected from H, CN, COOR161, CON(R162)2, S02N(R162)2, -N(R162)2, OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2, NHS02Rc, CONHS02Rc, S02NHCORc, tetrazole, triazole and CONHS02N(R162)2;;
q isOoM;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from O, N, and S, or a 9- or 10-membered aromatic heterobicycle having 1 to 4 heteroatoms selected from O, N, and S; and

wherein R°, Rc, RN2, R150, R160, R161 and R162 are defined as in claim 1.
24. The compound as claimed in claim 22 or 23, wherein
a) Q1a is phenyl, q is 1 and Q1c is a bond;
b) Q1a is phenyl, q is 0 and Q1c is vinyl; or
c) Q1a is a 9- or 10-membered aromatic heterobicycle having 1 or 2 heteroatoms selected from O, N, and S, said heterobicycle optionally being substituted with R160; q is 0 and Q1c is a bond, -CH2-CH2-
or -CH=CH-.
25. The compound as claimed in claim 22, 23 or 24, wherein the group Q1c-R1q
is -CH=CH-COOH.
26. The compound as claimed in one or more of the preceding claims, wherein
Z is defined as OR0, wherein R° is optionally substituted with R60; and
wherein R° is defined as in claim 1.
27. The compound as claimed in one or more of the preceding claims, wherein Z
is OR0 wherein
R° is H, C1-4alkyl, (C3-6)cycloalkyl, C1-3alkyl-(C3-6) cycloalkyl, (C2-6)alkenyl,
(C1-3alkyl)phenyl, (C1-3)alkyl-pyridinyl, wherein said alkyl, alkyl-cycloalkyl, cycloalkyi,
alkenyl, alkyl-phenyl, or alkyl-pyridinyl is optionally substituted with 1 to 3
substituents
independently selected from:
1, 2 or 3 fluorine substituents; and
- one of each substituent selected from chlorine, bromine, iodine, CN, nitro, C1-
4alkyl, CF3, COOR161, S02R161, OR161, N(R162)2, S02N(R162)2, NR162C0R162 or
CON(R162)2, wherein R161 and each R162 is independently H, (C1-4)alkyl,
(C3-7)cycloalkyl or (C1-3)alkyl(C3-7)cycloalkyl; or both R162 are covalently bonded
together and to the nitrogen to which they are attached to form a 5, 6 or 7-
membered saturated heterocycle.
28. The compound as claimed in one or more of the preceding claims, wherein Z
is OH.

29. The compound as claimed in one or more of the preceding claims, wherein Z is defined as N(RN2)RN1; said RN1, including any heterocycle or heterobicycle formed by RN1 and RN2, being optionally substituted with R60; and wherein R60, RN1 and RN2 are defined as in claim 1.
30. The compound as claimed in one or more of the preceding claims, wherein Z is defined as N(RN2)RN1 wherein RN2 is H, methyl, (C2-4)alkyl, (C3-6)cycloalkyl or (C1-3)alkyl-(C3-6)cycloalkyl, all of which being optionally substituted with halogen, carboxy or (C1-4)alkoxycarbonyl; and/or wherein said alkyl, cycloalkyl or alkyl-cycloalkyl is optionally substituted with hydroxy, d-3-alkyl, amino, -NH(C1-4-alkyl), -N(d-4-alkyl)2 and/or -0-(C1-4-alkyl);
RN1 is methyl, (C2-6)alkyl, (C1-4)alkyl-phenyl or (C1-4)alkyl-Het; wherein the methyl and
alkyl groups are optionally substituted with C1-3-alkyl, halogen, carboxy or
(C1-4)alkoxycarbonyl, CONH2, CONH(C1-4-alkyl), CON(C1-4-alkyl)2; and/or wherein
said alkyl is optionally substituted with hydroxy, amino, -NH(C1-4-alkyl), -N(C1-4-
alkyl)2 and/or -O-(C1-4-alkyl); and
wherein Het is a 4-, 5-, 6- or 7-membered monocyclic group which contains 1 or 2
heteroatoms selected from N, O and S, wherein a benzene ring may be fused to the
monocyclic group; and
wherein said phenyl group, heterocycle, heterobicycle or Het is optionally
substituted by 1 to 4 substituents independently selected from: -1 to 3 substituents selected from halogen; - one of each substituent selected from: N02, cyano, azido; and -1 to 3 substituents selected from: (C1-4)alkyl, hydroxy, 0-(C1-4)alkyl, amino, -COOH, -COO(C-4)alkyl, CONH2, CONH(d-*-alkyl), CON(C1-4-alkyl)2, -NH(d-4-alkyl), -N(C1-4-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl, -(C1-4)alkyl-OH, -(C1-4)alkyl-0-(C1-4)alkyl, -(C1-4)alkyl-COOH, -(C1-4)alkyl-COO(C1-4)alkyl, -(C1-4)alkyl-CONH2, -(C1-4)alkyl-CONH(C1-4-alkyl),-(C1-4)alkyl-CON(C1-4-alkyl)2,-(C1-4)alkyl-amino, -(C1-4)alkyl-NH(C1-4-alkyl), -(C1-4)alkyl-N(C1-4-alkyl)2,

wherein the alkyl-groups may be substituted with halogen; and wherein the N-piperazinyl-group may be N-substituted with (C1-4)alkyl, (C3-6)cycloalkyl or (C1-3)alkyl-(C3-6)cycloalkyl.
31. The compound as claimed in claim 29, wherein Z is defined as
N(RN2)RN1 wherein
RN2 is H, methyl, ethyl, n-propyl, i-propyl, all of which being optionally substituted
with methyl, fluorine, chlorine, carboxyl or methoxycarbonyl; and/or wherein said
ethyl, n-propyl or i-propyl is optionally substituted with hydroxy, amino, -
NH(CH3), -N(CH3)2 and/or -0-(CH3);
RN1 is methyl, ethyl, n-propyl, i-propyl, benzyl, phenylethyl, pyridinylmethyl or
pyridinylethyl; wherein all of said methyl, ethyl, n-propyl, and i-propyl, groups are
optionally substituted with fluorine, chlorine, methyl, ethyl, carboxy,
methoxycarbonyl, CONH2, CONH(CH3), CON(CH3)2; and/or wherein said ethyl, n-
propyl or i-propyl is optionally substituted with hydroxy, amino, -NH(CH3), -N(CH3)2
and/or -0-CH3; and
wherein said phenyl and pyridinyl group is optionally substituted by 1, 2 or 3
substituents independently selected from:
-1, 2 or 3 substituents selected from halogen;
- one of each substituent selected from: N02, cyano, azido; and
-1, 2 or 3 substituents selected from: methyl, trifluoromethyl, ethyl, n-propyl,
i-propyl, hydroxy, methoxy, ethoxy, -COOH, -COOCH3, CONH2,
CONH(CH3), CON(CH3)2, amino, -NH(CH3), -N(CH3)2, -CH2-OH, -CH2-0-
CH3, -CH2-NH2, -CH2-N(CH3)2 and -(CH2)2-OH.
32. The compound as claimed in one or more of the preceding claims, wherein
Z is NRN2-S02-Rc or NRN2-CO-Rc wherein
RN2 is H, (C1-4)alkyl, (C3-6)cycloalkyl or (C1-3)alkyl-(C3-6)cycloalkyl, and Rc is (C-6)aikyl, (C3-6)cycloalkyl, (C1-3)alkyl-(C3_6)cycloalkyl, (C2-6)alkenyl, phenyl, naphthyl, Het, (C1-3)alkyl-phenyl, (C1-4)alkyl-naphthyl, (C1-3)alkyl-Het, wherein said alkyl, cycloalkyl, alkyl-cycloalkyl, alkenyl, phenyl, Het, alkyl-phenyl, alkyl-naphthyl or alkyl-Het, are all optionally substituted with 1 to 4 substituents selected from R60; wherein Het and R60 are defined as in claim 1.

33. The compound as claimed in one or more of the preceding claims, wherein Z is OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is defined as:

(Formula Removed)
wherein
R7b is defined as H, COOH, CONH2, (C1-6)alkyl, (C3-6)cycloalkyl, (C1-4)alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl, (C1-4)alkyl-Het; all of which are optionally substituted with R60; and
R8b is H or (C1-4)alkyl; or
R7b and R8b are covalently bonded together to form a second (C3-7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; and
when Z is N(R5b)R6b, either of R7b or R8b may be covalently bonded to R5b to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R150; and
W2 is selected from
a) a single bond;
b) -CH2-;
c) -CH2-CH2-; and
d) -CH=CH-;
wherein the alkylene and alkenylene groups as claimed in b), c) and d) may be substituted with (C1-3) alkyl;
Q2 is a group of the subformula lllb

(Formula Removed)

wherein
Q2a is aryl, Hetaryl, (C1-3) alkyl-aryl or (C1-3)alkyl-Hetaryl;
Q2b is a phenyl or Hetaryl;
Q2c is a bond, 0-C1-4-alkyl, S-C1-4-alkyl, C1-4-alkyl, C2-4-alkenyl or C2-4-alkynyl,
wherein said O-C1-4-alkyl, S-C1-4-aIkyl, C1-4-alkyl, C2-4-alkenyl or C2-4-alkynyl
are optionally substituted with R170;
wherein R170 is defined as H or as 1, 2 or 3 substituents independently selected from:
-1, 2, or 3 substituents selected from halogen; - one or two of each substituent selected from (C1-4) alkyl, (C1.4) alkoxy, (C3.5) cycloalkyl, or cyano; wherein (C1.4) alkyl may optionally be substituted with 1 to 3 halogen atoms; and
R2q is selected from H, CN, COOR161, CON(R162)2, S02N(R162)2, -N(R162)2, OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2, NHS02Rc, CONHS02Rc, S02NHCORc, tetrazole, triazole and CONHS02N(R162)2;
qa isOor 1;
qb is 0 or 1;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is
optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from O, N, and S, or a 9- or 10-membered aromatic heterobicycle having 1 to 4 heteroatoms selected from O, N, and S; and
wherein Het, R°, Rc, RN2, R60, R150, R160, R161 and R162 are defined as in claim 1.

The compound as claimed in one or more of the preceding claims, wherein OR6b or N(R5b)R6b wherein R5b is defined as RN2 and R6b is:

(Formula Removed)
wherein R7band R8bare each independently defined as R°, wherein said R° is optionally substituted with R60; or
R7b and R8b are covalently bonded together to form a (C3-7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; or when Z is N(R5b)R6b, either of R7b or R8b may be covalently bonded to R5b to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R60; and
Y3 is O or S;
R9b is defined as R°, wherein said R° is optionally substituted with R150; or R9b is covalently bonded to either of R7b or R8b to form a 5- or 6-membered heterocycle;
Q2 is a group of the subformula 1Mb

(Formula Removed)
wherein
Q2a is aryl, Hetaryl, (C1-3) alkyl-aryl or (C1-3)alkyl-Hetaryl;
Q2b is a phenyl or Hetaryl;
Q2c is a bond, 0-C1-4-alkyl, S-C1-4-alkyl, C1-4-alkyl, C2-4-alkenyl or C2-4-
alkynyl, wherein said O-C1-4-alkyl, S-C1-4-alkyl, C1-4-alkyl, C2_4-alkenyl
or C2-4-alkynyl are optionally substituted with R170;
wherein R170 is defined as H or as 1, 2 or 3 substituents
independently selected from:
-1, 2, or 3 substituents selected from halogen;

- one or two of each substituent selected from (C1-4) alkyl, (C1- 4) alkoxy, (C3.5) cycloalkyl, or cyano; wherein (C1-4) alkyl may optionally be substituted with 1 to 3 halogen atoms; and
R2q is selected from H, CN; COOR161, CON(R162)2, S02N(R162)2l -N(R162)2 OR161, SR161, -NHCOR162, -NH-CO-COOR161, -NH-CO-CON(R162)2, CONHS02Rc, tetrazole, triazole and CONHS02N(R162)2;
qa is 0 or 1;
qb is Oor 1;
wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/or alkynyl-groups is
optionally substituted with R160; and
wherein Hetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from O, N, and S, or a 9- or 10-membered aromatic heterobicycle having 1 to 4 heteroatoms selected from O, N, and S; and
wherein R°, Rc, RN2, R60, R150, R160, R161 and R162 are defined as in claim 1.
The compound as claimed in claim 33 or 34, wherein
a) qa is 1, Q2a is phenyl, qb is 1 and Q2c is a bond;
b) qa is 1, Q2a is phenyl, qb is 0 and Q2c is -CH=C(R170)-, wherein R170 is selected from H, F, -CH3 or -CH2CH3; or
c) qa is 1, Q2a is a 9- or 10-membered aromatic heterobicycle having 1 or 2 heteroatoms selected from O, N, and S, said heterobicycle optionally being substituted with R160; qb is 0 and Q2c is a bond, -CH2-CH2-
or -CH=C(R170)-,
wherein R170 is selected from H, F, -CH3 or -CH2CH3.

36. The compound as claimed in claims 33, 34 or 35, wherein the group Q2c-R2q is -CH=C(R170)-COOH, wherein R170 is selected from H, F, -CH3 or -CH2CH3.
37. The compound as claimed in one or more of the preceding claims, wherein R2 is R21, wherein R21 is phenyl or Het selected from the group of formulas
(Formula Removed)

and wherein said R21 is unsubstituted or substituted with R150, being defined as in claim 1.

38. The compound as claimed in one or more of the preceding claims, wherein
R2 is R21, wherein R2i is defined as in claim 1 or 37, and wherein R21 is optionally
substituted with 1, 2 or 3 substituents selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: N02, cyano, azido; and
-1 to 2 substituents selected from:
a) (C1-4)alkyl or (C1-4)alkoxy, both optionally substituted with OH, 0(C1a4)alkyl, SO2(C1-4 alkyl), 1 to 3 halogen atoms, amino, NH(CH3) or N(CH3)2);
b) NR111R112 wherein both R111 and R112 are independently H, (C1-4)alkyl, or R112 is (C3-7)cycloalkyl, (C1-3)alky(3-7) cycloalkyl, phenyl, benzyl; or both R111 and R112 are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen-containing heterocycle, each of said alkyl, cycloalkyl, alkylcycloalkyl, phenyl and benzyl, being optionally substituted with halogen or:
- OR2h or N(R2h)2, wherein each R2h is independently H, (C1-4)alkyl, or both R2h are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen-containing heterocycle;
c) NHCOR117 wherein R117 is (C1-4)alkyl, 0(C1-4)alkyl or 0(C3.
7)cycloalkyl; and
e) CONH2, CONH(C1-4alkyl), CON(C1-4alkyl)2.
39. The compound as claimed in one or more of the preceding claims, wherein R3 is selected from (C3-7)cycloalkyl, (C5-7)cycIoalkenyl, (C6-10)bicycloalkyl, (C6-10)bicycloalkenyl, or HCy, wherein said groups are unsubstituted or mono- or disubstituted by halogen, hydroxy, C1-4alkyl and/or O-C1-4alkyl, wherein the alkyl groups may be fluorinated; wherein HCy is defined as in claim 1.
40. The compound as claimed in claim 39, wherein R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or a group selected from

(Formula Removed)

and
wherein all said groups are unsubstituted or substituted by fluorine, C1-3alkyl or CF3.
41. The compound as claimed in claim 40, wherein R3 is cyclopentyl, or cyclohexyl.
42. The compound as claimed in one or more of the preceding claims, wherein R60 is each defined as 1 to 4 substituents independently selected from:
-1 to 3 substituents selected from halogen;
- one of each substituent selected from: N02, cyano, azido; and
-1 to 3 substituents selected from:
a) (C1-4) alkyl, (C3.7)cycloalkyl, (C2-4)alkenyl, (C2-4)alkynyl, (C1-3)alkyl-(C3-7)cycloalkyl, all of which optionally being substituted with R150;
b) OR0;

e) N(RN2)RN1;
f) N(RN2)CORc; j) COOR0;
k) CON(RN2)RN1;
I) phenyl, Het, (C1-3alkyOphenyl or (C1-3alkyOHet; wherein Het is selected from furan, tetrahydrofuran, thiophene, tetrahydrothiophene, tetrahydropyran, pyridinyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine and homopiperazine, all of which optionally being substituted with R150;
wherein said RN1, Rc and/or R° are optionally substituted with R150as defined, and R150, RN1, RN2, Rc and R° are defined as in claim 1.
43. The compound as claimed in one or more of the preceding claims, wherein
R150 is defined as 1 to 4 substituents independently selected from:
-1 to 3 fluorine-substituents;
- one of each substituent selected from: chlorine, bromine, iodine, N02,
cyano, azido; and
-1 to 3 substituents selected from:
a) (C1-3) alkyl, CF3, (C3.6)cycloalkyl, (C1-3) alkyl-(C3-6)cycloalkyl, all of which optionally substituted with R160;

b) OR0;
e) N(RN2)RN1;
f) N(RN2)CORc; j) COOR0;
k) CON(RN2)RN1;
wherein said RN1, Rc and/or R° are optionally substituted with R160 as
defined; and
R160, RN1, RN2, Rc and R° are defined as in claim 1.
44. The compound as claimed in one or more of the preceding claims, wherein
R160 is defined as 1, 2 or 3 substituents independently selected from:
-1, 2 or 3 fluorine substituents; and
- one of each substituent selected from chlorine, bromine, iodine, CN, nitro, methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, COOH, COOCH3, OH, OCH3, OCF3, NH2, NHCH3, N(CH3)2, S02NH2, S02NHCOCH3, NHCOCH3 or CONH2, CONHCH3 and CON(CH3)2.
45. The compound as claimed in one or more of the preceding claims, wherein
R° and Rcare each defined as (C1-4)alkyl, (C3-6)cycloalkyl, (C1-3)alkyl-(C3-6)cycloalkyl,
phenyl, benzyl, Het, (C1-3)alkyl-Het; all of which are optionally substituted as
defined; and R° may also be H;
RN1 is H, (C1-4)alkyl, (C3-6)cycloalkyl, (C1-3)alkyl-(C3-6)cycloalkyl, phenyl, benzyl, phenylethyl, Het, (C1-3)alkyl-Het; wherein said alky!, cycloalkyl, alkyl-cycloalkyl, phenyl, benzyl, phenylethyl, Het and alkyl-Het are optionally substituted as defined; or
RN2, RN3, RN4 are independently H, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl; all of which being optionally substituted with fluorine, carboxy or methoxycarbonyl; and/or wherein said ethyl, n-propyl or i-propyl is optionally substituted with hydroxy, methyl, methoxy, amino, -NH(CH3) and/or -N(CH3)2; and
in the case

a) of a group N(RN2)RN1 the substituents RN2 and RN1 or
b) of a group NRN3-N(RN2)RN1 the substituents RN3 and RN1 or RN2 and RN1 may be covalently bonded together to form a 5-, 6- or 7-membered saturated heterocycle which may have additionally one heteroatom selected from O, N, and S, wherein said heterocycle is optionally substituted as defined;
wherein Het is defined as in claim 1.
46. The compound as claimed in one or more of the preceding claims wherein
R4a, R4b, Rs each are independently H, hydroxy, halogen, cyano, nitro, carboxyl,
(C1-4)alkyl, CF3, (C1-4)alkoxy, -0-(C3-7)cycloalkyl, -0-(C1-3)alkyl-(C3-7)cycloalkyl, -O-
aryl, -0-(Ci.3)alkyl-aryl, -O-Het, -0-(Ci.3)alkyl-Het, NRN1RN2, COR0, NRN2CORc,
CONRN2RN1, or NRN3CONRN1RN2,
wherein all said alkyl and alkoxy groups may be mono-, di- or trisubstituted with
fluorine or mono-substituted with chlorine or bromine; and
wherein R°, RN1, RN2, RN3 and Het are defined as in claim 1.
47. The compound as claimed in one or more of the preceding claims wherein R° and RN1 are independently H, (C1-4)alkyl, aryl, or (C1-3)alkyl-aryl; Rc is (C1-4)alkyl, aryl, or (C1-3)alkyl-aryl; wherein all of said aryl is phenyl optionally substituted with R160, wherein R160 is defined as in claim 1; and RN2 and RN3 are each H or methyl; wherein all said alkyl groups may be mono-, di- or trisubstituted with fluorine or mono-substituted with chlorine or bromine.
48. The compound as claimed in one or more of the preceding claims wherein R4a, R4b, R5 each are independently H, hydroxy, halogen, cyano, nitro, methyl, CF3, methoxy, carboxy, amino, -NMe2, -CONH2, NHCONH2, -CO-NHMe, -NHCONHMe, -CO-NMe2 or -NHCONMe2.
49. The compound as claimed in one or more of the preceding claims wherein R4a, R4b, R5 each are independently H, methyl or methoxy.
50. The compound as claimed in one or more of the preceding claims wherein at

least two of R4a, R4b, R5 are H.
51. A compound as claimed in claim 1 having the formula:
(Formula Removed)

wherein R3 is Cn-cycloalkyl and the index n and the substituents L, R2 are defined as claimed in the following table
(Table Removed)

52. A compound as claimed in claim 1 having the formula:
(Formula Removed)

wherein the substituents RN2 and Rc are defined as claimed in the following table
(Table Removed)

53. A compound as claimed in claim 1 having the formula:

(Formula Removed)
wherein R3 is Cn-cycloalkyl and the index n and the substituents L, R2, R R8b and Q2 are defined as claimed in the following table
(Table Removed)





54. A compound as claimed in claim 1 having the formula:
(Formula Removed)
55.

wherein R3 is Cn-cycloalkyl and the index n and the substituents L, R2 and Z are defined as claimed in the following table

(Table Removed)

56. A compound as claimed in claim 1 chosen from one of the following formulas:
(Table Removed)



56. A pharmaceutical composition for the treatment or prevention of HCV infection, comprising an effective amount of a compound of formula I as claimed in one or more of the claims 1 to 55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
57. A process for producing compounds of formula 1.1

wherein Y°, L, Sp, R°, R2 and R3 are defined as in claim 1, comprising the reaction of an indole derivative of the formula 2(iv)
(Formula Removed)


wherein R° and R3 are defined as hereinbefore and X is CI, Br or I;
1.) cross-coupling of the indole derivative of the formula 2(iv) with
a stannane derivative of the formula R2-SnR'3, wherein R2 is defined as hereinbefore and R' is a C1-8-alkyl or aryl group under transition metal catalysis to yield an indole derivative of the formula 2(vii)
(Formula Removed)


wherein R°, R2 and R3 are defined as hereinbefore;

2.) the indole derivative of the formula 2(vii) is further processed by N-alkylation using the electrophilic reagent X-Sp-C(=Y°)-L, wherein X is a leaving group, like e.g. CI, Br, I, mesylate, triflate, tosylate; and Sp, Y° and L are as defined hereinbefore, in the presence of a strong base, yielding the product of the formula 1.1.

Documents:

3125-DELNP-2005-Abstract-(21-04-2009).pdf

3125-delnp-2005-abstract.pdf

3125-DELNP-2005-Claims-(12-05-2009).pdf

3125-DELNP-2005-Claims-(21-04-2009).pdf

3125-delnp-2005-claims.pdf

3125-DELNP-2005-Correspondence-Others-(12-05-2009).pdf

3125-DELNP-2005-Correspondence-Others-(21-04-2009).pdf

3125-delnp-2005-correspondence-others.pdf

3125-DELNP-2005-Description (Complete)-(12-05-2009).pdf

3125-DELNP-2005-Description (Complete)-(21-04-2009).pdf

3125-delnp-2005-description (complete).pdf

3125-DELNP-2005-Form-1-(12-05-2009).pdf

3125-DELNP-2005-Form-1-(21-04-2009).pdf

3125-delnp-2005-form-1.pdf

3125-delnp-2005-form-18.pdf

3125-DELNP-2005-Form-2-(12-05-2009).pdf

3125-DELNP-2005-Form-2-(21-04-2009).pdf

3125-delnp-2005-form-2.pdf

3125-delnp-2005-form-3.pdf

3125-delnp-2005-form-5.pdf

3125-DELNP-2005-GPA-(21-04-2009).pdf

3125-delnp-2005-gpa.pdf

3125-delnp-2005-pct-101.pdf

3125-delnp-2005-pct-105.pdf

3125-delnp-2005-pct-210.pdf

3125-delnp-2005-pct-220.pdf

3125-delnp-2005-pct-306.pdf

3125-delnp-2005-pct-401.pdf

3125-delnp-2005-pct-409.pdf

3125-DELNP-2005-Petition-137-(21-04-2009).pdf

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Patent Number 234915
Indian Patent Application Number 3125/DELNP/2005
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 19-Jun-2009
Date of Filing 14-Jul-2005
Name of Patentee BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Applicant Address BINGER STRASSE 173,55216 INGELHEIM, GERMANY.
Inventors:
# Inventor's Name Inventor's Address
1 PIERRE LOUIS BEAULIEU 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
2 CHRISTIAN BROCHU 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
3 CATHERINE CHABOT 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
4 ERIC JOLICOEUR 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
5 MARC-ANDRE POUPART 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
6 YOULA STRATIGOULA TSANTRIZOS 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
7 STEPHEN KAWAI 2100 CUNARD STREET, LAVAL (QUEBEC) H7S 2G5, CANADA.
PCT International Classification Number C07D 209/08
PCT International Application Number PCT/CA2004/000018
PCT International Filing date 2004-01-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/441,871 2003-01-22 U.S.A.